Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

CXCL10

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_239

Synonyms

Historical Background

Chemokines/chemoattractant cytokines are small proteins with a mass of 8–10 kDa. Cytokines and chemokines are effector molecules that play a pivotal role in orchestrating both the innate and acquired immune responses. Additionally, they are involved in cell differentiation, division, and repair. The chemokine’s nomenclature has been established in the early 1990s at the International Symposium on Chemotactic Cytokines in Baden (Lindley et al. 1993) on the base of the N-term conserved cysteine motif. Chemokines are classified into four families: C, CC, CXC, CX3C, where X represent any amino acid residue. CXCL10, also called interferon-γ-inducible protein 10 (IP-10), has been initially identified as a chemokine induced by interferon-γ and secreted by a variety of tissues, for example, endothelial cells, monocytes, fibroblasts, and keratinocytes (Luster and Ravetch 1987). CXCL10 has been classified as inflammatory chemokine due to its ability to strongly attract lymphocytes, lack of the ELR motif (glutamic acid-leucine-arginine) which abolishes neovascularization, and function as angiostatic chemokine (Strieter et al. 1995). CXCL10 as well as CXCL9 (MIG) and CXCL11 (ITAC) exerts its action of immune response activator through its natural receptor CXCR3, but CXCL10 also binds to a member of the Toll-like receptor family, TLR4, shown in pancreatic β-cells (Schulthess, Paroni et al. 2009). Over the past few years, both serum levels and tissue expression of CXCL10 were monitored and correlated with various autoimmune diseases such as rheumatoid arthritis, systemic sclerosis, autoimmune thyroid disease, and diabetes mellitus (Hanaoka et al. 2003; Rotondi et al. 2007). Diabetes is a metabolic disease in which the body is unable to produce sufficient amounts of insulin to maintain normoglycemia. Diabetes was reported by Greek physicians already in 250 B.C. and is the Greek word for “syphon,” referring to the severe condition of polyuria, the production of large amounts of urine. The complete term “diabetes mellitus” was established later in the seventeenth century. Mellitus is Latin for honey, which is how the physician Thomas Willis described the taste of urine in patients.

Blood glucose levels are controlled by pancreatic hormones produced by different cell types within the organized structures of the islets of Langerhans that form the endocrine portion of the pancreas. In particular, the hormone insulin, produced by the β-cells, is responsible for decreasing blood glucose by inducing its uptake into target tissues after meals. Diabetes manifests when β-cells fail to produce sufficient amounts of insulin, due to a loss of function and the loss of β-cells themselves. A number of studies over the years, either performed on mouse models or by investigating autopsy material from human pancreata, show that a hallmark of diabetes in both autoimmune type 1 diabetes (T1DM) as well as obesity-related type 2 diabetes (T2DM) is the loss of insulin-producing β-cells by apoptosis (Donath and Halban 2004) (Fig. 1).
CXCL10, Fig. 1

Diabetes is caused by β-cell destruction triggered by environmental factors in genetically predisposed individuals

CXCL10 in T1DM

In T1DM, β-cell apoptosis is the result of an autoimmune attack. Interaction between antigen-presenting cells and T-cells leads to a prolonged presence of intra-islet inflammatory mediators (cytokines, chemokines, reactive oxygen species (ROS)), finally resulting in β-cell destruction (Paroni et al. 2009). T-helper 1 (Th1) cells are suggested to be crucial in triggering and amplifying such immune attack (Delovitch and Singh 1997) (Fig. 2). The production of IL-12 promotes the development of Th1 cells that produce IFN-γ, IL-2, and TNF-β (Frigerio et al. 2002). IFN-γ activates the transcription, production, and secretion of CXCL10 on target cells that in turn enhances the activation of the immune system (Th1 cells) in a paracrine way (Christen and Von Herrath 2004). CXCR3+ T-cells are recruited to β-cells within the islets. Increased CXCL10 serum levels in patients with T1DM as well as in at-risk individuals were shown in several studies (Shimada et al. 2001; Nicoletti et al. 2002). In contrast, one study reported no statistically significant differences in CXCL10 serum levels in a similar patient collective (Rotondi et al. 2003a, b). In pancreatic tissue from a patient with recent onset of T1DM, CXCL10 expression was measured within islets and lymphocytes (Roep et al. 2010). A positive correlation has been shown between CXCL10 and IFN-γ serum levels and GAD-reactive-IFN-γ producing CD4+ cells (Shimada et al. 2001). In contrast, disease duration and CXCL10 serum levels are negatively correlated (Shimada et al. 2001), similarly to most of the immune markers, which cannot or can rarely be detected in long-standing T1DM. Measurements of inflammatory markers at different time points after diagnosis of the disease may be one reason for the data variation in different studies (Fig. 3). In the non-obese diabetic (NOD) mouse model for T1DM, CXCL10 is produced in pancreatic islets even before detectable insulitis (Cardozo et al. 2003; Li et al. 2005). Inhibition of CXCL10 delayed immune-mediated diabetes in the NOD mouse (Morimoto et al. 2004) and transgenic mice expressing CXCL10 in β-cells show spontaneous infiltration of lymphocytes as well as impairment of β-cell function (Rhode et al. 2005).
CXCL10, Fig. 2

β-cell destruction in T1DM is triggered by inflammatory mediators. Activation of the immune system leads to increased levels of reactive oxygen species, autoantibodies and cytokines. Secreted cytokines act on the β-cell and/or via potentiation of the immune system activation

CXCL10, Fig. 3

Potentiation of the immune system activation by CXCL10. Triggering factors (virus, toxins) lead to T-cell differentiation and maturation. Cytokines produced by Th1 activated cells (IFN-γ, TNFα and IL-12) target β-cells leading to CXCL10 secretion. CXCL10 production and secretion is then boosted through a positive feedback leading to a further recruitment of macrophages and NK cells within the islets. Enhanced activation of the immune system leads to the immuno-mediated β-cell loss

CXCL10 in Virus-Mediated Diabetes

Basic and still unresolved questions regarding the onset of diabetes are how endogenous β-cell antigens become immunogenic and whether environmental factors such as viruses play a causative role in this process. Infection with viruses with a tropism for pancreatic islets highly increases CXCL10 levels both in vivo and in vitro. Mouse studies suggest a pivotal role of CXCL10 during virus-induced diabetes (Christen et al. 2003; Morimoto et al. 2004). Abolishing CXCL10 signaling using specific antibodies leads to a reduction of diabetes incidence (Morimoto et al. 2004). The reduction of diabetes incidence in mice is rather chemokine-specific than a redundant immune system effect. The protective effect is due to less lymphocyte infiltration combined with a reduction of CD8+ lymphocyte activation. In contrast, CXCL10 expression in mice is insufficient to trigger significant autoimmune damage of β-cells. CXCL10 was able to abrogate autoimmunity when it was expressed outside the pancreas (Christen and Von Herrath 2004).

CXCL10 in T2DM

Recently, the presence of immune cell infiltration within islets was also observed in T2DM (Ehses et al. 2007); elevated levels of cytokines in the serum and within islets and apoptotic β-cells characterize the disease. High serum levels of the chemokine CXCL10 have been found in patients with manifest T2DM and with a high risk to develop the disease (Nicoletti et al. 2002; Xu et al. 2005; Herder et al. 2006). CXCL10 does not only act as chemoattractant for the immune system but also triggers β-cell apoptosis in isolated human islets (Schulthess et al. 2009). CXCL10 expression was observed in islets in diabetes as well as in islets from obese patients (Schulthess et al. 2009) and in high-fat diet-fed mice (unpublished observation). Also in adipose tissue from obese individuals (Herder et al. 2007a) and obese mice, CXCL10 is increased.

Obesity is characterized by high levels of circulating free fatty acids (FFA) that stimulate the production of cytokines including CXCL10 that can be further amplified by IFN-γ which is also elevated in obesity (Shimabukuro et al. 1998; Herder et al. 2007b). In β-cells CXCL10 acts as pro-apoptotic effector through the alternative receptor TLR4 (Schulthess, Paroni et al. 2009). The canonical signaling pathway PI3K/Akt is essential for β-cell survival. Upon CXCL10/TLR4 interaction, Akt is at first activated and promotes β-cell survival together with transcription and secretion of cytokines like TNF-α, IFN-γ, IL-1β, and CXCL10, which then initiate a cascade and potentiate the apoptotic effect through a paracrine/autocrine effect. The CXCL10-TLR4 cascade activates JNK, induces caspase 3 cleavage, which in turn cleaves activated protein kinase 2 (PAK-2), which is downstream of Akt and reverses Akt signaling from proliferation/survival to apoptosis (Fig. 4). These data implicate an important role of CXCL10 in the disease progression of diabetes and suggest blocking CXCL10 signaling as a new therapeutic strategy for diabetes.
CXCL10, Fig. 4

Hypothetical model of CXCL10 mediated β-cell apoptosis. CXCL10, as well as IFN-γ, IL-1β and TNF-α potentiate their effect via a self activation loop that can be further enhanced by the free fatty acids (FFA). CXCL10 mediated activation of TLR4 leads to activation of the PI3K/Akt pathway followed by JNK and PAK2 cleavage, which reverses the signaling from survival to apoptosis (Adapted from Paroni et al. 2009)

Summary

There is strong evidence that CXCL10 plays a causative role for the onset and development of diabetes. However, serum levels of CXCL10 during the development of the disease are discordant among studies. Such discrepancy can be produced by limitation of the analysis as well as the comparison groups (sex, age and especially duration of the autoimmune disease). Serum levels of CXCL10 may not reflect its expression within the islet of Langerhans, observed in obesity, T1DM and T2DM. Different tissue vascularization and time and duration of CXCL10 expression during the disease are important considerable variables. The dual effect of initiation/maintenance or abolition of the immune response and its relation to time and location of CXCL10 expression was already described in mice during virus-induced diabetes (Christen and Von Herrath 2004). Such a complex scenario is strengthening the role of CXCL10 during the onset of both T1DM and T2DM. Due to its potential role as diagnostic marker as well as its intriguing apoptotic activity, further studies are required in order to: (1) establish a consistent analysis method to bring uniformity in the results among different studies, (2) further elucidate the activation pathways that lead β-cells to undergo apoptosis upon CXCL10 signaling activation, and (3) clarify the extent of the contribution of CXCL10 in vivo during the onset of autoimmune disease.

This work was supported by the European Research Council (ERC), the German Research Foundation (DFG), and the Juvenile Diabetes Research Foundation (JDRF).

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Center for Biomolecular InteractionsUniversity of BremenBremenGermany