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 RORĪ³t and BATF pathways. Thus, IL-23-induced neutrophil polarization expresses a unique cytokine-producing profile, which may contribute to IL-23-mediated inflammatory diseases.
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References
Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol 2013; 13: 159ā175.
Amulic B, Cazalet C, Hayes GL, Metzler KD, Zychlinsky A. Neutrophil function: from mechanisms to disease. Annu Rev Immunol 2012; 30: 459ā489.
Mantovani A, Cassatella MA, Costantini C, Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 2011; 11: 519ā531.
Borregaard N. Neutrophils, from marrow to microbes. Immunity 2010; 33: 657ā670.
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: 6172ā6182.
Nemeth T, Mocsai A. The role of neutrophils in autoimmune diseases. Immunol Lett 2012; 143: 9ā19.
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: 4989ā5000.
Colgan SP. Neutrophils and inflammatory resolution in the mucosa. Semin Immunol 2015; 27: 177ā183.
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: 6052ā6058.
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: 565ā580.
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: 85ā91.
Muller I, Munder M, Kropf P, Hansch GM. Polymorphonuclear neutrophils and T lymphocytes: strange bedfellows or brothers in arms? Trends Immunol 2009; 30: 522ā530.
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: 2796ā2806.
Takashima A, Yao Y. Neutrophil plasticity: acquisition of phenotype and functionality of antigen-presenting cell. J Leukoc Biol 2015; 98: 489ā496.
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: 297ā302.
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: 697ā704.
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: 12768ā12773.
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: 170ā180.
Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: āN1ā versus āN2ā TAN. Cancer Cell 2009; 16: 183ā194.
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: 418ā431.
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: 719ā729.
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: 5688ā5691.
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: 2655ā2660.
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: 698ā702.
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: 314ā324.
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: 1133ā1141.
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: 5904ā5908.
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.
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: 221ā242.
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: 722ā725.
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: 8816ā8829.
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: 100ā108.
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.
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: 2835ā2846.
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: 130ā138.
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: 1184ā1195.
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/EBPĪ² pathway. Cell Mol Immunol 2016; 13: 640ā650.
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: 3979ā3990.
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: 519ā529.
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: 1171ā1180.
Cassatella MA. Neutrophil-derived proteins: selling cytokines by the pound. Adv Immunol 1999; 73: 369ā509.
Tecchio C, Micheletti A, Cassatella MA. Neutrophil-derived cytokines: facts beyond expression. Front Immunol 2014; 5: 508.
Yin J, Ferguson TA. Identification of an ifn-gamma-producing neutrophil early in the response to listeria monocytogenes. J Immunol 2009; 182: 7069ā7073.
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, RORĪ³t and dectin-2. Nat Immunol 2014; 15: 143ā151.
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: 289ā303.
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: 576ā587.
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: 20846ā20851.
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: 5652ā5661.
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: 985ā990.
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: 1461ā1463.
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: 1951ā1957.
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: 744ā748.
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: 477ā512.
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: 880ā886.
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: 130ā134.
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.
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.
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: 143ā146.
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: 2696ā2706.
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: 6117ā6124.
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: 3319ā3327.
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: 490ā500.
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: 331ā342.
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: 79ā89.
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: 127ā142.
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: 715ā725.
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 āYangfan Programā (ZYLX201408, XZ), and the CAS/SAFEA International Partnership Program for Creative Research Teams (YZ).
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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.
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Li, Y., Zhu, L., Chu, Z. et al. Characterization and biological significance of IL-23-induced neutrophil polarization. Cell Mol Immunol 15, 518ā530 (2018). https://doi.org/10.1038/cmi.2017.39
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DOI: https://doi.org/10.1038/cmi.2017.39
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