IL‐17A produced by both γδ T and Th17 cells promotes renal fibrosis via RANTES‐mediated leukocyte infiltration after renal obstruction

IL‐17A‐producing T lymphocytes play a crucial role in inflammatory kidney diseases, but their role in renal fibrosis remains to be explored. Here, we demonstrated that up‐regulation of IL‐17A was associated with the development of obstructive kidney injury. The primary source of IL‐17A production in obstructed kidneys was infiltrating γδ T lymphocytes and CD4+ T cells. IL‐17A‐deficient mice were protected from myofibroblast activation and extracellular matrix deposition, leading to reduced kidney fibrosis in response to obstructive injury. Mechanistically, IL‐17A deficiency suppressed the expression of the chemokine RANTES in infiltrated CD3+ T cells and peritubular inflammation following renal obstruction. Administration of RANTES‐neutralizing antibody significantly reduced the accumulation of T cells and macrophages, and of collagen deposition in obstructed kidneys. Taken together, our results indicate that IL‐17A contributes significantly to the pathogenesis of renal fibrosis by regulating RANTES‐mediated inflammatory cell infiltration. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd

[1]  U. Panzer,et al.  Deficiency of the Interleukin 17/23 Axis Accelerates Renal Injury in Mice With Deoxycorticosterone Acetate+Angiotensin II–Induced Hypertension , 2014, Hypertension.

[2]  S. Rong,et al.  Interleukin 17 Receptor A Modulates Monocyte Subsets and Macrophage Generation In Vivo , 2014, PloS one.

[3]  B. Ryffel,et al.  IL-17A Plays a Critical Role in the Pathogenesis of Liver Fibrosis through Hepatic Stellate Cell Activation , 2013, The Journal of Immunology.

[4]  H. Fujii,et al.  Interleukin-17A plays a pivotal role in cholestatic liver fibrosis in mice. , 2013, The Journal of surgical research.

[5]  D. Proud,et al.  Role of IL-17A and neutrophils in fibrosis in experimental hypersensitivity pneumonitis. , 2013, The Journal of allergy and clinical immunology.

[6]  T. Mak,et al.  IL-17A secretion by CD8+ T cells supports Th17-mediated autoimmune encephalomyelitis. , 2013, The Journal of clinical investigation.

[7]  Liqun He,et al.  Effect of Interleukin 6 Deficiency on Renal Interstitial Fibrosis , 2012, PloS one.

[8]  Gang Xu,et al.  CD4+ T Lymphocytes, Especially Th2 Cells, Contribute to the Progress of Renal Fibrosis , 2012, American Journal of Nephrology.

[9]  T. Korn,et al.  IL-17A production by renal γδ T cells promotes kidney injury in crescentic GN. , 2012, Journal of the American Society of Nephrology : JASN.

[10]  Fabrizio Montecucco,et al.  CC chemokine CCL5 plays a central role impacting infarct size and post-infarction heart failure in mice. , 2012, European heart journal.

[11]  Hui-Hua Li,et al.  Serum-Glucocorticoid Regulated Kinase 1 Regulates Alternatively Activated Macrophage Polarization Contributing to Angiotensin II–Induced Inflammation and Cardiac Fibrosis , 2012, Arteriosclerosis, thrombosis, and vascular biology.

[12]  K. Mills,et al.  Interleukin-1 accounts for intrarenal Th17 cell activation during ureteral obstruction. , 2012, Kidney international.

[13]  Youhua Liu,et al.  Tubular cell dedifferentiation and peritubular inflammation are coupled by the transcription regulator Id1 in renal fibrogenesis , 2011, Kidney international.

[14]  R. Flavell,et al.  Vγ4 γδ T Cell-Derived IL-17A Negatively Regulates NKT Cell Function in Con A-Induced Fulminant Hepatitis , 2011, The Journal of Immunology.

[15]  V. Jala,et al.  Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation. , 2011, Immunity.

[16]  Youhua Liu.  Cellular and molecular mechanisms of renal fibrosis , 2011, Nature Reviews Nephrology.

[17]  S. Gaffen.  Recent advances in the IL-17 cytokine family. , 2011, Current opinion in immunology.

[18]  Liqun He,et al.  CXCL16 recruits bone marrow-derived fibroblast precursors in renal fibrosis. , 2011, Journal of the American Society of Nephrology : JASN.

[19]  D. Harris,et al.  Macrophages in renal disease. , 2011, Journal of the American Society of Nephrology : JASN.

[20]  Philip M. Murphy,et al.  Organ-Specific Innate Immune Responses in a Mouse Model of Invasive Candidiasis , 2010, Journal of Innate Immunity.

[21]  D. Nikolic-Paterson,et al.  CD4+ T cells: a potential player in renal fibrosis. , 2010, Kidney international.

[22]  N. Sheerin,et al.  Pivotal role of CD4+ T cells in renal fibrosis following ureteric obstruction. , 2010, Kidney international.

[23]  U. Panzer,et al.  The Th17 immune response in renal inflammation. , 2010, Kidney international.

[24]  J. Renauld,et al.  IL-17A–Producing γδ T and Th17 Lymphocytes Mediate Lung Inflammation but Not Fibrosis in Experimental Silicosis , 2010, The Journal of Immunology.

[25]  J. Duffield.  Macrophages and immunologic inflammation of the kidney. , 2010, Seminars in nephrology.

[26]  H. Anders,et al.  Targeting the recruitment of monocytes and macrophages in renal disease. , 2010, Seminars in nephrology.

[27]  J. Hughes,et al.  Macrophages and renal fibrosis. , 2010, Seminars in nephrology.

[28]  T. Wynn,et al.  Bleomycin and IL-1β–mediated pulmonary fibrosis is IL-17A dependent , 2010, The Journal of experimental medicine.

[29]  R. Strieter,et al.  IL-17 produced by neutrophils regulates IFN-gamma-mediated neutrophil migration in mouse kidney ischemia-reperfusion injury. , 2010, The Journal of clinical investigation.

[30]  M. T. Grande,et al.  Role of inflammation in túbulo-interstitial damage associated to obstructive nephropathy , 2010, Journal of Inflammation.

[31]  J. Duffield,et al.  Bone Marrow Ly6Chigh Monocytes Are Selectively Recruited to Injured Kidney and Differentiate into Functionally Distinct Populations1 , 2009, The Journal of Immunology.

[32]  K. Schmidbauer,et al.  CD4+ T cells control the differentiation of Gr1+ monocytes into fibrocytes , 2009, Proceedings of the National Academy of Sciences.

[33]  K. Mills,et al.  Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. , 2009, Immunity.

[34]  B. Thornhill,et al.  Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy. , 2009, Kidney international.

[35]  U. Panzer,et al.  The IL-23/Th17 axis contributes to renal injury in experimental glomerulonephritis. , 2009, Journal of the American Society of Nephrology : JASN.

[36]  C. Sasakawa,et al.  Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. , 2009, Immunity.

[37]  Bone Marrow Ly6C Monocytes Are Selectively Recruited to Injured Kidney and Differentiate into Functionally Distinct Populations , 2009 .

[38]  H. van Goor,et al.  Macrophage diversity in renal injury and repair. , 2008, The Journal of clinical investigation.

[39]  Jay K Kolls,et al.  The Biological Functions of T Helper 17 Cell Effector Cytokines in Inflammation , 2022 .

[40]  J. Iredale,et al.  Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis. , 2008, The American journal of pathology.

[41]  A. Maitra,et al.  Cutting edge: evidence for ligand-independent multimerization of the IL-17 receptor , 2007, The Journal of Immunology.

[42]  Scott R. Presnell,et al.  Identification of the IL-17 Receptor Related Molecule IL-17RC as the Receptor for IL-17F , 2007, The Journal of Immunology.

[43]  Jie Du,et al.  Mechanical Stretch Simulates Proliferation of Venous Smooth Muscle Cells Through Activation of the Insulin-Like Growth Factor-1 Receptor , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[44]  S. Kaneko,et al.  Blockade of IP-10/CXCR3 Promotes Progressive Renal Fibrosis , 2007, Nephron Experimental Nephrology.

[45]  S. Segerer,et al.  Role of chemokines for the localization of leukocyte subsets in the kidney. , 2007, Seminars in nephrology.

[46]  A. Krensky,et al.  Mechanisms of Disease: regulation of RANTES (CCL5) in renal disease , 2007, Nature Clinical Practice Nephrology.

[47]  D. Littman,et al.  The Orphan Nuclear Receptor RORγt Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells , 2006, Cell.

[48]  K. Meldrum,et al.  TNF-α neutralization decreases nuclear factor-κB activation and apoptosis during renal obstruction , 2006 .

[49]  A. Maitra,et al.  Cutting Edge: Evidence for Ligand-Independent Multimerization of the IL-17 Receptor1 , 2006, The Journal of Immunology.

[50]  U. Panzer,et al.  Kidney diseases and chemokines. , 2006, Current drug targets.

[51]  R. D. Hatton,et al.  Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages , 2005, Nature Immunology.

[52]  A. Eddy.  Progression in chronic kidney disease. , 2005, Advances in chronic kidney disease.

[53]  佐藤 三佐子.  Targeted disruption of TGF-β1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction , 2005 .

[54]  K. Matsushima,et al.  Blockade of CCR2 ameliorates progressive fibrosis in kidney. , 2004, The American journal of pathology.

[55]  Yasunori Iwata,et al.  Gene therapy via blockade of monocyte chemoattractant protein-1 for renal fibrosis. , 2004, Journal of the American Society of Nephrology : JASN.

[56]  Junwei Yang,et al.  Disruption of tissue-type plasminogen activator gene in mice reduces renal interstitial fibrosis in obstructive nephropathy. , 2002, The Journal of clinical investigation.

[57]  H. Anders,et al.  Obstructive nephropathy in the mouse: progressive fibrosis correlates with tubulointerstitial chemokine expression and accumulation of CC chemokine receptor 2- and 5-positive leukocytes. , 2001, Journal of the American Society of Nephrology : JASN.

[58]  J. Banchereau,et al.  Interleukin-17 activates human renal epithelial cells in vitro and is expressed during renal allograft rejection. , 1998, Journal of the American Society of Nephrology : JASN.