Skip to main content

Advertisement

SpringerLink
Log in

Characterization and biological significance of IL-23-induced neutrophil polarization

  • Article
  • Published:
Cellular & Molecular Immunology Submit manuscript

Abstract

Neutrophils are heterogeneous with distinct subsets, and can switch phenotypes to exert regulatory functions on immunity. We herein demonstrate that IL-23-treated neutrophils selectively produce IL-17A, IL-17F and IL-22, and display a distinct gene expression profile in contrast to resting and lipopolysaccharide-treated neutrophils. IL-17+ neutrophils are present in the colons of mice with dextran sulfate sodium-induced colitis. Adoptive transfer of IL-23-treated neutrophils significantly promotes pathogenesis in this model. IL-23 induces neutrophil polarization through STAT3-dependent RORγt and BATF pathways. Thus, IL-23-induced neutrophil polarization expresses a unique cytokine-producing profile, which may contribute to IL-23-mediated inflammatory diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol 2013; 13: 159–175.

    Article  CAS  Google Scholar 

  2. Amulic B, Cazalet C, Hayes GL, Metzler KD, Zychlinsky A. Neutrophil function: from mechanisms to disease. Annu Rev Immunol 2012; 30: 459–489.

    Article  CAS  Google Scholar 

  3. Mantovani A, Cassatella MA, Costantini C, Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 2011; 11: 519–531.

    Article  CAS  Google Scholar 

  4. Borregaard N. Neutrophils, from marrow to microbes. Immunity 2010; 33: 657–670.

    Article  CAS  Google Scholar 

  5. Kreisel D, Sugimoto S, Zhu J, Nava R, Li W, Okazaki M et al. Emergency granulopoiesis promotes neutrophil-dendritic cell encounters that prevent mouse lung allograft acceptance. Blood 2011; 118: 6172–6182.

    Article  CAS  Google Scholar 

  6. Nemeth T, Mocsai A. The role of neutrophils in autoimmune diseases. Immunol Lett 2012; 143: 9–19.

    Article  CAS  Google Scholar 

  7. Wu T, Sun C, Chen Z, Zhen Y, Peng J, Qi Z et al. Smad3-deficient CD11b(+)Gr1(+) myeloid-derived suppressor cells prevent allograft rejection via the nitric oxide pathway. J Immunol 2012; 189: 4989–5000.

    Article  CAS  Google Scholar 

  8. Colgan SP. Neutrophils and inflammatory resolution in the mucosa. Semin Immunol 2015; 27: 177–183.

    Article  CAS  Google Scholar 

  9. Bennouna S, Bliss SK, Curiel TJ, Denkers EY. Cross-talk in the innate immune system: neutrophils instruct recruitment and activation of dendritic cells during microbial infection. J Immunol 2003; 171: 6052–6058.

    Article  CAS  Google Scholar 

  10. Jaeger BN, Donadieu J, Cognet C, Bernat C, Ordonez-Rueda D, Barlogis V et al. Neutrophil depletion impairs natural killer cell maturation, function, and homeostasis. J Exp Med 2012; 209: 565–580.

    Article  CAS  Google Scholar 

  11. Chiewchengchol D, Midgley A, Sodsai P, Deekajorndech T, Hirankarn N, Beresford MW et al. The protective effect of GM-CSF on serum-induced neutrophil apoptosis in juvenile systemic lupus erythematosus patients. Clin Rheumatol 2015; 34: 85–91.

    Article  Google Scholar 

  12. Muller I, Munder M, Kropf P, Hansch GM. Polymorphonuclear neutrophils and T lymphocytes: strange bedfellows or brothers in arms? Trends Immunol 2009; 30: 522–530.

    Article  Google Scholar 

  13. Cross A, Bucknall RC, Cassatella MA, Edwards SW, Moots RJ. Synovial fluid neutrophils transcribe and express class II major histocompatibility complex molecules in rheumatoid arthritis. Arthritis Rheum 2003; 48: 2796–2806.

    Article  CAS  Google Scholar 

  14. Takashima A, Yao Y. Neutrophil plasticity: acquisition of phenotype and functionality of antigen-presenting cell. J Leukoc Biol 2015; 98: 489–496.

    Article  CAS  Google Scholar 

  15. Scapini P, Nardelli B, Nadali G, Calzetti F, Pizzolo G, Montecucco C et al. G-CSF-stimulated neutrophils are a prominent source of functional BLyS. J Exp Med 2003; 197: 297–302.

    Article  CAS  Google Scholar 

  16. Mhawech-Fauceglia P, Kaya G, Sauter G, McKee T, Donze O, Schwaller J et al. The source of APRIL up-regulation in human solid tumor lesions. J Leukoc Biol 2006; 80: 697–704.

    Article  CAS  Google Scholar 

  17. Zindl CL, Lai JF, Lee YK, Maynard CL, Harbour SN, Ouyang W et al. Il-22-producing neutrophils contribute to antimicrobial defense and restitution of colonic epithelial integrity during colitis. Proc Natl Acad Sci USA 2013; 110: 12768–12773.

    Article  CAS  Google Scholar 

  18. Puga I, Cols M, Barra CM, He B, Cassis L, Gentile M et al. B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nat Immunol 2012; 13: 170–180.

    Article  CAS  Google Scholar 

  19. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: ‘N1’ versus ‘N2’ TAN. Cancer Cell 2009; 16: 183–194.

    Article  CAS  Google Scholar 

  20. Song X, He X, Li X, Qian Y. The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity. Cell Mol Immunol 2016; 13: 418–431.

    Article  CAS  Google Scholar 

  21. Teng MW, Bowman EP, McElwee JJ, Smyth MJ, Casanova JL, Cooper AM et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat Med 2015; 21: 719–729.

    Article  CAS  Google Scholar 

  22. Tonel G, Conrad C, Laggner U, Di Meglio P, Grys K, McClanahan TK et al. Cutting edge: a critical functional role for IL-23 in psoriasis. J Immunol 2010; 185: 5688–5691.

    Article  CAS  Google Scholar 

  23. Kadi A, Costantino F, Izac B, Leboime A, Said-Nahal R, Garchon HJ et al. Brief report: the IL23R nonsynonymous polymorphism rs11209026 is associated with radiographic sacroiliitis in spondyloarthritis. Arthritis Rheum 2013; 65: 2655–2660.

    CAS  PubMed  Google Scholar 

  24. Remmers EF, Cosan F, Kirino Y, Ombrello MJ, Abaci N, Satorius C et al. Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease. Nat Genet 2010; 42: 698–702.

    Article  CAS  Google Scholar 

  25. McGeachy MJ, Chen Y, Tato CM, Laurence A, Joyce-Shaikh B, Blumenschein WM et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol 2009; 10: 314–324.

    Article  CAS  Google Scholar 

  26. Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005; 6: 1133–1141.

    Article  CAS  Google Scholar 

  27. Awasthi A, Riol-Blanco L, Jager A, Korn T, Pot C, Galileos G et al. Cutting edge: IL-23 receptor GFP reporter mice reveal distinct populations of IL-17-producing cells. J Immunol 2009; 182: 5904–5908.

    Article  CAS  Google Scholar 

  28. Aychek T, Mildner A, Yona S, Kim KW, Lampl N, Reich-Zeliger S et al. IL-23-mediated mononuclear phagocyte crosstalk protects mice from citrobacter rodentium-induced colon immunopathology. Nat Commun 2015; 6: 6525.

    Article  CAS  Google Scholar 

  29. Kastelein RA, Hunter CA, Cua DJ. Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu Rev Immunol 2007; 25: 221–242.

    Article  CAS  Google Scholar 

  30. Cella M, Fuchs A, Vermi W, Facchetti F, Otero K, Lennerz JK et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 2009; 457: 722–725.

    Article  CAS  Google Scholar 

  31. Paget C, Ivanov S, Fontaine J, Renneson J, Blanc F, Pichavant M et al. Interleukin-22 is produced by invariant natural killer T lymphocytes during influenza a virus infection: potential role in protection against lung epithelial damages. J Biol Chem 2012; 287: 8816–8829.

    Article  CAS  Google Scholar 

  32. Du J, Shen X, Zhao Y, Hu X, Sun B, Guan W et al. Wip1-deficient neutrophils significantly promote intestinal ischemia/reperfusion injury in mice. Curr Mol Med 2015; 15: 100–108.

    Article  CAS  Google Scholar 

  33. Zhu L, Yang T, Li L, Sun L, Hou Y, Hu X et al. TSC1 controls macrophage polarization to prevent inflammatory disease. Nat Commun 2014; 5: 4696.

    Article  CAS  Google Scholar 

  34. Hou Y, Lin H, Zhu L, Liu Z, Hu F, Shi J et al. Lipopolysaccharide increases the incidence of collagen-induced arthritis in mice through induction of protease HTRA-1 expression. Arthritis Rheum 2013; 65: 2835–2846.

    Article  CAS  Google Scholar 

  35. Hou Y, Lin H, Zhu L, Liu Z, Hu F, Shi J et al. The inhibitory effect of IFN-gamma on protease HTRA1 expression in rheumatoid arthritis. J Immunol 2014; 193: 130–138.

    Article  CAS  Google Scholar 

  36. Sun B, Hu X, Liu G, Ma B, Xu Y, Yang T et al. Phosphatase Wip1 negatively regulates neutrophil migration and inflammation. J Immunol 2014; 192: 1184–1195.

    Article  CAS  Google Scholar 

  37. Yang T, Zhu L, Zhai Y, Zhao Q, Peng J, Zhang H et al. TSC1 controls IL-1beta expression in macrophages via mTORC1-dependent C/EBPβ pathway. Cell Mol Immunol 2016; 13: 640–650.

    Article  CAS  Google Scholar 

  38. Chen H, Zhang L, Zhang H, Xiao Y, Shao L, Li H et al. Disruption of TSC1/2 signaling complex reveals a checkpoint governing thymic CD4+ CD25+ Foxp3+ regulatory T-cell development in mice. FASEB J 2013; 27: 3979–3990.

    Article  CAS  Google Scholar 

  39. Liu G, Hu X, Sun B, Yang T, Shi J, Zhang L et al. Phosphatase Wip1 negatively regulates neutrophil development through p38 MAPK-STAT1. Blood 2013; 121: 519–529.

    Article  CAS  Google Scholar 

  40. Itoh-Nakadai A, Hikota R, Muto A, Kometani K, Watanabe-Matsui M, Sato Y et al. The transcription repressors Bach2 and Bach1 promote B cell development by repressing the myeloid program. Nat Immunol 2014; 15: 1171–1180.

    Article  CAS  Google Scholar 

  41. Cassatella MA. Neutrophil-derived proteins: selling cytokines by the pound. Adv Immunol 1999; 73: 369–509.

    Article  CAS  Google Scholar 

  42. Tecchio C, Micheletti A, Cassatella MA. Neutrophil-derived cytokines: facts beyond expression. Front Immunol 2014; 5: 508.

    Article  Google Scholar 

  43. Yin J, Ferguson TA. Identification of an ifn-gamma-producing neutrophil early in the response to listeria monocytogenes. J Immunol 2009; 182: 7069–7073.

    Article  CAS  Google Scholar 

  44. Taylor PR, Roy S, Leal SM Jr, Sun Y, Howell SJ et al. Activation of neutrophils by autocrine IL-17a-IL-17RC interactions during fungal infection is regulated by IL-6, IL-23, RORγt and dectin-2. Nat Immunol 2014; 15: 143–151.

    Article  CAS  Google Scholar 

  45. Ciofani M, Madar A, Galan C, Sellars M, Mace K, Pauli F et al. A validated regulatory network for Th17 cell specification. Cell 2012; 151: 289–303.

    Article  CAS  Google Scholar 

  46. Chung Y, Chang SH, Martinez GJ, Yang XO, Nurieva R, Kang HS et al. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 2009; 30: 576–587.

    Article  CAS  Google Scholar 

  47. Huber M, Brustle A, Reinhard K, Guralnik A, Walter G, Mahiny A et al. Irf4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotype. Proc Natl Acad Sci USA 2008; 105: 20846–20851.

    Article  CAS  Google Scholar 

  48. Cho ML, Kang JW, Moon YM, Nam HJ, Jhun JY, Heo SB et al. STAT3 and NF-kappaB signal pathway is required for IL-23-mediated IL-17 production in spontaneous arthritis animal model IL-1 receptor antagonist-deficient mice. J Immunol 2006; 176: 5652–5661.

    Article  CAS  Google Scholar 

  49. Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control ConsortiumGenetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control ConsortiumStrange A Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control ConsortiumCapon F Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control ConsortiumSpencer CC Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control ConsortiumKnight J et al. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat Genet 2010; 42: 985–990.

    Article  Google Scholar 

  50. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006; 314: 1461–1463.

    Article  CAS  Google Scholar 

  51. Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 2003; 198: 1951–1957.

    Article  CAS  Google Scholar 

  52. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003; 421: 744–748.

    Article  CAS  Google Scholar 

  53. Weaver CT, Elson CO, Fouser LA, Kolls JK. The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin. Annu Rev Pathol 2013; 8: 477–512.

    Article  CAS  Google Scholar 

  54. Zenaro E, Pietronigro E, Della Bianca V, Piacentino G, Marongiu L, Budui S et al. Neutrophils promote Alzheimer's disease-like pathology and cognitive decline via LFA-1 integrin. Nat Med 2015; 21: 880–886.

    Article  CAS  Google Scholar 

  55. Karthikeyan RS, Vareechon C, Prajna NV, Dharmalingam K, Pearlman E, Lalitha P. Interleukin 17 expression in peripheral blood neutrophils from fungal keratitis patients and healthy cohorts in Southern India. J Infect Dis 2015; 211: 130–134.

    Article  CAS  Google Scholar 

  56. Milanova V, Ivanovska N, Dimitrova P. TLR2 elicits IL-17-mediated RANKL expression, IL-17, and OPG production in neutrophils from arthritic mice. Mediators Inflamm 2014; 2014: 643406.

    Article  Google Scholar 

  57. Ramirez-Velazquez C, Castillo EC, Guido-Bayardo L, Ortiz-Navarrete V. Il-17-producing peripheral blood CD177+ neutrophils increase in allergic asthmatic subjects. Allergy Asthma Clin Immunol 2013; 9: 23.

    Article  CAS  Google Scholar 

  58. Tan Z, Jiang R, Wang X, Wang Y, Lu L, Liu Q et al. Rorgammat+il-17+ neutrophils play a critical role in hepatic ischemia-reperfusion injury. J Mol Cell Biol 2013; 5: 143–146.

    Article  Google Scholar 

  59. Ishida H, Imai T, Suzue K, Hirai M, Taniguchi T, Yoshimura A et al. Il-23 protection against plasmodium berghei infection in mice is partially dependent on il-17 from macrophages. Eur J Immunol 2013; 43: 2696–2706.

    Article  CAS  Google Scholar 

  60. Song C, Luo L, Lei Z, Li B, Liang Z, Liu G et al. Il-17-producing alveolar macrophages mediate allergic lung inflammation related to asthma. J Immunol 2008; 181: 6117–6124.

    Article  CAS  Google Scholar 

  61. Taylor PR, Leal SM Jr., Sun Y, Pearlman E. Aspergillus and fusarium corneal infections are regulated by th17 cells and il-17-producing neutrophils. J Immunol 2014; 192: 3319–3327.

    Article  CAS  Google Scholar 

  62. Lin AM, Rubin CJ, Khandpur R, Wang JY, Riblett M, Yalavarthi S et al. Mast cells and neutrophils release il-17 through extracellular trap formation in psoriasis. J Immunol 2011; 187: 490–500.

    Article  CAS  Google Scholar 

  63. Li L, Huang L, Vergis AL, Ye H, Bajwa A, Narayan V et al. Il-17 produced by neutrophils regulates ifn-gamma-mediated neutrophil migration in mouse kidney ischemia-reperfusion injury. J Clin Invest 2010; 120: 331–342.

    Article  CAS  Google Scholar 

  64. Hoshino A, Nagao T, Nagi-Miura N, Ohno N, Yasuhara M, Yamamoto K et al. Mpo-anca induces il-17 production by activated neutrophils in vitro via classical complement pathway-dependent manner. J Autoimmun 2008; 31: 79–89.

    Article  CAS  Google Scholar 

  65. Ratsimandresy RA, Indramohan M, Dorfleutner A, Stehlik C. The aim2 inflammasome is a central regulator of intestinal homeostasis through the il-18/il-22/stat3 pathway. Cell Mol Immunol 2017; 14: 127–142.

    Article  CAS  Google Scholar 

  66. Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B et al. Novel p19 protein engages il-12p40 to form a cytokine, il-23, with biological activities similar as well as distinct from il-12. Immunity 2000; 13: 715–725.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr Aqeel Javeed for his kind review of the manuscript. This work was supported by grants from the National Basic Research Program of China (2014ZX10002002-001-002, YZ; 2011CB710903, YZ), the National Natural Science Foundation of China for General and Key Programs (81530049, 81130055, YZ), the Knowledge Innovation Program of the Chinese Academy of Sciences (XDA04020202-19, YZ), the Beijing Municipal Hospital Authority ‘Yangfan Program’ (ZYLX201408, XZ), and the CAS/SAFEA International Partnership Program for Creative Research Teams (YZ).

Author information

Author notes

  1. These authors contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, 100020, Beijing, China

    Yang Li, Linnan Zhu, Zhulang Chu, Tao Yang, Hai-Xi Sun, Fan Yang, Yuzhu Hou, Peng Wang, Qingjie Zhao, Yaling Tao & Yong Zhao

  2. University of Chinese Academy of Sciences, 100020, Beijing, China

    Yang Li & Zhulang Chu

  3. Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, 100020, Beijing, China

    Wei Wang & Xiaodong Zhang

  4. Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China

    Lianfeng Zhang

Authors
  1. Yang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Linnan Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhulang Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tao Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hai-Xi Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yuzhu Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Peng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Qingjie Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yaling Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Lianfeng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Xiaodong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yong Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YL, LZ, ZC and TY designed and carried out the experiments, analyzed the data and wrote the manuscript; H-XS analyzed the microarray data; FY, WW and YH performed the animal model experiments and real-time PCR assays; PW performed the ELISA assays; QZ and YT performed the flow cytometry; LZ, XZ and YZ designed the experiments, analyzed the data, wrote the manuscript and provided overall supervision.

Corresponding authors

Correspondence to Lianfeng Zhang, Xiaodong Zhang or Yong Zhao.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Y., Zhu, L., Chu, Z. et al. Characterization and biological significance of IL-23-induced neutrophil polarization. Cell Mol Immunol 15, 518–530 (2018). https://doi.org/10.1038/cmi.2017.39

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cmi.2017.39

  • Springer Nature Limited

Keywords

This article is cited by

Search

Navigation