Cellular and Molecular Life Sciences

, Volume 74, Issue 14, pp 2569–2586 | Cite as

Immunoregulatory properties of the cytokine IL-34

  • Carole Guillonneau
  • Séverine Bézie
  • Ignacio Anegon
Review

Abstract

Interleukin-34 is a cytokine with only partially understood functions, described for the first time in 2008. Although IL-34 shares very little homology with CSF-1 (CSF1, M-CSF), they share a common receptor CSF-1R (CSF-1R) and IL-34 has also two distinct receptors (PTP-ζ) and CD138 (syndecan-1). To make the situation more complex, IL-34 has also been shown as pairing with CSF-1 to form a heterodimer. Until now, studies have demonstrated that this cytokine is released by some tissues that differ to those where CSF-1 is expressed and is involved in the differentiation and survival of macrophages, monocytes, and dendritic cells in response to inflammation. The involvement of IL-34 has been shown in areas as diverse as neuronal protection, autoimmune diseases, infection, cancer, and transplantation. Our recent work has demonstrated a new and possible therapeutic role for IL-34 as a Foxp3+ Treg-secreted cytokine mediator of transplant tolerance. In this review, we recapitulate most recent findings on IL-34 and its controversial effects on immune responses and address its immunoregulatory properties and the potential of targeting this cytokine in human.

Keywords

Immune tolerance Tregs Ischemia reperfusion Macrophages Osteopetrosis CSF-1(M-CSF) 

Introduction

The CSF-1/CSF-1R interaction delivers a well-characterized signaling cascade leading in hematopoietic cells to proliferation, differentiation, and function of the monocytic lineage. The discovery in 2008 of IL-34, identified by screening of human protein library as a protein involved in monocyte viability [1] and subsequently, as a new ligand of CSF-1R, has opened new perspectives. IL-34 actions have been rendered more complex by the discovery of receptors for IL-34, others than CSF-1R: the receptor-type protein-tyrosine phosphatase zeta (PTP-ζ), identified only in the brain and in the kidney [2, 3], and syndecan-1, with a broad distribution [4], altogether suggesting additional roles for IL-34. IL-34 is a 241 amino acid (aa) protein in humans that were originally characterized as a protein with no evident sequence similarity with other cytokines or proteins (26% sequence homology with CSF-1). IL-34 exists in two isoforms, differing by the addition of a glutamine inserted between position 80 and 81 in the 241 aa isoform, and generated by alternative splicing [5]. IL-34 is formed by four α-helix and disulfides bond that lead to the formation of a homodimeric protein, but the existence also of a heterodimeric protein between IL-34 and CSF-1, inducing a different signaling cascade in CSF-1R receptor, has been described, although the physiopathological significance of this discovery remains unclear [6]. Finally, IL-34 is a cytokine relatively conserved between species with 99.6% homology between human and chimpanzee and 72% between human, rat, or mouse [1]. Since 2008, studies have identified roles for IL-34 in areas as remote as neuronal protection, bone-degenerative diseases, delayed-type hypersensitivity, infection, cancer, and more recently transplantation.

Here, we summarize recent finding on IL-34 biology, signaling, and downstream effects and discuss in particular its controversial effect on immunity vs. immune tolerance (Table 1).

Table 1

Biological and pathophysiological studies with IL-34

Pathophysiological situation

Model

Species

Major findings

References

Biology and targets of IL-34

Monocytes,

THP1 cell line

Human

Identification of IL-34

Identification of CSF1-R as a receptor for IL-34

Kd of IL-34 to CSF-1R = 1 pM (Kd of CSF-1 to CSF-1R = 34 pM)

[1]

Monocytic THP1 and J774A.1 cell lines

Human and mouse

IL-34 and CSF-1 are distinct in biological activity and signal activation

IL-34 and CSF-1 both support cell growth or survival

IL-34 and CSF-1 are different in the ability to induce chemokines production, morphological change in THP1 cells and migration of J774A.1 cells

IL-34 induced a stronger but transient tyrosine phosphorylation of CSF-1 and downstream molecules, and rapidly downregulated CSF-1

[31]

Macrophages

Human

Generation of M2 macrophages = CSF-1, ≠GM-CSF-1

[105]

Macrophages

Mouse

huIL-34 was much less active at stimulating mouse

macrophage proliferation than huCSF-1

Overexpression of muIL-34 rescued defects of Csf1op/op mice

CSF-1 and IL-34 similarly activate CSF-1R tyrosine phosphorylation and ERK1/2 activation

[5]

KO for IL-34

Mouse

Keratynocytes produce IL-34 that maintains LCs

IL-34 is a non-redundant cytokine for the development of LCs during embryo-genesis and homeostasis in the adult skin

Inflammation-induced repopulation of LCs is dependent on CSF-1, once inflammation is resolved, LC survival is again IL-34-dependent

[8, 93]

Skin

Mouse

IL-34 produced in skin epidermis of the embryo promotes the final differentiation of LCs precursors

Adult LCs required IL-34 to continually self-renew in the steady-state During skin damage, LCs regeneration depended on CSF-1 produced by infiltrating neutrophils

[110]

PBMCs

Human

IL-34 and CSF-1 ↗ IL-6, CXCL10, CXCL8 and CCL2

[111]

IL-34 and CSF-1 interactions

Human

Hybrid structural approach reveal bivalent binding of human IL-34 to CSF-1R with similarities to the CSF-1:CSF-1R complex

C-terminal region of IL-34 is heavily glycosylated and can be proteolytically cleaved from the IL-34:hCSF-1R complex

[112]

Monocytes

Human

Transcriptional profiling of monocytes induced by IL-34 or CSF-1 has 75% similarity with dampened effect on 25% of them by IL-34

A major ≠ in CCR2 expression repressed by CSF-1

[113]

Folicular dendritic cell line

Mouse

Cell line produce both CSF-1 and IL-34, but only IL-34 was responsible for mononuclear phagocytes generation

[114]

KO for IL-34

Mouse

Keratinocytes produce IL-34 that maintains LCs

Neurons produce IL-34 that maintains microglia

[8]

Syndecan-1

Human

IL-34 binds to chondroitin sulphate chains on syndecan-1 and this modulates the IL-34-induced CSF-1R signaling pathways

IL-34 induced the migration of myeloid cells in a syndecan-1 dependent manner

[4]

Macrophages

Human

IL-34 and CSF-1 bind CSF-1R through different interfaces

IL-34 ↗ association stability with CSF-1R than CSF-1

[30]

PTP-z

Human and mouse

IL-34 binds to chondroitin sulphate chains on PTP-z is (Kd ~ 10−7 M)

PTP-z is primarily expressed on neural progenitors, glial cells and human glioblastomas

IL-34 inhibited the proliferation, clonogenicity and motility of glioma cells

[2]

IL-34 and CSF-1 interactions

Human

IL-34 and CSF-1 showed additive effects on cellular proliferation or viability

Heteromeric interaction between CSF-1 and IL-34 was confirmed by surface plasmon resonance and proximity ligation assays

[6]

Neuronal protection

Alzheimer’s disease

Mouse

Neurons primarily produce IL-34 and microglia expresses the CSF-1R

IL-34 promoted microglial proliferation clearance of soluble oligomeric amyloid and production of the antioxidant enzyme HO-1

Neuronal protection by IL-34 was dependent on HO-1

[90]

KO for IL-34

Mouse

Neurons produce IL-34 that maintains microglia

Microglia and their yolk sac precursors develop independently of IL-34 but rely on it for their maintenance in the adult brain

[8, 93]

Neural development

Mouse

In the CNS, IL-34 exhibited a broader regional expression than CSF-1

High levels of IL-34 in the absence of CSF-1R expression

IL-34 > CSF-1 to suppress neural progenitor self-renewal and enhance neuronal differentiation

[115]

Neuronal toxicity

Mouse

Neurons express CSF-1R

CSF-1 and IL-34 strongly reduced excitotoxin-induced neuronal cell loss and gliosis

[92]

Blood–brain barrier

Mouse

IL-34 ↗ endothelial cell protection

IL-34 ↗ tight junction proteins

[91]

Peripheral nerve injury

Rat

IL-34 constitutively expressed in the spinal cord

IL-34 not affected by nerve injury in contrast to CSF-1

[116]

Induction of microglia from monocytes

Human

Human monocytes cultured with GCSF-1 and IL-34 showed microglial characteristics

[88]

Bone physiology

Gingival fibroblasts

Human

IL-34 expressed by gingival fibroblasts

↗ by TNFa and IL-1

[53]

Osteoclasts

Human and mouse

IL-34 together with RANKL induced the formation of osteoclasts

Systemic administration of IL-34 to mice increases the proportion of CD11b+ cells and reduces trabecular bone mass

[55]

Osteoblasts

Mouse

TNF-alpha induces IL-34 in an osteoblast cell line

[54]

Autoimmunity and Inflammation

Rheumatoid arthritis

Human

IL-34 ↗ in synovial fluid, synovial fibroblasts and sera of RA vs. OA

IL-34 ↗ by TNF-alpha

IL-34 in sera ↘ by RA treatment

[59]

Rheumatoid arthritis

Human

IL-34 was expressed in 24/27 biopsies from RA patients

Significant correlation between IL-34 expression and synovitis severity and the total leukocyte count in the synovial fluid

IL-34 expression by the synovial fibroblasts ↗ by TNF-alpha and IL-1β

[9]

Rheumatoid arthritis

Human

Synovial fluid IL-34 levels were higher in patients with RA than in those with OA and were positively associated with IL-6 levels in serum from patients with RA and OA

Synovial fluid IL-34 concentration correlated significantly with IL-6 and RANKL levels only in RA

Serum levels of IL-34 were not correlated with radiographic joint damage in RA and were positively correlated with rheumatoid factor and anti-citrullinated antibody titers

[56]

Rheumatoid arthritis

Human

IL-34 ↗ in synovial fluid, synovial fibroblasts and sera of RA vs. OA

IL-34 in sera ↘ by anti-TNFalpha treatment

IL-34 ↗ IL-17 production by PBMCs

[60]

Rheumatoid arthritis

Human

IL-34 in sera ↗ vs. OA

IL-34 serum levels correlated with: rheumatoid factor, erythrocyte sedimentation rate and C-reactive protein levels but not disease activity

Serum IL-34 levels were an independent risk factor for radiographic progression

[61]

Rheumatoid arthritis

Human

Synovial fluid IL-34 levels were significantly higher in patients with RA with high Disease Activity Score

IL-34 stimulation strengthened the activation of p-STAT3, resulting in increment of miR-21 expression

CSF-1R participated in the biological functions of IL-34 in RA

[58]

Rheumatoid arthritis

Human

IL-34 level in serum phase III >phase II

[57]

Rheumatoid arthritis

Human

CSF-1 and IL-34 expression was similar in RA and psoriatic arthrititis synovial tissue, but lower in controls

CSF-1 expression was observed in the synovial sublining, and IL-34 in the sublining and the intimal lining layer. Anti-CSF1R Ab significantly reduced IL-6 and other inflammatory mediator production in RA synovial explants, and paw swelling and joint destruction in CIA

[117]

Rheumatoid arthritis, Psoriatic arthritis and osteoarthritis

Human

CSF-1 and IL-34 express at same level in RA and PsA tissues, but lower in OA

CSF-1 expression in synovial sublining

IL-34 expression in sublining and intimal layer

No effect of IL-34 and CSF-1 addition or neutralization in inflammatory mediators production

Blockade of receptor CSF-1R reduced RA and CIA

[65]

Rheumatoid arthritis

Human

IL-34 serum level <194 pg/ml predicts a good response to TNF-alpha antagonist treatment to RA at 3 months

[62]

Atopic dermatitis

 

IL-34 is decreased in lesional zones

[87]

Inflammatory bowel diseases

Human

IL-34 expression in inflamed areas

↗ IL-34 expression by TNF-alpha and TLR ligands in lamina propia mononuclear cells and ↘ by infliximab

IL-34 ↗ TNF-alpha and IL-6 synthesis by mucosal explants

[68]

Inflammatory bowel diseases

Human

IL-34 in ileum, CSF1 in colon

[69]

mouse

IL-34 in CD and UC

CSF1 in CD

TNFa ↗ IL-34 and CSF1 in epithelial cells, NFkb-dependent only for IL-34

Mo-treated with IL-34 showed expression of IL-10 whereas CSF-1 ↘ expression

DSS model: ↗ IL-34 and CSF1

Inflammatory bowel diseases

Human

IL-34 increased CCL20 production by an epithelial cell line through an ERK1/2-dependent mechanism

[118]

Obesity, metabolic syndrome

Human

↗ in serum of obese women

IL-34 expressed by adipocytes and ↗ by TNFα

IL-34 ↗ insulin resistance

[72]

Type 2 diabetes GWAS studies

Human

IL-34 SNP 5′ UTR associated with type 2 diabetes

[71]

Type 2 diabetes

Human

IL-34 has more discriminatory power than C-reactive protein (CRP) for the risk of diabetic complications

[73]

Non-alcoholic fatty liver disease

Human

IL-34 increased with the progression of fibrosis and was an independent marker for liver fibrosis

[119]

Sjogren’s syndrome

Human

IL-34 was overexpressed in inflamed salivary glands of Sjogren’s syndrome and associated with ↗ expression of TNF-α, IL-1β, IL-17 and IL-23p19

IL-34 expression was accompanied by the expansion of CD14brightCD16+ monocytes in salivary glands

[66]

Infection

Parasites, macrophages

Teleost fish

IL-34, CSF-1 and the isoform CSF-2 are differentially expressed in tissues and cell lines

Lack of induction of IL-34, but not of CSF-1 and CSF-2 expression by PAMPs, inflammatory cytokines and a parasitic proliferative kidney disease model in rainbow trout macrophages

[120]

Hepatitis C virus

Human

IL-34 and CSF-1 correlated with fibrosis

IL-34 produced by hepatocytes

IL-34 induces profibrogenic macrophages

IL-34 ↗ collagen 1 by hepatic stellate cells

[83]

Viral infection, macrophages

X. laevis

IL-34 and CSF-1 different tissue expression

IL-34 vs. CSF-1 Mo: ↘ phagocytic, ↘ susceptible to infection, ↗ antiviral, ↗ type I IFN, ↗ NADPH

[100]

Influenza A

Human PBMCs

IL-34 ↗ in influenza A patients

IL-22 ↗ IL-34

IL-34 ↘ IL-22

[84]

SIV, Mo

Macaque microglia and human Mo

IL-34 and CSF-1 ↗ CD163+ cells in CNS

IL-34 produced by neurons and CSF-1 by neurons and CD163+ Mo

IL-34 and CSF-1 act through CSF-1R

[121]

SIV, Mo

Macaque and human

IL-34 and CSF-1 ↗ HIV production by SIV+ microglia through CSF-1R

[85]

Macrophages/Candida

Mouse

IL-34 ↘ TNF-alpha production by M1 macrophages challenged with C. albicans by the inhibition of expression of TLR2 and Dectin-1

[86]

Monocytes

X. laevis

IL-34 vs. CSF-1 Mo: ↘ iNOs, ↘ phagocytic activity, ↘ bactericidal activity, ↗ arginase-1, ↗ NADPH, ↗ antiviral activity

[101]

Transplantation

Organ transplantation

Human and rat

IL-34 was expressed and played a role in the suppressive function of both CD8+ and CD4+ rat and human Tregs

In a rat cardiac allograft model treatment with IL-34 promoted allograft tolerance that mediated by induction of tolerogenic macrophages and Tregs

Human macrophages cultured with IL-34 expanded and increased the suppressive capacity of CD8+ and CD4+ Foxp3+ Tregs

[51]

Kidney ischemia/Reperfusion injury

Human and mouse

Renal I/R was reduced in IL-34-KO mice

IL-34, CSF1-R and PTPζ were upregulated in the kidney after I/R in mice and in kidney transplant patients

[3]

Cancer

bone giant cell tumor

Human

IL-34 is expressed in Giant cell tumors

IL-34 promotes osteoclastogenesis

[7]

Mammary cancer

Human and mouse

Cytotoxic therapies induce mammary cancer cells to produce CSF-1 and IL-34

Blockade of CSF-1R- improved survival of mammary tumor-bearing mice with decreased vessel density and appearance of CD8+ antitumor immune responses

[81]

Differentiation of T cells by macrophages

Human

CSF-1- or IL-34-treated macrophages and TAM switch memory but not naive CD4+ T cells into conventional Th17 cells, expressing or not IFN-gamma via membrane IL-1α

[102]

Teratoma

Mouse

ES cells produce IL-34 but not CSF-1

IL-34 ↗ M2 macrophages

IL-34 ↗ neo-angiogenesis

[80]

Liver metastasis

Human

miR-28-5p down-regulation in HCCs correlated with tumor metastasis, recurrence, and poor survival

IL-34 is a direct target of miR-28-5p

Effects of miR-28-5p deficiency on HCC growth and metastasis are dependent on IL-34-mediated TAM infiltration

miR-28-5p-IL-34-macrophage-positive feedback loop modulates HCC metastasis

In clinical HCC samples, miR-28-5p levels were inversely correlated with IL-34 expression and the number of TAMs

[82]

Tumor cells and macrophages

Human

IL-34 binds to chondroitin sulphate chains on syndecan-1 and this modulates the IL-34-induced CSF-1R signaling pathways

IL-34 induced the migration of myeloid cells in a syndecan-1 dependent manner

[4]

Osteosarcoma

Human and mouse

IL-34 produced by osteosarcoma cells

IL-34 ↗: osteosarcoma development, M2 macrophages, neo-angiogenesis and monocyte adhesion to ECs

[79]

Several solid cancers

Fish, amphibians, birds, mammals

IL-34 exists in all species with similar gene organization

In human IL-34 gene: 32 SNPs causing missense mutations, 3 exonic splicing enhancer SNPs and 20 SNPs causing nonsense mutations

↘ IL-34 expression correlated with poor survival in NSCLC, blood cancer and colorectal cancer

↗ IL-34 expression correlated with poor survival in adenocarcinoma and brain cancer

[122]

Metastases and microglia

Human and mouse

Macrophage-induced metastases was reduced by anti- CSF-1 treatment while microglia-induced invasion was reduced to a lower extend

Lung and breast brain metastases express CSF-1 and IL-34

[109]

Differentiation monoblastic leukemias to monocyte-like cells

Human

Induction of IL-1α and β production

Induction of CD64 and CD86, CD14 and CD68 expression

Induction of endocytosis and respiratory burst activities

[123]

GWAS genome-wide association studies, IBD inflammatory bowel diseases, I/R ischemia/reperfusion injury, Mo macrophages, LCs Langerhans cells, RA rheumatoid arthritis, OA osteoarthritis, NSCLC non-small cell lung cancer

IL-34, a cytokine with a complex biology, which is a lot more than a substitute of CSF-1

Until recently, IL-34 was described as expressed in spleen, thymus, heart, brain, lung, liver, kidney, testis, prostate, ovary, small intestine, and colon [1]. Additional and more detailed expression has been described in “osteoclasts-like” bone giant cell tumors, osteoblasts but not osteoclasts [7], keratinocytes, hair follicles, proximal kidney cells, germ cells, neurons in the brain (cortex, hippocampus) as well as in the cerebrospinal fluid [8]. A weak expression of the protein in the spleen, especially in the red pulp, was also reported [1, 8]. Finally, expression in fibroblasts and synoviocytes from patients with rheumatoid arthritis has been described [9]. IL-34 and CSF-1 have partially non-overlapping expression. IL-34 but not CSF-1 is expressed by keratynocytes and neurons, whereas both cytokines share several other cellular sources [10] (Fig. 1).

IL-34 shares some partially overlapping actions with CSF-1, such as its effect on macrophages and neurons (Fig. 1). The CSF-1R is encoded by a proto-oncogen and has a tyrosine kinase activity, and ligation of CSF-1R induces the phosphorylation of a tyrosine residue of the CSF-1R cytoplasmic domain and its homodimerisation, and initiates a cascade of phosphorylation of other proteins, such as ERK1/2 (extracellular signal-regulated kinase) or AKT (protein kinase B) [11, 12, 13]. CSF-1R is expressed by dendritic cells (DCs) and macrophages, excluding CD11c+ precursors of DCs. However, its expression has been described in CD11cdimB220+ plasmacytoid DCs using green fluorescent protein (GFP) transgenic mice (with GFP under control of CSF-1R promoter), in Langerhans cells, B cells, smooth muscle cells of the vessels, osteoclasts as well as trophoblast cell lineages, and to some extent granulocytes [14, 15, 16, 17, 18, 19, 20]. CSF-1R deficient mice and CSF-1-deficient rat toothless/toothless (tl/tl) both present a defect in macrophages, osteopetrosis, are toothless, and have growth retardation, low fertility, and skeletal defects, which cannot be compensated by CSF-1 administration [21, 22]. CSF-1R gene polymorphism has been demonstrated as a susceptibility marker of asthma with higher frequencies of two intronic polymorphisms and higher expression of CSF-1R on CD14+ monocytes and neutrophils in asthmatic subjects than in normal controls [23]. CSF-1R gene expression was increased in inflammatory bowel disease (IBD) patients with colon cancer than in active chronic IBD [24].

Fig. 1

IL-34, a cytokine described in 2008, and CSF-1 have non-overlapping expression in cells. While CSF-1 only binds to CSF-1R, IL-34 binds to CSF-1R, PTPz, and CD138. IL-34 and CSF-1 binding to CSF-1R result in partially overlapping actions in some cell subsets. Asterisk chondroitin sulphate chains on protein-tyrosine-phosphatase zeta (PTP-z) and CD138

Inhibition of CSF-1R has shown its involvement in proliferation and kidney graft infiltration by macrophages [25] and its potential in reducing macrophages proliferation and associated pathology in inflammatory arthritis [26] and myelin oligodendrocyte glycoprotein (MOG)-induced EAE in mice [27]. CSF-1R is also involved in induction of regulatory macrophages and it has been demonstrated that CSF-1R blockade using antibodies reduced resident tumor-associated macrophages (TAM) number in tumors [28] and exacerbate graft-versus-host disease (GVHD) following bone-marrow transplantation in mice [29].

CSF-1 ligation to CSF-1R is only based on saline bonds, while IL-34 ligation to CSF-1R needs hydrophobic amino acids and hydrogen bonds, suggesting a rather specific structure and chemical constraints supporting a co-evolution of CSF-1R with IL-34 rather than CSF-1 [10]. However, affinity of IL-34 for the receptor CSF-1R is stronger than CSF-1 for CSF-1R; indeed, IL-34 recruits two domains of CSF-1R, while CSF-1 recruits only one [1, 30]. Signal transduction through CSF-1R after ligation by IL-34 involves a stronger but shorter phosphorylation of ERK1/2 and AKT than CSF-1 and decreases CSF-1R expression, leading to differentiated macrophages with distinct morphology (few aggregates vs. many large aggregates with CSF-1) and phenotype (less CD54 expression and monocyte chemoattractant protein-1 (MCP-1/CCL2) production, more HLA-DR expression, and eotaxin-2 production) [31]. In addition, it has been reported that IL-34 and CSF-1 have different levels of expression in different organs.

Since IL-34 acts through the same receptor as CSF-1, therapies directed to block CSF-1R could be viewed as sufficient to neutralize the effects of IL-34; however, more recently, it has been described that IL-34 binds to other receptors through low affinity interactions with chondroitin sulphate chains, such as PTP-ζ [2] and syndecan-1 [4]. Thus, blocking of CSF-1R is not expected to inhibit the actions of IL-34 through these other receptors but blockade of these receptors and not of CSF1-R has not been reported yet. PTP-ζ is expressed as a cell surface or as a soluble receptor by neural progenitors, glia, glioblastoma, B cells, and kidney tubular cells [2, 3, 32]. Activation of PTP-ζ leads to increased tyrosine phosphorylation of several transduction pathways and is upregulated in many human cancers (such as lung and prostate cancers) in chronic oxidative stress in kidney cells and regulates their proliferation and metastasis [3, 33, 34, 35, 36, 37]. PTP-ζ has other ligands, such as pleiotrophin [38], the cell surface protein contactin [39], and the extracellular matrix protein tenascin-R [40]. The role of IL-34 binding on PTP-ζ remains unexplored. IL-34 binding to syndecan-1 modulates the IL-34-induced CSF-1R signaling pathways, and IL-34 induced the migration of myeloid cells in a syndecan-1-dependent manner [4]. Syndecan-1 is expressed by many cancers [41], like myeloma [42], melanoma [43, 44], and pancreas carcinomas [45]. Through chondroitin sulphate chains, syndecan-1 is a co-receptor for growth factors, such as epidermal growth factor [46], hepatocyte growth factor [47], vascular endothelial growth factor [48], Wnt factors [49], or members of the transforming growth factors [50]. Syndecan-1 exhibits a stimulatory or inhibitory role on IL-34 actions, probably depending on its expression levels. A low/moderate level of syndecan-1 may sequestrate IL-34 at the cell surface through its chondroitin sulphate chains, limiting the interaction between IL-34 and the CSF-1R. In contrast, the overexpression of syndecan-1 may increase the proximity between the CSF-1R, favoring the effects of IL-34. More recently, to add another level of complexity, the heterodimeric interaction of IL-34 with CSF-1 has been described by surface plasmon resonance and proximity ligation assays. Such heterodimer showed additive effects on cell proliferation and viability [6].

So far, it was thought that IL-34 played mainly a role in the differentiation and survival of microglia and Langerhans cells in the brain and in the skin, respectively. This vision on the actions of IL-34 was recently expanded with the description of its specific and restricted expression by CD4+ and CD8+ Foxp3+ Tregs [51]. This suggests a role for IL-34 in immune tolerance, and at least in an organ transplantation model through actions on macrophages. This report from our group provided the first description of co-expression of Foxp3 and IL-34 in CD4+ and CD8+ Tregs from healthy human individuals, and also at least by CD8+ Tregs from rat. Such expression had not been looked for or evidenced in mice or humans before and emerged from deoxyribonucleic acid (DNA) microarray analysis of CD8+ Tregs in a model of organ transplantation tolerance in the rat compared to CD8+ Tregs from naive animals [52]. In this model, we observed that one of the most upregulated genes was IL-34. IL-34 produced by CD8+ Treg-suppressed CD4+ T effector cells in vitro and treatment in vivo prolonged cardiac allografts [51]. Further analysis revealed that IL-34 is also expressed in human and specifically by Foxp3+ Tregs (half of them) and both CD4+ and CD8+ Tregs [51]. However, IL-34-deficient mice failed to demonstrate major autoimmune lesions [8], probably because IL-34 is expressed by half of the Foxp3+ Tregs in healthy individuals, and Tregs secrete other cytokines, such as IL-10, IL-35, and TGFβ that might compensate for the lost of IL-34 activity. In addition, and to the best of our knowledge, there are no reports on the impact of IL-34 deficiency on autoimmune models in mice and these models could show an increase in lesions vs. controls. Finally, differences between rats and mice cannot be excluded, and to address this point, IL-34 deficient rats have been generated and are under analysis.

Yin and yang of IL-34

IL-34 and inflammatory diseases

IL-34 expression has been correlated with several inflammatory diseases in patients and in animal models involving monocytes/macrophages over-proliferation, such as rheumatoid arthritis (Table 1). IL-34 is expressed by gingival fibroblasts in human and osteoblasts in human and mouse [53, 54]. Systemic administration of IL-34 to mice increases the proportion of CD11b+ cells in bone and reduces trabecular bone mass [55]. High level of IL-34 in synovial fluids, synovial fibroblasts, and serum has been reported in patients suffering from rheumatoid arthritis (RA). Indeed, IL-34 overexpression correlates with the presence of autoantibodies (rheumatoid factors) in serum and in synovial fluid of patients [56], with the synovitis severity [9] and with the stage of RA development [57]. In addition, IL-34 levels were significantly higher in synovial fluids of RA patients with a high disease severity score [58]. The high IL-34 expression was reduced by anti-RA treatments [59, 60]. Furthermore, a correlation analysis suggested IL-34 as a biomarker of RA progression [61] and as a predictive marker of TNF-alpha antagonist therapy efficiency (better prognosis if <194.12 pg/ml of IL-34 in serum at 3 month treatment) [62]. Dysregulation of osteoclastogenesis promoted by IL-34 was associated with RA inflammation [55], despite of the absence of osteopetrosis symptoms in IL-34-deficient mice (probably due to a compensation by CSF-1) [8]. In this context, blockade of IL-34 should reduce osteoclastogenesis and thus inflammation symptoms. However, this strategy should be associated with a CSF-1 blockade to avoid compensatory effect as IL-34-deficient mice showed no osteopetrosis [8]. In CSF-1-deficient mice, the osteoclast deficiency is compensated over time by IL-34-responsive cells originating from the spleen [63]. Both IL-34 and CSF-1 are upregulated in RA synovium [64]; however, exogenous addition of IL-34 or CSF-1 or blockade with IL-34 or anti-CSF-1 Abs had no effect on RA synovial inflammatory mediator production [65].

Similarly, IL-34 overexpression has been linked to other autoimmune diseases for its role as stimulator of monocyte proliferation (Table 1). For example, IL-34 is highly expressed in inflamed salivary glands from patients affected by Sjogren’s syndrome, characterized by a high expression of inflammatory cytokine, such as TNF-α or IL-17 and expansion of pro-inflammatory CD14brightCD16+ monocytes [66]. IL-34 has also been involved in IBD, where monocytes might play a major role [67]. A positive correlation was observed between inflammation levels, IL-34 overexpression in ileon’s inflamed mucosa from patients affected by Crohn’s disease or by ulcerative colitis [68, 69], and monocytes number supporting the inflammation [70]. IL-34 and CSF-1 are upregulated or in blood and urine of patients with lupus nephritis [64]. A positive correlation has been reported between high IL-34 level expression and the insulin-resistant type II diabetes chronic inflammation and susceptibility [71, 72, 73]. The cause and effect relationship should also be considered, since pancreatic islets infiltration by macrophages remains unclear [74, 75]. Finally, in obesity, IL-34 is expressed by adipocytes and increased in serum of obese women, and IL-34 increases insulin resistance [72].

Despite these observations, some pro-inflammatory cytokines, such as TNFα, play a major role in the pathogenesis of inflammatory diseases and we should consider the possibility that IL-34 could be increased as an inhibitory mechanism initiated as a consequence of acute or chronic inflammation, instead of a cause of the disease, and could thus be used as an inhibitory mechanism of inflammation. In IBD, IL-34 overexpression was suggested to coincide with protective IL-10 producing macrophages contributing to the integrity of the intestinal epithelium [69]. In addition, CSF-1 and CSF-1R deficient mice both display defective proliferation of colon epithelial cells [76], thus arguing for a protective functions of both CSF-1 and IL-34 on survival and proliferation of colon epithelial cells in IBD. IL-34 transgenic mice do not show exacerbated inflammatory responses [77]. Finally, IL-34 in these pathologies could facilitate macrophages differentiation and migration in the spleen to injured tissues for healing of lesions, as the spleen appears to be a source and site of storage of monocytes for rapid deployment to regulate inflammation [78].

An emerging role for IL-34 in immune tolerance

Many studies showed a positive correlation between high IL-34 expression level and tumor development (Table 1). For giant cell tumors of bone, the pathogenesis results directly from the supporting/proliferative action of IL-34 on osteoclastogenesis [7]. In other types of tumors, IL-34 is rather involved in TAM recruitment [79]. Indeed, IL-34 promotes the survival and the differentiation of type 2 macrophages which are important for teratoma development after ES cells graft, and promote neo-angiogenesis [80]. Produced in response to cytotoxic therapies in mammary cancer, IL-34 would also participate to cancer recurrence through TAM recruitment [81]. Indeed, a higher IL-34 level has been associated with shorter survival and time to recurrence [82]. Blockade of CSF-1R improves survival of mammary tumor-bearing mice with decreased vessel density and appearance of antitumor CD8+ cell immune responses.

IL-34 also allows and even promotes some pathogens persistence (Table 1). IL-34 has been reported highly expressed in serum of chronically Hepatitis C (HCV)-infected patients and correlating with fibrosis [83]. IL-34 differentiates monocytes into profibrogenic type 2 macrophages in liver lesions, preventing destruction of hepatic stellate cells by NK cells, and thus increasing collagen 1 [83]. Besides, IL-34 is highly expressed in serum of influenza A virus-infected patients by the IL-22 inflammatory cytokine-producing cells and acts in an autocrine/paracrine manner to control IL-22 production [84]. IL-34 would help human immunodeficiency virus (HIV)-infected microglial cells to survive as a reservoir for the virus in brain [85]. Notably in skin, IL-34 inhibits C. albicans pattern recognition receptors (PRRs) expression by M1 macrophages, maintaining mucosal and dermal skin tolerance to the fungal infection [86]. Otherwise, IL-34 is less expressed in atopic dermatitis skin lesions than in non-lesional skin [87]. The higher expression of IL-34 in non-inflamed lesions suggests the inhibition of inflammatory cascade propagation from lesioned to non-lesioned skin [87].

Furthermore, IL-34 has an immune protective role in brain (Table 1). In vitro, IL-34 has been described to induce monocyte differentiation into cells with microglial characteristics [88]. Produced by neurons, IL-34 promotes microglia proliferation and beta oligomeric amyloid degradation, increases heme oxygenase-1 and TGF-beta production and decreases oxidative stress [89, 90]. Moreover, IL-34 restores hemato-encephalic barrier by acting on endothelial cells and tight junction proteins [91] and decreases neuronal toxicity in mice [92]. Microglia and their yolk sac precursors rely on IL-34 for their maintenance in adult brain [93].

Finally, our group was the first to report the expression of IL-34 by Foxp3+CD4+ and CD8+ Tregs and to demonstrate IL-34 involvement in human and rat Treg-mediated suppressive function. We demonstrated also IL-34 capacity to induce in vivo and in vitro CD4+ and CD8+ Tregs through monocytes polarization toward M2-type macrophages to protect allograft from acute and chronic rejection [51, 94] (Table 1). Accordingly, although IL-34 was not investigated, Conde et al. demonstrated that CSF-1/CSF1-R interactions differentiated monocytes into CD209+ (DC-SIGN) macrophages able to induce CD4+ Tregs and transplantation tolerance [95].

Targeting IL-34 in the clinic? (Fig. 2)

Tolerogenic IL-34 in patients with deleterious inflammatory responses

First, IL-34 is a promising tool for inducing tolerance in solid organ transplanted patients. As CSF-1, IL-34 has been reported as capable of inhibiting T-cell proliferation in response to allogeneic stimulation in vitro, and treatment of rats with a viral vector encoding for IL-34 efficiently prolonged cardiac allograft survival [51]. Moreover, short-term IL-34 treatment was sufficient to induce potent antigen-specific Tregs in vivo through early M2 macrophage polarization mediating altogether long-term tolerance to the allograft. These results suggest that a short period treatment of transplanted patients with IL-34 protein could be sufficient to induce tolerance and to replace or at least reduce large spectral and lifelong immunosuppressive treatments. Recently, the expression of PTPζ by the kidney in mice and human was described and a role in mice was suggested for IL-34 in mediating macrophage infiltration during experimental kidney ischemia–reperfusion [96]. These results are in contradiction with the protective action of CSF-1 from kidney injury acting on tubular cells and macrophages [97, 98]. This potential controversial action of IL-34 highlights the need for a more thorough analysis on the role of IL-34 in ischemia reperfusion in other models [37]. In humans, an increased expression of tubular IL-34 was found in a cohort of 17 kidney patients with acute rejection in the 6 months following transplantation compared with controls. Analysis of a larger cohort of transplanted patients with different outcomes at different timings will determine the importance of IL-34 in promoting macrophage accumulation in the graft and the most appropriate treatment window. A potential deleterious action of IL-34 on kidney tubular cells highlights the need for a more thorough analysis in new models of kidney injury not only in mice but also in other species. In addition, a thorough analysis of macrophages skewing to repair vs. profibrotic macrophages in the kidney would improve our understanding of the action of IL-34 in this setting.

Fig. 2

Therapeutic applications of IL-34 and antagonist potential of blocking anti-IL-34 Ab

The capacity of IL-34 to instruct efficient and rapid myeloid reconstitution following myelosuppressive chemotherapy and hematopoietic stem cell (HSC) transplantation could be beneficial to defense against opportunistic pathogens while preserving the graft-versus-leukemia effect. Indeed, CSF-1 treatment showed shortening recovery time of myeloid cells without influencing the relapse of leukemia or GVHD in mice studies [29, 99] and treatment with CSF-1 inhibited GVHD [29]. Similarly, IL-34 has been shown to improve monocyte viability [1] and macrophage growth [10]. Thus, IL-34 treatment could be used as myeloid growth factor and as an inhibitor of GVHD after hematopoietic stem cells (HSC) transplantation.

IL-34 treatment could be used for preventing skin lesions in atopic dermatitis diseases. Indeed, the lower expression of IL-34 in wounded epidermis and its expression co-localization with CD163+ macrophages suggest a role in inhibiting the propagation of inflammatory cascade through macrophage M2 polarization [87].

Many evidences of a neuroprotective role suggest the use of IL-34 as therapeutic tool for brain diseases, such as Alzheimer disease and multiple sclerosis. IL-34 has been shown to promote degradation of oligomeric amyloid beta and production of the immunoregulatory cytokines heme oxygenase-1 (HO-1) and TGF-beta, reducing oxidative stress and neuronal toxicity [89, 90], as well as for restoring hematoencephalique barrier integrity through tight junction protein production, which were downregulated by pro-inflammatory cytokines [91]. Indeed, systemic administration of IL-34 strongly reduced excitotoxin-induced neuronal cell loss and gliosis in mice model of Alzheimer’s disease [92]. Nevertheless, there have not been until now reports on the effect of IL-34 in animal models of multiple sclerosis or in patients with this disease.

Finally, IL-34 could have antiviral properties due to a lower susceptibility to infection of IL-34-derived macrophages. Indeed, IL-34 administration significantly prolonged Frog Virus 3-challenged animal survival from which IL-34-derived macrophages exhibited significantly greater in vitro anti-ranaviral activity [100, 101].

IL-34-derived M2 macrophages and optimized Treg cell therapy

It has been reported that IL-34 induces type 2 macrophages polarization. Indeed, culture of human monocytes with IL-34-induced regulatory M2 expressing high level of IL-10 and low levels of IL-12 [102]. Moreover, M2 macrophages have a key role in IL-34-mediated induction of tolerance to cardiac allograft in the rat, since tolerance was not established after macrophages depletion [51]. More detailed phenotypic and functional analysis is still necessary to fully characterize these tolerogenic IL-34-induced M2 macrophages.

Interestingly, tolerogenic macrophages have already been assessed for cell therapy in a clinical pilot study in kidney-transplanted patients. Indeed, donor-derived regulatory macrophages infusion to these patients was associated with graft survival with minimal immunosuppression without signs of graft rejection at 1 year [103]. Thus, macrophage polarization by IL-34 cytokine could be considered for future macrophages-based tolerogenic therapies.

Furthermore, M2 macrophages are known to convert effector cells in CD4+ Tregs [104]. Recently, we have shown the higher efficiency for expanding both human CD8+ and CD4+ Tregs in vitro using IL-34-differentiated macrophages compared to macrophages without IL-34 [51]. Our results also showed a higher suppressive function of Tregs expanded with IL-34-macrophages compared to without. Moreover, tolerance to allograft induced by IL-34 overexpression in rat was mediated by both CD8+ and CD4+ Tregs. Thus, IL-34-differentiated macrophages should also be considered for in vitro Treg cell expansion in a cell-therapy aim.

It should be noted that other cytokines can associate with IL-34 to induce even more potent regulatory cells. First, IL-34 and CSF-1 could have an additive effect on regulatory cells differentiation [6]. IL-6 has been shown to potentiate IL-34 induced differentiation of immunosuppressive macrophages [105]. Finally, IFNγ has been closely related to Tregs function [52, 106, 107] and regulatory macrophage differentiation with CSF-1 [108].

Unwanted tolerance could be abrogated by IL-34 inhibition

In cancer, the tolerogenic role of IL-34 is an unwanted effect. Bone giant cell tumor characterized by over-osteoclastogenesis is promoted by IL-34 [7]. Blocking of IL-34 action could stop tumor progression by reducing osteoclasts proliferation and survival signal to these cells. TAMs are major players in the inhibition of antitumor immune responses, and IL-34 and CSF-1 have both been shown to actively participate in CSF-1R-dependent TAM infiltration in the tumor. Indeed, blocking of CSF1R signaling, in combination with paclitaxel, slowed primary tumor and metastasis development improving survival of mammary tumor-bearing mice [81]. Similarly, anti-CSF-1 treatment of cells was efficient to prevent tumor colonization by monocyte-derived cells. However, this effect could be annihilated by the adding of IL-34 [109]. These results highlight the potential of targeting CSF-1R pathway for inhibiting TAMs recruitment, but also suggest the requirement of blocking both IL-34 and CSF-1 to efficiently/definitely control TAMs recruitment. This could be obtained by targeting the CSF-1R but IL-34 could still have actions through its other receptors. An alternative strategy could be to use recombinant bispecific anti-CSF-1 and anti-IL-34 antibodies that would neutralize both cytokines. Thus, for applications, such as cancer, blocking of CSF-1R, CSF-1, and/or IL-34 seems an interesting approach. Blocking of IL-34 or CSF-1 with MAbs can neutralize the other one at least partially, since heterodimers of both molecules can be formed [50]. Nevertheless, the proportion of hetero vs. homodimers is not known. Blocking CSF-1R would eliminate the action of both CSF-1 and IL-34 through this receptor but not IL-34 actions through PTPzeta and/or syndecan-1. PTPzeta is expressed by glioma, astrocytoma, and neuroblastoma cells [35, 36], and IL-34 is produced by astrocytes. CSF-1 has been implicated in increasing lung and brain metastases, and brain metastases express CSF-1 and IL-34 [109], and thus glioma and brain metastasis of CSF-1R+ or PTPzeta+ or syndecan-1+ cancers are areas of particular interest.

Following the same reasoning and since IL-34 is produced by keratinocytes and that melanoma are PTPzeta+ [44] and syndecan-1+ [43], treatment with IL-34 would be particularly relevant. If IL-34 plays a role in the biology of PTPzeta+ [33, 34, 35, 36] and/or syndecan-1+ tumors [41, 42, 45], then anti-IL-34 neutralizing antibodies could be an interesting approach.

Positive correlations between IL-34 overexpression in patients and pathogens infections have been reported. High level of IL-34 would promote infection of patients by influenza A virus [84], HIV [85], HCV [83], and C. albicans [86] and could contribute to the generation of anti-inflammatory M2 macrophage polarization. Blocking of IL-34 would thus be helpful to activate the immune response against pathogens.

Conclusions

Thus, although IL-34 and CSF-1 share effects, the two cytokines are not equivalent (Fig. 1) and IL-34 is potentially pathogenic in inflammatory pathophysiological situations, such as IBD and RA, although a possible increase as a suppressive mechanism to inhibit inflammation cannot be ruled out. IL-34 has a distinct pathogenic role in cancer (Table 1; Fig. 2). In general, IL-34 favors the generation of tolerogenic macrophages, such as TAM/M2 macrophages which inhibit immune responses and favor tumor growth. In infectious models, IL-34 has been associated with increase pathogenic burden. Therefore, in light of these studies, neutralizing IL-34 would be desirable to increase immune responses in cancer and infectious diseases and delivering IL-34 could be used to decrease immune responses in autoimmunity and solid organ transplantation or GVHD.

Notes

Acknowledgements

We thank the Fondation Progreffe and the Labex IGO project (No. ANR-11-LABX-0016-01) for financial support. This work was realized in the context of the IHU-Cesti project (ANR-10-IBHU-005). Both, Labex IGO and IHU-CESTI, are part of the «Investissements d’Avenir» ANR French Government program. The IHU-Cesti project is also supported by Nantes Métropole and Région Pays-de-la-Loire.

References

  1. 1.
    Lin H, Lee E, Hestir K, Leo C, Huang M, Bosch E, Halenbeck R, Wu G, Zhou A, Behrens D, Hollenbaugh D, Linnemann T, Qin M, Wong J, Chu K, Doberstein SK, Williams LT (2008) Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science 320(5877):807–811. doi:10.1126/science.1154370 PubMedCrossRefGoogle Scholar
  2. 2.
    Nandi S, Cioce M, Yeung YG, Nieves E, Tesfa L, Lin H, Hsu AW, Halenbeck R, Cheng HY, Gokhan S, Mehler MF, Stanley ER (2013) Receptor-type protein-tyrosine phosphatase zeta is a functional receptor for interleukin-34. J Biol Chem 288(30):21972–21986. doi:10.1074/jbc.M112.442731 PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Baek JH, Zeng R, Weinmann-Menke J, Valerius MT, Wada Y, Ajay AK, Colonna M, Kelley VR (2015) IL-34 mediates acute kidney injury and worsens subsequent chronic kidney disease. J Clin Invest 125(8):3198–3214. doi:10.1172/JCI81166 PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Segaliny AI, Brion R, Mortier E, Maillasson M, Cherel M, Jacques Y, Le Goff B, Heymann D (2015) Syndecan-1 regulates the biological activities of interleukin-34. Biochim Biophys Acta 1853(5):1010–1021. doi:10.1016/j.bbamcr.2015.01.023 PubMedCrossRefGoogle Scholar
  5. 5.
    Wei S, Nandi S, Chitu V, Yeung YG, Yu W, Huang M, Williams LT, Lin H, Stanley ER (2010) Functional overlap but differential expression of CSF-1 and IL-34 in their CSF-1 receptor-mediated regulation of myeloid cells. J Leukoc Biol 88(3):495–505. doi:10.1189/jlb.1209822 PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Segaliny AI, Brion R, Brulin B, Maillasson M, Charrier C, Teletchea S, Heymann D (2015) IL-34 and M-CSF form a novel heteromeric cytokine and regulate the M-CSF receptor activation and localization. Cytokine. doi:10.1016/j.cyto.2015.05.029 PubMedGoogle Scholar
  7. 7.
    Baud’huin M, Renault R, Charrier C, Riet A, Moreau A, Brion R, Gouin F, Duplomb L, Heymann D (2010) Interleukin-34 is expressed by giant cell tumours of bone and plays a key role in RANKL-induced osteoclastogenesis. J Pathol 221(1):77–86. doi:10.1002/path.2684 PubMedCrossRefGoogle Scholar
  8. 8.
    Wang Y, Szretter KJ, Vermi W, Gilfillan S, Rossini C, Cella M, Barrow AD, Diamond MS, Colonna M (2012) IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat Immunol 13(8):753–760. doi:10.1038/ni.2360 PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Chemel M, Le Goff B, Brion R, Cozic C, Berreur M, Amiaud J, Bougras G, Touchais S, Blanchard F, Heymann MF, Berthelot JM, Verrecchia F, Heymann D (2012) Interleukin 34 expression is associated with synovitis severity in rheumatoid arthritis patients. Ann Rheum Dis 71(1):150–154. doi:10.1136/annrheumdis-2011-200096 PubMedCrossRefGoogle Scholar
  10. 10.
    Garceau V, Smith J, Paton IR, Davey M, Fares MA, Sester DP, Burt DW, Hume DA (2010) Pivotal Advance: Avian colony-stimulating factor 1 (CSF-1), interleukin-34 (IL-34), and CSF-1 receptor genes and gene products. J Leukoc Biol 87(5):753–764. doi:10.1189/jlb.0909624 PubMedCrossRefGoogle Scholar
  11. 11.
    Sherr CJ, Rettenmier CW, Sacca R, Roussel MF, Look AT, Stanley ER (1985) The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF-1. Cell 41(3):665–676PubMedCrossRefGoogle Scholar
  12. 12.
    Chen X, Liu H, Focia PJ, Shim AH, He X (2008) Structure of macrophage colony stimulating factor bound to FMS: diverse signaling assemblies of class III receptor tyrosine kinases. Proc Natl Acad Sci USA 105(47):18267–18272. doi:10.1073/pnas.0807762105 PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Li W, Stanley ER (1991) Role of dimerization and modification of the CSF-1 receptor in its activation and internalization during the CSF-1 response. EMBO J 10(2):277–288PubMedPubMedCentralGoogle Scholar
  14. 14.
    MacDonald KP, Rowe V, Bofinger HM, Thomas R, Sasmono T, Hume DA, Hill GR (2005) The colony-stimulating factor 1 receptor is expressed on dendritic cells during differentiation and regulates their expansion. J Immunol 175(3):1399–1405PubMedCrossRefGoogle Scholar
  15. 15.
    Sasmono RT, Williams E (2012) Generation and characterization of MacGreen mice, the Cfs1r-EGFP transgenic mice. Methods Mol Biol 844:157–176. doi:10.1007/978-1-61779-527-5_11 PubMedCrossRefGoogle Scholar
  16. 16.
    Ginhoux F, Tacke F, Angeli V, Bogunovic M, Loubeau M, Dai XM, Stanley ER, Randolph GJ, Merad M (2006) Langerhans cells arise from monocytes in vivo. Nat Immunol 7(3):265–273. doi:10.1038/ni1307 PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Takashima A, Edelbaum D, Kitajima T, Shadduck RK, Gilmore GL, Xu S, Taylor RS, Bergstresser PR, Ariizumi K (1995) Colony-stimulating factor-1 secreted by fibroblasts promotes the growth of dendritic cell lines (XS series) derived from murine epidermis. J Immunol 154(10):5128–5135PubMedGoogle Scholar
  18. 18.
    Baker AH, Ridge SA, Hoy T, Cachia PG, Culligan D, Baines P, Whittaker JA, Jacobs A, Padua RA (1993) Expression of the colony-stimulating factor 1 receptor in B lymphocytes. Oncogene 8(2):371–378PubMedGoogle Scholar
  19. 19.
    Inaba T, Gotoda T, Shimano H, Shimada M, Harada K, Kozaki K, Watanabe Y, Hoh E, Motoyoshi K, Yazaki Y et al (1992) Platelet-derived growth factor induces c-fms and scavenger receptor genes in vascular smooth muscle cells. J Biol Chem 267(18):13107–13112PubMedGoogle Scholar
  20. 20.
    Hofstetter W, Wetterwald A, Cecchini MC, Felix R, Fleisch H, Mueller C (1992) Detection of transcripts for the receptor for macrophage colony-stimulating factor, c-fms, in murine osteoclasts. Proc Natl Acad Sci USA 89(20):9637–9641PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Leonard EP, Cotton WR, Keene HJ (1974) Morphological and histochemical observations on the lack of osteoclasis in the “tl” strain of rat. Proc Soc Exp Biol Med 147(3):596–598PubMedCrossRefGoogle Scholar
  22. 22.
    Dai XM, Ryan GR, Hapel AJ, Dominguez MG, Russell RG, Kapp S, Sylvestre V, Stanley ER (2002) Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects. Blood 99(1):111–120PubMedCrossRefGoogle Scholar
  23. 23.
    Shin EK, Lee SH, Cho SH, Jung S, Yoon SH, Park SW, Park JS, Uh ST, Kim YK, Kim YH, Choi JS, Park BL, Shin HD, Park CS (2010) Association between colony-stimulating factor 1 receptor gene polymorphisms and asthma risk. Hum Genet 128(3):293–302. doi:10.1007/s00439-010-0850-3 PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Alexander RJ, Panja A, Kaplan-Liss E, Mayer L, Raicht RF (1995) Expression of growth factor receptor-encoded mRNA by colonic epithelial cells is altered in inflammatory bowel disease. Dig Dis Sci 40(3):485–494PubMedCrossRefGoogle Scholar
  25. 25.
    Jose MD, Le Meur Y, Atkins RC, Chadban SJ (2003) Blockade of macrophage colony-stimulating factor reduces macrophage proliferation and accumulation in renal allograft rejection. Am J Transplant 3(3):294–300PubMedCrossRefGoogle Scholar
  26. 26.
    Ohno H, Uemura Y, Murooka H, Takanashi H, Tokieda T, Ohzeki Y, Kubo K, Serizawa I (2008) The orally-active and selective c-Fms tyrosine kinase inhibitor Ki20227 inhibits disease progression in a collagen-induced arthritis mouse model. Eur J Immunol 38(1):283–291. doi:10.1002/eji.200737199 PubMedCrossRefGoogle Scholar
  27. 27.
    Uemura Y, Ohno H, Ohzeki Y, Takanashi H, Murooka H, Kubo K, Serizawa I (2008) The selective M-CSF receptor tyrosine kinase inhibitor Ki20227 suppresses experimental autoimmune encephalomyelitis. J Neuroimmunol 195(1–2):73–80. doi:10.1016/j.jneuroim.2008.01.015 PubMedCrossRefGoogle Scholar
  28. 28.
    MacDonald KP, Palmer JS, Cronau S, Seppanen E, Olver S, Raffelt NC, Kuns R, Pettit AR, Clouston A, Wainwright B, Branstetter D, Smith J, Paxton RJ, Cerretti DP, Bonham L, Hill GR, Hume DA (2010) An antibody against the colony-stimulating factor 1 receptor depletes the resident subset of monocytes and tissue- and tumor-associated macrophages but does not inhibit inflammation. Blood 116(19):3955–3963. doi:10.1182/blood-2010-02-266296 PubMedCrossRefGoogle Scholar
  29. 29.
    Hashimoto D, Chow A, Greter M, Saenger Y, Kwan WH, Leboeuf M, Ginhoux F, Ochando JC, Kunisaki Y, van Rooijen N, Liu C, Teshima T, Heeger PS, Stanley ER, Frenette PS, Merad M (2011) Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation. J Exp Med 208(5):1069–1082. doi:10.1084/jem.20101709 PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Liu H, Leo C, Chen X, Wong BR, Williams LT, Lin H, He X (2012) The mechanism of shared but distinct CSF-1R signaling by the non-homologous cytokines IL-34 and CSF-1. Biochim Biophys Acta 1824(7):938–945. doi:10.1016/j.bbapap.2012.04.012 PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Chihara T, Suzu S, Hassan R, Chutiwitoonchai N, Hiyoshi M, Motoyoshi K, Kimura F, Okada S (2010) IL-34 and M-CSF share the receptor Fms but are not identical in biological activity and signal activation. Cell Death Differ 17(12):1917–1927. doi:10.1038/cdd.2010.60 PubMedCrossRefGoogle Scholar
  32. 32.
    Cohen S, Shoshana OY, Zelman-Toister E, Maharshak N, Binsky-Ehrenreich I, Gordin M, Hazan-Halevy I, Herishanu Y, Shvidel L, Haran M, Leng L, Bucala R, Harroch S, Shachar I (2012) The cytokine midkine and its receptor RPTPzeta regulate B cell survival in a pathway induced by CD74. Journal of immunology 188(1):259–269. doi:10.4049/jimmunol.1101468 CrossRefGoogle Scholar
  33. 33.
    Diamantopoulou Z, Kitsou P, Menashi S, Courty J, Katsoris P (2012) Loss of receptor protein tyrosine phosphatase beta/zeta (RPTPbeta/zeta) promotes prostate cancer metastasis. J Biol Chem 287(48):40339–40349. doi:10.1074/jbc.M112.405852 PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Feng ZJ, Gao SB, Wu Y, Xu XF, Hua X, Jin GH (2010) Lung cancer cell migration is regulated via repressing growth factor PTN/RPTP beta/zeta signaling by menin. Oncogene 29(39):5416–5426. doi:10.1038/onc.2010.282 PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Muller S, Kunkel P, Lamszus K, Ulbricht U, Lorente GA, Nelson AM, von Schack D, Chin DJ, Lohr SC, Westphal M, Melcher T (2003) A role for receptor tyrosine phosphatase zeta in glioma cell migration. Oncogene 22(43):6661–6668. doi:10.1038/sj.onc.1206763 PubMedCrossRefGoogle Scholar
  36. 36.
    Ulbricht U, Brockmann MA, Aigner A, Eckerich C, Muller S, Fillbrandt R, Westphal M, Lamszus K (2003) Expression and function of the receptor protein tyrosine phosphatase zeta and its ligand pleiotrophin in human astrocytomas. J Neuropathol Exp Neurol 62(12):1265–1275PubMedCrossRefGoogle Scholar
  37. 37.
    Sanchez-Nino MD, Sanz AB, Ortiz A (2016) Chronicity following ischaemia-reperfusion injury depends on tubular-macrophage crosstalk involving two tubular cell-derived CSF-1R activators: CSF-1 and IL-34. Nephrol Dial Transplant 31(9):1409–1416. doi:10.1093/ndt/gfw026 PubMedCrossRefGoogle Scholar
  38. 38.
    Maeda N, Nishiwaki T, Shintani T, Hamanaka H, Noda M (1996) 6B4 proteoglycan/phosphacan, an extracellular variant of receptor-like protein-tyrosine phosphatase zeta/RPTPbeta, binds pleiotrophin/heparin-binding growth-associated molecule (HB-GAM). J Biol Chem 271(35):21446–21452PubMedCrossRefGoogle Scholar
  39. 39.
    Peles E, Nativ M, Campbell PL, Sakurai T, Martinez R, Lev S, Clary DO, Schilling J, Barnea G, Plowman GD, Grumet M, Schlessinger J (1995) The carbonic anhydrase domain of receptor tyrosine phosphatase beta is a functional ligand for the axonal cell recognition molecule contactin. Cell 82(2):251–260PubMedCrossRefGoogle Scholar
  40. 40.
    Milev P, Chiba A, Haring M, Rauvala H, Schachner M, Ranscht B, Margolis RK, Margolis RU (1998) High affinity binding and overlapping localization of neurocan and phosphacan/protein-tyrosine phosphatase-zeta/beta with tenascin-R, amphoterin, and the heparin-binding growth-associated molecule. J Biol Chem 273(12):6998–7005PubMedCrossRefGoogle Scholar
  41. 41.
    Palaiologou M, Delladetsima I, Tiniakos D (2014) CD138 (syndecan-1) expression in health and disease. Histol Histopathol 29(2):177–189PubMedGoogle Scholar
  42. 42.
    Yang Y, Yaccoby S, Liu W, Langford JK, Pumphrey CY, Theus A, Epstein J, Sanderson RD (2002) Soluble syndecan-1 promotes growth of myeloma tumors in vivo. Blood 100(2):610–617PubMedCrossRefGoogle Scholar
  43. 43.
    Orecchia P, Conte R, Balza E, Petretto A, Mauri P, Mingari MC, Carnemolla B (2013) A novel human anti-syndecan-1 antibody inhibits vascular maturation and tumour growth in melanoma. Eur J Cancer 49(8):2022–2033. doi:10.1016/j.ejca.2012.12.019 PubMedCrossRefGoogle Scholar
  44. 44.
    Goldmann T, Otto F, Vollmer E (2000) A receptor-type protein tyrosine phosphatase PTP zeta is expressed in human cutaneous melanomas. Folia Histochem Cytobiol 38(1):19–20PubMedGoogle Scholar
  45. 45.
    Conejo JR, Kleeff J, Koliopanos A, Matsuda K, Zhu ZW, Goecke H, Bicheng N, Zimmermann A, Korc M, Friess H, Buchler MW (2000) Syndecan-1 expression is up-regulated in pancreatic but not in other gastrointestinal cancers. Int J Cancer 88(1):12–20. doi:10.1002/1097-0215(20001001)88:1<12::AID-IJC3>3.0.CO;2-T PubMedCrossRefGoogle Scholar
  46. 46.
    Takazaki R, Shishido Y, Iwamoto R, Mekada E (2004) Suppression of the biological activities of the epidermal growth factor (EGF)-like domain by the heparin-binding domain of heparin-binding EGF-like Growth Factor. J Biol Chem 279(45):47335–47343. doi:10.1074/jbc.M408556200 PubMedCrossRefGoogle Scholar
  47. 47.
    Kemp LE, Mulloy B, Gherardi E (2006) Signalling by HGF/SF and Met: the role of heparan sulphate co-receptors. Biochem Soc Trans 34 (Pt 3):414–417. doi:10.1042/BST0340414 PubMedGoogle Scholar
  48. 48.
    Dai J, Rabie AB (2007) VEGF: an essential mediator of both angiogenesis and endochondral ossification. J Dent Res 86(10):937–950PubMedCrossRefGoogle Scholar
  49. 49.
    Niehrs C (2012) The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol 13(12):767–779. doi:10.1038/nrm3470 PubMedCrossRefGoogle Scholar
  50. 50.
    Rider CC (2006) Heparin/heparan sulphate binding in the TGF-beta cytokine superfamily. Biochem Soc Trans 34 (Pt 3):458–460. doi:10.1042/BST0340458 Google Scholar
  51. 51.
    Bezie S, Picarda E, Ossart J, Tesson L, Usal C, Renaudin K, Anegon I, Guillonneau C (2015) IL-34 is a Treg-specific cytokine and mediates transplant tolerance. J Clin Invest 125(10):3952–3964. doi:10.1172/JCI81227 PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Guillonneau C, Hill M, Hubert FX, Chiffoleau E, Herve C, Li XL, Heslan M, Usal C, Tesson L, Menoret S, Saoudi A, Le Mauff B, Josien R, Cuturi MC, Anegon I (2007) CD40Ig treatment results in allograft acceptance mediated by CD8CD45RC T cells, IFN-gamma, and indoleamine 2,3-dioxygenase. J Clin Invest 117(4):1096–1106PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Bostrom EA, Lundberg P (2013) The newly discovered cytokine IL-34 is expressed in gingival fibroblasts, shows enhanced expression by pro-inflammatory cytokines, and stimulates osteoclast differentiation. PLoS One 8(12):e81665. doi:10.1371/journal.pone.0081665 PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Yu Y, Yang D, Qiu L, Okamura H, Guo J, Haneji T (2014) Tumor necrosis factor-alpha induces interleukin-34 expression through nuclear factorkappaB activation in MC3T3-E1 osteoblastic cells. Mol Med Rep 10(3):1371–1376. doi:10.3892/mmr.2014.2353 PubMedPubMedCentralGoogle Scholar
  55. 55.
    Chen Z, Buki K, Vaaraniemi J, Gu G, Vaananen HK (2011) The critical role of IL-34 in osteoclastogenesis. PLoS One 6(4):e18689. doi:10.1371/journal.pone.0018689 PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Moon SJ, Hong YS, Ju JH, Kwok SK, Park SH, Min JK (2013) Increased levels of interleukin 34 in serum and synovial fluid are associated with rheumatoid factor and anticyclic citrullinated peptide antibody titers in patients with rheumatoid arthritis. J Rheumatol 40(11):1842–1849. doi:10.3899/jrheum.130356 PubMedCrossRefGoogle Scholar
  57. 57.
    Zhang F, Ding R, Li P, Ma C, Song D, Wang X, Ma T, Bi L (2015) Interleukin-34 in rheumatoid arthritis: potential role in clinical therapy. Int J Clin Exp Med 8(5):7809–7815PubMedPubMedCentralGoogle Scholar
  58. 58.
    Yang S, Jiang S, Wang Y, Tu S, Wang Z, Chen Z (2016) Interleukin 34 upregulation contributes to the increment of microRNA 21 expression through STAT3 activation associated with disease activity in rheumatoid arthritis. J Rheumatol 43(7):1312–1319. doi:10.3899/jrheum.151253 PubMedCrossRefGoogle Scholar
  59. 59.
    Hwang SJ, Choi B, Kang SS, Chang JH, Kim YG, Chung YH, Sohn DH, So MW, Lee CK, Robinson WH, Chang EJ (2012) Interleukin-34 produced by human fibroblast-like synovial cells in rheumatoid arthritis supports osteoclastogenesis. Arthritis Res Ther 14(1):R14. doi:10.1186/ar3693 PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Tian Y, Shen H, Xia L, Lu J (2013) Elevated serum and synovial fluid levels of interleukin-34 in rheumatoid arthritis: possible association with disease progression via interleukin-17 production. J Interferon Cytokine Res 33(7):398–401. doi:10.1089/jir.2012.0122 PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Chang SH, Choi BY, Choi J, Yoo JJ, Ha YJ, Cho HJ, Kang EH, Song YW, Lee YJ (2015) Baseline serum interleukin-34 levels independently predict radiographic progression in patients with rheumatoid arthritis. Rheumatol Int 35(1):71–79. doi:10.1007/s00296-014-3056-5 PubMedCrossRefGoogle Scholar
  62. 62.
    Ding R, Li P, Song D, Zhang X, Bi L (2015) Predictors of response to TNF-alpha antagonist therapy in Chinese rheumatoid arthritis. Clin Rheumatol 34(7):1203–1210. doi:10.1007/s10067-015-2973-3 PubMedCrossRefGoogle Scholar
  63. 63.
    Nakamichi Y, Udagawa N, Takahashi N (2013) IL-34 and CSF-1: similarities and differences. J Bone Miner Metab 31(5):486–495. doi:10.1007/s00774-013-0476-3 PubMedCrossRefGoogle Scholar
  64. 64.
    Masteller EL, Wong BR (2014) Targeting IL-34 in chronic inflammation. Drug Discov Today 19(8):1212–1216. doi:10.1016/j.drudis.2014.05.016 PubMedCrossRefGoogle Scholar
  65. 65.
    Garcia S, Hartkamp LM, Malvar-Fernandez B, van Es IE, Lin H, Wong J, Long L, Zanghi JA, Rankin AL, Masteller EL, Wong BR, Radstake TR, Tak PP, Reedquist KA (2016) Colony-stimulating factor (CSF) 1 receptor blockade reduces inflammation in human and murine models of rheumatoid arthritis. Arthritis Res Therapy 18:75. doi:10.1186/s13075-016-0973-6 CrossRefGoogle Scholar
  66. 66.
    Ciccia F, Alessandro R, Rodolico V, Guggino G, Raimondo S, Guarnotta C, Giardina A, Sireci G, Campisi G, De Leo G, Triolo G (2013) IL-34 is overexpressed in the inflamed salivary glands of patients with Sjogren’s syndrome and is associated with the local expansion of pro-inflammatory CD14(bright)CD16+ monocytes. Rheumatology 52(6):1009–1017. doi:10.1093/rheumatology/kes435 PubMedCrossRefGoogle Scholar
  67. 67.
    Zhou L, Braat H, Faber KN, Dijkstra G, Peppelenbosch MP (2009) Monocytes and their pathophysiological role in Crohn’s disease. Cell Mol Life Sci 66(2):192–202. doi:10.1007/s00018-008-8308-7 PubMedCrossRefGoogle Scholar
  68. 68.
    Franze E, Monteleone I, Cupi ML, Mancia P, Caprioli F, Marafini I, Colantoni A, Ortenzi A, Laudisi F, Sica G, Sileri P, Pallone F, Monteleone G (2015) Interleukin-34 sustains inflammatory pathways in the gut. Clin Sci 129(3):271–280. doi:10.1042/CS20150132 PubMedCrossRefGoogle Scholar
  69. 69.
    Zwicker S, Martinez GL, Bosma M, Gerling M, Clark R, Majster M, Soderman J, Almer S, Bostrom EA (2015) Interleukin 34: a new modulator of human and experimental inflammatory bowel disease. Clin Sci 129(3):281–290. doi:10.1042/CS20150176 PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Tanida S, Ozeki K, Mizoshita T, Tsukamoto H, Katano T, Kataoka H, Kamiya T, Joh T (2015) Managing refractory Crohn’s disease: challenges and solutions. Clin Exp Gastroenterol 8:131–140. doi:10.2147/CEG.S61868 PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Below JE, Gamazon ER, Morrison JV, Konkashbaev A, Pluzhnikov A, McKeigue PM, Parra EJ, Elbein SC, Hallman DM, Nicolae DL, Bell GI, Cruz M, Cox NJ, Hanis CL (2011) Genome-wide association and meta-analysis in populations from Starr County, Texas, and Mexico City identify type 2 diabetes susceptibility loci and enrichment for expression quantitative trait loci in top signals. Diabetologia 54(8):2047–2055. doi:10.1007/s00125-011-2188-3 PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Chang EJ, Lee SK, Song YS, Jang YJ, Park HS, Hong JP, Ko AR, Kim DY, Kim JH, Lee YJ, Heo YS (2014) IL-34 is associated with obesity, chronic inflammation, and insulin resistance. J Clin Endocrinol Metab 99(7):E1263–E1271. doi:10.1210/jc.2013-4409 PubMedCrossRefGoogle Scholar
  73. 73.
    Zorena K, Jachimowicz-Duda O, Waz P (2016) The cut-off value for interleukin 34 as an additional potential inflammatory biomarker for the prediction of the risk of diabetic complications. Biomarkers 21(3):276–282. doi:10.3109/1354750X.2016.1138321 PubMedCrossRefGoogle Scholar
  74. 74.
    Marchetti P (2016) Islet inflammation in type 2 diabetes. Diabetologia 59(4):668–672. doi:10.1007/s00125-016-3875-x PubMedCrossRefGoogle Scholar
  75. 75.
    Moraes-Vieira PM, Castoldi A, Aryal P, Wellenstein K, Peroni OD, Kahn BB (2016) Antigen presentation and T-cell activation are critical for RBP4-induced insulin resistance. Diabetes 65(5):1317–1327. doi:10.2337/db15-1696 PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Huynh D, Akcora D, Malaterre J, Chan CK, Dai XM, Bertoncello I, Stanley ER, Ramsay RG (2013) CSF-1 receptor-dependent colon development, homeostasis and inflammatory stress response. PLoS One 8(2):e56951. doi:10.1371/journal.pone.0056951 PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Wang Y, Colonna M (2014) Interkeukin-34, a cytokine crucial for the differentiation and maintenance of tissue resident macrophages and Langerhans cells. Eur J Immunol 44(6):1575–1581. doi:10.1002/eji.201344365 PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, Figueiredo JL, Kohler RH, Chudnovskiy A, Waterman P, Aikawa E, Mempel TR, Libby P, Weissleder R, Pittet MJ (2009) Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325(5940):612–616. doi:10.1126/science.1175202 PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Segaliny AI, Mohamadi A, Dizier B, Lokajczyk A, Brion R, Lanel R, Amiaud J, Charrier C, Boisson-Vidal C, Heymann D (2015) Interleukin-34 promotes tumor progression and metastatic process in osteosarcoma through induction of angiogenesis and macrophage recruitment. Int J Cancer 137(1):73–85. doi:10.1002/ijc.29376 PubMedCrossRefGoogle Scholar
  80. 80.
    Chen T, Wang X, Guo L, Wu M, Duan Z, Lv J, Tai W, Renganathan H, Didier R, Li J, Sun D, Chen X, He X, Fan J, Young W, Ren Y (2014) Embryonic stem cells promoting macrophage survival and function are crucial for teratoma development. Front Immunol 5:275. doi:10.3389/fimmu.2014.00275 PubMedPubMedCentralGoogle Scholar
  81. 81.
    DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF, Gallagher WM, Wadhwani N, Keil SD, Junaid SA, Rugo HS, Hwang ES, Jirstrom K, West BL, Coussens LM (2011) Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 1 (1):54–67. doi:10.1158/2159-8274.CD-10-0028 PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Zhou SL, Hu ZQ, Zhou ZJ, Dai Z, Wang Z, Cao Y, Fan J, Huang XW, Zhou J (2016) miR-28-5p-IL-34-macrophage feedback loop modulates hepatocellular carcinoma metastasis. Hepatology 63(5):1560–1575. doi:10.1002/hep.28445 PubMedCrossRefGoogle Scholar
  83. 83.
    Preisser L, Miot C, Le Guillou-Guillemette H, Beaumont E, Foucher ED, Garo E, Blanchard S, Fremaux I, Croue A, Fouchard I, Lunel-Fabiani F, Boursier J, Roingeard P, Cales P, Delneste Y, Jeannin P (2014) IL-34 and macrophage colony-stimulating factor are overexpressed in hepatitis C virus fibrosis and induce profibrotic macrophages that promote collagen synthesis by hepatic stellate cells. Hepatology 60(6):1879–1890. doi:10.1002/hep.27328 PubMedCrossRefGoogle Scholar
  84. 84.
    Yu G, Bing Y, Zhu S, Li W, Xia L, Li Y, Liu Z (2015) Activation of the interleukin-34 inflammatory pathway in response to influenza A virus infection. Am J Med Sci 349(2):145–150. doi:10.1097/MAJ.0000000000000373 PubMedCrossRefGoogle Scholar
  85. 85.
    Gerngross L, Fischer T (2015) Evidence for cFMS signaling in HIV production by brain macrophages and microglia. J Neurovirol 21(3):249–256. doi:10.1007/s13365-014-0270-6 PubMedCrossRefGoogle Scholar
  86. 86.
    Xu R, Sun HF, Williams DW, Jones AV, Al-Hussaini A, Song B, Wei XQ (2015) IL-34 suppresses Candida albicans induced TNFalpha production in M1 macrophages by downregulating expression of Dectin-1 and TLR2. J Immunol Res 2015:328146. doi:10.1155/2015/328146 PubMedPubMedCentralGoogle Scholar
  87. 87.
    Esaki H, Ewald DA, Ungar B, Rozenblit M, Zheng X, Xu H, Estrada YD, Peng X, Mitsui H, Litman T, Suarez-Farinas M, Krueger JG, Guttman-Yassky E (2015) Identification of novel immune and barrier genes in atopic dermatitis by means of laser capture microdissection. J Allergy Clin Immunol 135(1):153–163. doi:10.1016/j.jaci.2014.10.037 PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Ohgidani M, Kato TA, Setoyama D, Sagata N, Hashimoto R, Shigenobu K, Yoshida T, Hayakawa K, Shimokawa N, Miura D, Utsumi H, Kanba S (2014) Direct induction of ramified microglia-like cells from human monocytes: dynamic microglial dysfunction in Nasu-Hakola disease. Sci Rep 4:4957. doi:10.1038/srep04957 PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Ma D, Doi Y, Jin S, Li E, Sonobe Y, Takeuchi H, Mizuno T, Suzumura A (2012) TGF-beta induced by interleukin-34-stimulated microglia regulates microglial proliferation and attenuates oligomeric amyloid beta neurotoxicity. Neurosci Lett 529(1):86–91. doi:10.1016/j.neulet.2012.08.071 PubMedCrossRefGoogle Scholar
  90. 90.
    Mizuno T, Doi Y, Mizoguchi H, Jin S, Noda M, Sonobe Y, Takeuchi H, Suzumura A (2011) Interleukin-34 selectively enhances the neuroprotective effects of microglia to attenuate oligomeric amyloid-beta neurotoxicity. Am J Pathol 179(4):2016–2027. doi:10.1016/j.ajpath.2011.06.011 PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Jin S, Sonobe Y, Kawanokuchi J, Horiuchi H, Cheng Y, Wang Y, Mizuno T, Takeuchi H, Suzumura A (2014) Interleukin-34 restores blood-brain barrier integrity by upregulating tight junction proteins in endothelial cells. PLoS One 9(12):e115981. doi:10.1371/journal.pone.0115981 PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Luo J, Elwood F, Britschgi M, Villeda S, Zhang H, Ding Z, Zhu L, Alabsi H, Getachew R, Narasimhan R, Wabl R, Fainberg N, James ML, Wong G, Relton J, Gambhir SS, Pollard JW, Wyss-Coray T (2013) Colony-stimulating factor 1 receptor (CSF1R) signaling in injured neurons facilitates protection and survival. J Exp Med 210(1):157–172. doi:10.1084/jem.20120412 PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Greter M, Lelios I, Pelczar P, Hoeffel G, Price J, Leboeuf M, Kundig TM, Frei K, Ginhoux F, Merad M, Becher B (2012) Stroma-derived interleukin-34 controls the development and maintenance of langerhans cells and the maintenance of microglia. Immunity 37(6):1050–1060. doi:10.1016/j.immuni.2012.11.001 PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Kim JI, Turka LA (2015) Transplant tolerance: a new role for IL-34. J Clin Invest 125(10):3751–3753. doi:10.1172/JCI84010 PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Conde P, Rodriguez M, van der Touw W, Jimenez A, Burns M, Miller J, Brahmachary M, Chen HM, Boros P, Rausell-Palamos F, Yun TJ, Riquelme P, Rastrojo A, Aguado B, Stein-Streilein J, Tanaka M, Zhou L, Zhang J, Lowary TL, Ginhoux F, Park CG, Cheong C, Brody J, Turley SJ, Lira SA, Bronte V, Gordon S, Heeger PS, Merad M, Hutchinson J, Chen SH, Ochando J (2015) DC-SIGN(+) macrophages control the induction of transplantation tolerance. Immunity 42(6):1143–1158. doi:10.1016/j.immuni.2015.05.009 PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Edwards JK (2015) Acute kidney injury: IL-34 promotes persistent ischaemia-induced AKI. Nat Rev Nephrol 11(9):504. doi:10.1038/nrneph.2015.116 PubMedCrossRefGoogle Scholar
  97. 97.
    Wang Y, Chang J, Yao B, Niu A, Kelly E, Breeggemann MC, Abboud Werner SL, Harris RC, Zhang MZ (2015) Proximal tubule-derived colony stimulating factor-1 mediates polarization of renal macrophages and dendritic cells, and recovery in acute kidney injury. Kidney Int 88(6):1274–1282. doi:10.1038/ki.2015.295 PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Zhang MZ, Yao B, Yang S, Jiang L, Wang S, Fan X, Yin H, Wong K, Miyazawa T, Chen J, Chang I, Singh A, Harris RC (2012) CSF-1 signaling mediates recovery from acute kidney injury. J Clin Invest 122(12):4519–4532. doi:10.1172/JCI60363 PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Masaoka T, Shibata H, Ohno R, Katoh S, Harada M, Motoyoshi K, Takaku F, Sakuma A (1990) Double-blind test of human urinary macrophage colony-stimulating factor for allogeneic and syngeneic bone marrow transplantation: effectiveness of treatment and 2-year follow-up for relapse of leukaemia. Br J Haematol 76(4):501–505PubMedCrossRefGoogle Scholar
  100. 100.
    Grayfer L, Robert J (2014) Divergent antiviral roles of amphibian (Xenopus laevis) macrophages elicited by colony-stimulating factor-1 and interleukin-34. J Leukoc Biol 96(6):1143–1153. doi:10.1189/jlb.4A0614-295R PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Grayfer L, Robert J (2015) Distinct functional roles of amphibian (Xenopus laevis) colony-stimulating factor-1- and interleukin-34-derived macrophages. J Leukoc Biol 98(4):641–649. doi:10.1189/jlb.4AB0315-117RR PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Foucher ED, Blanchard S, Preisser L, Descamps P, Ifrah N, Delneste Y, Jeannin P (2015) IL-34- and M-CSF-induced macrophages switch memory T cells into Th17 cells via membrane IL-1alpha. Eur J Immunol 45(4):1092–1102. doi:10.1002/eji.201444606 PubMedCrossRefGoogle Scholar
  103. 103.
    Hutchinson JA, Riquelme P, Sawitzki B, Tomiuk S, Miqueu P, Zuhayra M, Oberg HH, Pascher A, Lutzen U, Janssen U, Broichhausen C, Renders L, Thaiss F, Scheuermann E, Henze E, Volk HD, Chatenoud L, Lechler RI, Wood KJ, Kabelitz D, Schlitt HJ, Geissler EK, Fandrich F (2011) Cutting Edge: Immunological consequences and trafficking of human regulatory macrophages administered to renal transplant recipients. J Immunol 187(5):2072–2078. doi:10.4049/jimmunol.1100762 PubMedCrossRefGoogle Scholar
  104. 104.
    Liu G, Duan K, Ma H, Niu Z, Peng J, Zhao Y (2011) An instructive role of donor macrophages in mixed chimeras in the induction of recipient CD4(+)Foxp3(+) Treg cells. Immunol Cell Biol 89(8):827–835. doi:10.1038/icb.2011.65 PubMedCrossRefGoogle Scholar
  105. 105.
    Foucher ED, Blanchard S, Preisser L, Garo E, Ifrah N, Guardiola P, Delneste Y, Jeannin P (2013) IL-34 induces the differentiation of human monocytes into immunosuppressive macrophages. antagonistic effects of GM-CSF and IFNgamma. PLoS One 8(2):e56045. doi:10.1371/journal.pone.0056045 PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Li XL, Menoret S, Bezie S, Caron L, Chabannes D, Hill M, Halary F, Angin M, Heslan M, Usal C, Liang L, Guillonneau C, Le Mauff B, Cuturi MC, Josien R, Anegon I (2010) Mechanism and localization of CD8 regulatory T cells in a heart transplant model of tolerance. J Immunol 185(2):823–833. doi:10.4049/jimmunol.1000120 PubMedCrossRefGoogle Scholar
  107. 107.
    Picarda E, Bezie S, Venturi V, Echasserieau K, Merieau E, Delhumeau A, Renaudin K, Brouard S, Bernardeau K, Anegon I, Guillonneau C (2014) MHC-derived allopeptide activates TCR-biased CD8+ Tregs and suppresses organ rejection. J Clin Invest 124(6):2497–2512. doi:10.1172/JCI71533 PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Riquelme P, Tomiuk S, Kammler A, Fandrich F, Schlitt HJ, Geissler EK, Hutchinson JA (2013) IFN-gamma-induced iNOS expression in mouse regulatory macrophages prolongs allograft survival in fully immunocompetent recipients. Mol Ther 21(2):409–422. doi:10.1038/mt.2012.168 PubMedCrossRefGoogle Scholar
  109. 109.
    Rietkotter E, Bleckmann A, Bayerlova M, Menck K, Chuang HN, Wenske B, Schwartz H, Erez N, Binder C, Hanisch UK, Pukrop T (2015) Anti-CSF-1 treatment is effective to prevent carcinoma invasion induced by monocyte-derived cells but scarcely by microglia. Oncotarget 6(17):15482–15493. doi:10.18632/oncotarget.3855 PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Wang Y, Bugatti M, Ulland TK, Vermi W, Gilfillan S, Colonna M (2016) Nonredundant roles of keratinocyte-derived IL-34 and neutrophil-derived CSF1 in langerhans cell renewal in the steady state and during inflammation. Eur J Immunol 46(3):552–559. doi:10.1002/eji.201545917 PubMedCrossRefGoogle Scholar
  111. 111.
    Eda H, Zhang J, Keith RH, Michener M, Beidler DR, Monahan JB (2010) Macrophage-colony stimulating factor and interleukin-34 induce chemokines in human whole blood. Cytokine 52(3):215–220. doi:10.1016/j.cyto.2010.08.005 PubMedCrossRefGoogle Scholar
  112. 112.
    Felix J, Elegheert J, Gutsche I, Shkumatov AV, Wen Y, Bracke N, Pannecoucke E, Vandenberghe I, Devreese B, Svergun DI, Pauwels E, Vergauwen B, Savvides SN (2013) Human IL-34 and CSF-1 establish structurally similar extracellular assemblies with their common hematopoietic receptor. Structure 21(4):528–539. doi:10.1016/j.str.2013.01.018 PubMedCrossRefGoogle Scholar
  113. 113.
    Barve RA, Zack MD, Weiss D, Song RH, Beidler D, Head RD (2013) Transcriptional profiling and pathway analysis of CSF-1 and IL-34 effects on human monocyte differentiation. Cytokine 63(1):10–17. doi:10.1016/j.cyto.2013.04.019 PubMedCrossRefGoogle Scholar
  114. 114.
    Yamane F, Nishikawa Y, Matsui K, Asakura M, Iwasaki E, Watanabe K, Tanimoto H, Sano H, Fujiwara Y, Stanley ER, Kanayama N, Mabbott NA, Magari M, Ohmori H (2014) CSF-1 receptor-mediated differentiation of a new type of monocytic cell with B cell-stimulating activity: its selective dependence on IL-34. J Leukoc Biol 95(1):19–31. doi:10.1189/jlb.0613311 PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Nandi S, Gokhan S, Dai XM, Wei S, Enikolopov G, Lin H, Mehler MF, Stanley ER (2012) The CSF-1 receptor ligands IL-34 and CSF-1 exhibit distinct developmental brain expression patterns and regulate neural progenitor cell maintenance and maturation. Dev biol 367(2):100–113. doi:10.1016/j.ydbio.2012.03.026 PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Okubo M, Yamanaka H, Kobayashi K, Dai Y, Kanda H, Yagi H, Noguchi K (2016) Macrophage-colony stimulating factor derived from injured primary afferent induces proliferation of spinal microglia and neuropathic pain in rats. PLoS One 11(4):e0153375. doi:10.1371/journal.pone.0153375 PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Garcia S, Hartkamp LM, Malvar-Fernandez B, van Es IE, Lin H, Wong J, Long L, Zanghi JA, Rankin AL, Masteller EL, Wong BR, Radstake TR, Tak PP, Reedquist KA (2015) Colony-stimulating factor (CSF) 1 receptor blockade reduces inflammation in human and murine models of rheumatoid arthritis. Arthr Res Ther 18:75. doi:10.1186/s13075-016-0973-6 CrossRefGoogle Scholar
  118. 118.
    Franze E, Marafini I, De Simone V, Monteleone I, Caprioli F, Colantoni A, Ortenzi A, Crescenzi F, Izzo R, Sica G, Sileri P, Rossi P, Pallone F, Monteleone G (2016) Interleukin-34 induces cc-chemokine ligand 20 in gut epithelial cells. J Crohn’s Colitis 10(1):87–94. doi:10.1093/ecco-jcc/jjv181 CrossRefGoogle Scholar
  119. 119.
    Shoji H, Yoshio S, Mano Y, Kumagai E, Sugiyama M, Korenaga M, Arai T, Itokawa N, Atsukawa M, Aikata H, Hyogo H, Chayama K, Ohashi T, Ito K, Yoneda M, Nozaki Y, Kawaguchi T, Torimura T, Abe M, Hiasa Y, Fukai M, Kamiyama T, Taketomi A, Mizokami M, Kanto T (2016) Interleukin-34 as a fibroblast-derived marker of liver fibrosis in patients with non-alcoholic fatty liver disease. Sci rep 6:28814. doi:10.1038/srep28814 PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Wang T, Kono T, Monte MM, Kuse H, Costa MM, Korenaga H, Maehr T, Husain M, Sakai M, Secombes CJ (2013) Identification of IL-34 in teleost fish: differential expression of rainbow trout IL-34, MCSF1 and MCSF2, ligands of the MCSF receptor. Mol Immunol 53(4):398–409. doi:10.1016/j.molimm.2012.09.008 PubMedCrossRefGoogle Scholar
  121. 121.
    Gerngross L, Lehmicke G, Belkadi A, Fischer T (2015) Role for cFMS in maintaining alternative macrophage polarization in SIV infection: implications for HIV neuropathogenesis. J Neuroinflammation 12:58. doi:10.1186/s12974-015-0272-1 PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Wang B, Xu W, Tan M, Xiao Y, Yang H, Xia TS (2015) Integrative genomic analyses of a novel cytokine, interleukin-34 and its potential role in cancer prediction. Intern J Mol Med 35(1):92–102. doi:10.3892/ijmm.2014.2001 Google Scholar
  123. 123.
    Booker BE, Clark RS, Pellom ST, Adunyah SE (2015) Interleukin-34 induces monocytic-like differentiation in leukemia cell lines. Int J Biochem Mol Biol 6(1):1–16PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing 2017

Authors and Affiliations

  1. 1.INSERM UMR1064, Center for Research in Transplantation and Immunology-ITUNUniversité de NantesNantes Cedex 01France
  2. 2.Institut de Transplantation Urologie Néphrologie (ITUN), CHU NantesNantesFrance

Personalised recommendations