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• W2575953348 abstract "Crescentic glomerulonephritis is a life-threatening renal disease that has been extensively studied by the experimental anti–glomerular basement membrane glomerulonephritis (anti-GBM-GN) model. Although T cells have a significant role in this model, athymic/nude mice and rats still develop severe renal disease. Here we further explored the contribution of intrinsic renal cells in the development of T-cell–independent GN lesions. Anti-GBM-GN was induced in three strains of immune-deficient mice (Rag2-/-, Rag2-/-Il2rg-/-, and Rag2-/-Il2rb-/-) that are devoid of either T/B cells or T/B/NK cells. The Rag2-/-Il2rg-/- or Rag2-/-Il2rb-/- mice harbor an additional deletion of either the common gamma chain (γC) or the interleukin-2 receptor β subunit (IL-2Rβ), respectively, impairing IL-15 signaling in particular. As expected, all these strains developed severe anti-GBM-GN. Additionally, bone marrow replenishment experiments allowed us to deduce a protective role for the glomerular-expressed γC during anti-GBM-GN. Given that IL-15 has been found highly expressed in nephritic kidneys despite the absence of lymphocytes, we then studied this cytokine in vitro on primary cultured podocytes from immune-deficient mice (Rag2-/-Il2rg-/- and Rag2-/-Il2rb-/-) compared to controls. IL-15 induced downstream activation of JAK1/3 and SYK in primary cultured podocytes. IL-15–dependent JAK/SYK induction was impaired in the absence of γC or IL-2Rβ. We found γC largely induced on podocytes during human glomerulonephritis. Thus, renal lesions are indeed modulated by intrinsic glomerular cells through the γC/IL-2Rβ receptor response, to date classically described only in immune cells. Crescentic glomerulonephritis is a life-threatening renal disease that has been extensively studied by the experimental anti–glomerular basement membrane glomerulonephritis (anti-GBM-GN) model. Although T cells have a significant role in this model, athymic/nude mice and rats still develop severe renal disease. Here we further explored the contribution of intrinsic renal cells in the development of T-cell–independent GN lesions. Anti-GBM-GN was induced in three strains of immune-deficient mice (Rag2-/-, Rag2-/-Il2rg-/-, and Rag2-/-Il2rb-/-) that are devoid of either T/B cells or T/B/NK cells. The Rag2-/-Il2rg-/- or Rag2-/-Il2rb-/- mice harbor an additional deletion of either the common gamma chain (γC) or the interleukin-2 receptor β subunit (IL-2Rβ), respectively, impairing IL-15 signaling in particular. As expected, all these strains developed severe anti-GBM-GN. Additionally, bone marrow replenishment experiments allowed us to deduce a protective role for the glomerular-expressed γC during anti-GBM-GN. Given that IL-15 has been found highly expressed in nephritic kidneys despite the absence of lymphocytes, we then studied this cytokine in vitro on primary cultured podocytes from immune-deficient mice (Rag2-/-Il2rg-/- and Rag2-/-Il2rb-/-) compared to controls. IL-15 induced downstream activation of JAK1/3 and SYK in primary cultured podocytes. IL-15–dependent JAK/SYK induction was impaired in the absence of γC or IL-2Rβ. We found γC largely induced on podocytes during human glomerulonephritis. Thus, renal lesions are indeed modulated by intrinsic glomerular cells through the γC/IL-2Rβ receptor response, to date classically described only in immune cells. Human crescentic glomerulonephritis (CG) and rapidly progressive glomerulonephritis (GN) are life-threatening immune-mediated diseases.1Couser W.G. Rapidly progressive glomerulonephritis: classification, pathogenetic mechanisms, and therapy.Am J Kidney Dis. 1988; 11: 449-464Abstract Full Text PDF PubMed Scopus (323) Google Scholar For many years, the pathogenesis of human rapidly progressive GN has been studied using the experimental model of passive anti–glomerular basement membrane GN (anti-GBM-GN), whereby heterologous anti-GBM serum is injected into rats or mice.2El Nahas A.M. Masugi nephritis: a model for all seasons.in: Gretz N. Strauch M. Experimental and Genetic Rat Models of Chronic Renal Failure. Karger, Basel, New York, NY1993: 49-67Crossref Google Scholar Following injection, there is a strong inflammatory response, which in a few days leads to severe glomerular and tubulointerstitial injuries3Salant D.J. Cybulsky A.V. Experimental glomerulonephritis.Methods Enzymol. 1988; 162: 421-461Crossref PubMed Scopus (121) Google Scholar, 4Tipping P.G. Holdsworth S.R. T cells in crescentic glomerulonephritis.J Am Soc Nephrol. 2006; 17: 1253-1263Crossref PubMed Scopus (150) Google Scholar: renal cells become surrounded by lymphocytes, a feature reminiscent of human CG.5Bohle A. Mackensen-Haen S. von Gise H. et al.The consequences of tubulo-interstitial changes for renal function in glomerulopathies: a morphometric and cytological analysis.Pathol Res Pract. 1990; 186: 135-144Crossref PubMed Scopus (186) Google Scholar, 6Kriz W. Elger M. Hosser H. et al.How does podocyte damage result in tubular damage?.Kidney Blood Press Res. 1999; 22: 26-36Crossref PubMed Scopus (26) Google Scholar, 7Kriz W. LeHir M. Pathways to nephron loss starting from glomerular diseases—insights from animal models.Kidney Int. 2005; 67: 404-419Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar, 8Rodríguez-Iturbe B. García García G. The role of tubulointerstitial inflammation in the progression of chronic renal failure.Nephron Clin Pract. 2010; 116: c81-c88Crossref PubMed Scopus (75) Google Scholar, 9Sánchez-Lozada L.G. Tapia E. Johnson R.J. et al.Glomerular hemodynamic changes associated with arteriolar lesions and tubulointerstitial inflammation.Kidney Int Suppl. 2003; : S9-S14Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 10Scholz J. Lukacs-Kornek V. Engel D.R. et al.Renal dendritic cells stimulate IL-10 production and attenuate nephrotoxic nephritis.J Am Soc Nephrol. 2008; 19: 527-537Crossref PubMed Scopus (102) Google Scholar The development of anti-GBM-GN lesions in mice has been shown to involve a CD4+ T-cell response through either Th14Tipping P.G. Holdsworth S.R. T cells in crescentic glomerulonephritis.J Am Soc Nephrol. 2006; 17: 1253-1263Crossref PubMed Scopus (150) Google Scholar, 11Kitching A.R. Holdsworth S.R. Tipping P.G. Crescentic glomerulonephritis—a manifestation of a nephritogenic Th1 response?.Histol Histopathol. 2000; 15: 993-1003PubMed Google Scholar, 12Kitching A.R. Tipping P.G. Timoshanko J.R. Holdsworth S.R. Endogenous interleukin-10 regulates Th1 responses that induce crescentic glomerulonephritis.Kidney Int. 2000; 57: 518-525Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 13Kitching A.R. Turner A.L. Wilson G.R. et al.IL-12p40 and IL-18 in crescentic glomerulonephritis: IL-12p40 is the key Th1-defining cytokine chain, whereas IL-18 promotes local inflammation and leukocyte recruitment.J Am Soc Nephrol. 2005; 16: 2023-2033Crossref PubMed Scopus (75) Google Scholar, 14Tipping P.G. Kitching A.R. Glomerulonephritis, Th1 and Th2: what’s new?.Clin Exp Immunol. 2005; 142: 207-215Crossref PubMed Scopus (67) Google Scholar or Th1715Paust H.J. Turner J.E. Steinmetz O.M. et al.The IL-23/Th17 axis contributes to renal injury in experimental glomerulonephritis.J Am Soc Nephrol. 2009; 20: 969-979Crossref PubMed Scopus (193) Google Scholar, 16Steinmetz O.M. Summers S.A. Gan P.Y. et al.The Th17-defining transcription factor RORγt promotes glomerulonephritis.J Am Soc Nephrol. 2011; 22: 472-483Crossref PubMed Scopus (72) Google Scholar, 17Turner J.E. Krebs C. Tittel A.P. et al.IL-17A production by renal γδ T cells promotes kidney injury in crescentic GN.J Am Soc Nephrol. 2012; 23: 1486-1495Crossref PubMed Scopus (70) Google Scholar pathways, whereas the T-cell subset of invariant natural killer (NK) T cells exerts a protective role independently of T-cell polarization.18Mesnard L. Keller A.C. Michel M.L. et al.Invariant natural killer T cells and TGF-beta attenuate anti-GBM glomerulonephritis.J Am Soc Nephrol. 2009; 20: 1282-1292Crossref PubMed Scopus (49) Google Scholar Interestingly, other studies have reported that mice or rats born athymic or “nude” (i.e., constitutively lacking T cells) still develop classical features of GN after anti-GBM serum injection, which is hypothesis generating and provides an opportunity to explore the particular role potentially played by renal cells, independently from T cells19Kusuyama Y. Nishihara T. Saito K. Nephrotoxic nephritis in nude mice.Clin Exp Immunol. 1981; 46: 20-26PubMed Google Scholar, 20Sato T. Oite T. Nagase M. Shimizu F. Nephrotoxic serum nephritis in nude rats: the roles of host immune reactions.Clin Exp Immunol. 1991; 84: 139-144Crossref PubMed Scopus (8) Google Scholar and by intrarenal signaling pathways or local factors normally used by lymphocytes. We thus induced an experimental GN in several immunodeficient mice strains: Rag2-/-, Rag2-/-Il2rg-/-, and Rag2-/-Il2rb-/- that are devoid of either T/B cells or T/B/NK cells. Compared with Rag2-/- mice, Rag2-/-Il2rg-/- and Rag2-/-Il2rb-/- strains carry the additional deletion of either the interleukin (IL)-2 receptor common gamma chain (γC) gene (Rag2-/-Il2rg-/-) or the IL-2 receptor β subunit (IL-2Rβ) gene (Rag2-/-Il2rb-/-). Several IL receptor complexes share the γC subunit (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21).21Ring A.M. Lin J.X. Feng D. et al.Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15.Nat Immunol. 2012; 13: 1187-1195Crossref PubMed Scopus (149) Google Scholar Importantly, IL-15 and IL-2, together with an IL-15Rα or IL-2Rα coreceptor, respectively, have their action further restricted to the β subunit. The trimeric IL-15 receptor (IL-15Rα, IL-2Rβ, γC) is necessary for NK cell ontogeny and explains the absence of NK cells in Rag2-/-Il2rg-/- or Rag2-/-Il2rb-/- mice. Here we show that γC/ IL-2Rβ complexes expressed at the surface of intrinsic renal cells play an important role in the organization of renal lesions during severe immune-mediated GN. Experiments were first carried out to test the effect of anti-GBM serum in Rag2-/- mice devoid of T/B cells, Rag2-/-Il2rg-/- mice devoid of T/B/NK cells, and wild-type (WT) mice from the same C57BL/6J background. Administration of anti-GBM serum impaired renal function parameters and induced lesions typical of GN in WT, Rag2-/-, and Rag2-/-Il2rg-/- mice (Figure 1a) evaluated at day 9. No marked differences were observed in the levels of blood urea nitrogen and percentage of pathologic glomeruli between anti-GBM–treated WT mice and Rag2-/- mice (Figures 1b and c). However, the score of interstitial lesions, assessed by tubular dilations and epithelial atrophy, was lower in anti-GBM–treated Rag2-/- mice than in anti-GBM-GN–treated WT mice (Figure 1d). The levels of plasma urea, proteinuria, and the severity of renal histological lesions were even greater in anti-GBM–treated Rag2-/-Il2rg-/- mice than in anti-GBM–treated Rag2-/- mice (Figure 1b–e). Anti-GBM-GN–treated Rag2-/-Il2rg-/- mice consistently exhibited more significant tubulointerstitial lesions, CD44 de novo staining (Supplementary Figure S1), a higher percentage of pathologic glomeruli (Figures 1c and d) and a more important decrease in the podocytic marker podocalyxin (Figure 1f) than anti-GBM–treated Rag2-/- mice. Therefore, Rag2-/- mice appeared only partially protected against anti-GBM-GN, whereas Rag2-/-Il2rg-/- mice were found to be more susceptible to anti-GBM serum than WT or Rag2-/- mice were. Rag2-/- mice have been shown to have a significant proportion of circulating NK cells (around 25% vs. 5% in WT mice), whereas Rag2-/-Il2rg-/- mice totally lack NK cells.22Shinkai Y. Rathbun G. Lam K.P. et al.RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement.Cell. 1992; 68: 855-867Abstract Full Text PDF PubMed Scopus (2188) Google Scholar To determine the role of NK cells in the results shown, Rag2-/-Il2rg-/- mice were replenished by NK cells (1 × 106 cells/mouse), isolated from the spleen of WT C57BL/6J mice, and injected together with anti-GBM serum. At day 7, flow cytometry analysis showed that ∼2% of circulating cells in Rag2-/-Il2rg-/- mice were NK cells (Figure 2a). At day 9, NK cells were also detected in the mice kidneys (Figure 2b), where an increase in mRNA expression of the Nkg2b/Cd159a NK cell receptor (Figure 2c) was detectable. Despite that, plasma urea levels and renal lesions were similar to nonreplenished Rag2-/-Il2rg-/- mice (Figures 2d to 2f). These findings suggest that NK cells do not account for the severity of GN in Rag2-/-Il2rg-/- mice. Using bone marrow graft experiments, we then analyzed the role of kidney-expressed γC in the development of renal lesions in anti-GBM-GN. Bone marrow cells isolated from WT or Rag2-/- CD45.1+ mice were grafted into irradiated Rag2-/-Il2rg-/- CD45.2+ (referred to as ep.γc-/-) mice, in order to obtain chimeric mice knockout only for the γC chain in nonimmune cells. Six weeks after bone marrow transplantation, at least 90% of circulating cells expressed the CD45.1+ marker in Rag2-/-Il2rg-/- CD45.2+ recipients (Supplementary Figure S2A). NK cell counts measured after bone marrow transplantation are represented in Supplementary Figure S2B. In all anti-GBM-GN–induced ep.γc-/- chimeric mice, plasma urea levels were consistently higher than in mice with WT epithelia (Figure 3a). All ep.γc-/- chimeric mice exhibited significantly severe glomerular lesions with numerous extracapillary crescents (Figures 3b and e) and proteinuria (Figure 3d). In addition, the tubulointerstitial lesions were more severe in ep.γc-/- mice than in mice with WT epithelia, independent of the origin of the bone marrow (WT or Rag2-/-) (Figures 3c and e). These findings suggest that γC expressed on renal cells plays a protective role during anti-GBM-GN. We next analyzed relative expression levels of cytokines (e.g., IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21) acting through receptor complexes containing the common γC subunit in the renal cortex of WT, Rag2-/-, or Rag2-/-γc-/- mice (Figure 4a) after anti-GBM-GN. In all cases, IL-21 and IL-4 mRNA were undetectable. The level of IL-2 mRNA remained very low in all mouse strains (Figure 4a). IL-7 and IL-9 mRNA were detectable in the renal cortex, but no difference was observed among WT, Rag2-/-, or Rag2-/-Il2rg-/- mice. Interestingly, IL-15 mRNA was found to be highly expressed in the renal cortex after anti-GBM-GN in the absence of T/B lymphocytes (Rag2-/- mice) or even in the absence of T/B/NK cells in Rag2-/-Il2rg-/- animals (Figure 4a). Thus, and as described by others,23Shinozaki M. Hirahashi J. Lebedeva T. et al.IL-15, a survival factor for kidney epithelial cells, counteracts apoptosis and inflammation during nephritis.J Clin Invest. 2002; 109: 951-960Crossref PubMed Scopus (76) Google Scholar IL-15 is abundantly produced by intrinsic renal cells, which we confirmed by immunohistochemistry of the renal cortex (Figure 4b). We also showed that from cytokines classically associated with the γC response, only IL-15 plasma levels were found to be higher in Rag2-/-Il2rg-/- mice when compared with WT animals (Supplementary Figure S3A). To explore the role of IL-15, we challenged Rag2-/-Il15-/- and Rag2-/- littermates with anti-GBM serum: plasma urea and proteinuria were found to be higher in Rag2-/-Il15-/- mice than in Rag2-/- mice (Supplementary Figure S4A–C). Next, we induced an anti-GBM-GN in Rag2-/-Il2rb-/- mice lacking the γC coreceptor IL-2Rβ. Again, Rag2-/-Il2rb-/- mice were found to be highly sensitive to anti-GBM serum when compared with Rag2-/- mice. Both strains developed acute renal failure, yet plasma urea levels (Figure 4c), tubulointerstitial lesions (Figures 4e and g) and proteinuria (Figure 4f) were significantly greater in Rag2-/-Il2rb-/- than in Rag2-/- mice (Figure 4d). Taken together, these results suggest that in the absence of lymphocytes, IL-15 and its coreceptors γC and IL-2Rβ have a protective role during anti-GBM-GN. Immunohistochemical studies evidenced noticeable intrarenal expression of γC and its coreceptor complexes, IL-2Rβ and IL-15Rα. Interestingly, γC and IL-15 coreceptors IL-15Rα and IL-2Rβ were not expressed at the basal state in glomeruli. Nevertheless, they are induced during anti-GBM-GN (Figures 5a to c). Colocalization studies in Rag2-/- mice showed that γC is mainly induced in podocytes during anti-GBM-GN (Figure 5d). These findings indicate that γC, IL-2Rβ, and IL-15Rα are expressed in renal epithelium and in particular by injured glomeruli during anti-GBM-GN. We also demonstrated the presence of IL15Rα and IL2Rβ proteins from the renal cortex by immunoblot (Supplementary Figure S3B). These receptors were not kidney-specific Il2rg (γC) or Il2rb splice variants. In particular, RNA-sequencing analysis revealed that all “classical” transcripts and exons of γC, originally described in lymphocytes, are expressed in the kidneys of Rag2-/- mice (Supplementary Figure S5A–C). In vitro experiments were carried out on primary cultured podocytes in which γC has been demonstrated to be highly expressed. Mice primary podocytes from the Rag2-/-Il2rb-/-, Rag2-/-Il2rg-/-, or WT kidney cortex were cultivated from glomerular extracts and stimulated by IL-15 (Figure 6a). The purity of glomerular extracts was also confirmed by microscopy (Figure 6a). To confirm the functionality of IL-15 receptors, we studied downstream effectors classically known in lymphocytes: phosphorylated JAK1/3 and spleen tyrosine kinase (SYK). As described in immune cells, IL-15 induced JAK1/3 and SYK phosphorylation in primary cultured podocytes (Figure 6a, d–e). However, despite the absence of γC, JAK1/3 was still induced in primary podocytes from Rag2-/-Il2rg-/- mice (Figure 6a, c, d), whereas SYK phosphorylation dramatically decreased (Figure 6a and e). There was no JAK and SYK phosphorylation in the absence of IL-2Rβ (Figure 6a, c–e). Thus, IL-15 signaling on primary podocytes appears to be more dependent on IL-2Rβ than on γC. We finally analyzed the expression of γC on human renal biopsies from patients with CG, using pristine 3-month posttransplant renal biopsies as control biopsies. Interestingly, γC was weakly expressed in control biopsies, but was largely induced in glomeruli during GN. Despite being weaker than in its severe form, the expression of γC appears at the early stage of GN and is visible on fibrotic glomerular lesions (Figure 7a). We determined that γC was expressed by human podocytes during GN, indeed γC colocalized with nephrin and synaptopodin (Figure 7b). These results suggest that γC could be an early danger signal expressed by podocytes during GN. Previous studies have described the role of immune cells during the development of renal injury in the passive experimental model of anti-GBM-GN.4Tipping P.G. Holdsworth S.R. T cells in crescentic glomerulonephritis.J Am Soc Nephrol. 2006; 17: 1253-1263Crossref PubMed Scopus (150) Google Scholar, 13Kitching A.R. Turner A.L. Wilson G.R. et al.IL-12p40 and IL-18 in crescentic glomerulonephritis: IL-12p40 is the key Th1-defining cytokine chain, whereas IL-18 promotes local inflammation and leukocyte recruitment.J Am Soc Nephrol. 2005; 16: 2023-2033Crossref PubMed Scopus (75) Google Scholar, 17Turner J.E. Krebs C. Tittel A.P. et al.IL-17A production by renal γδ T cells promotes kidney injury in crescentic GN.J Am Soc Nephrol. 2012; 23: 1486-1495Crossref PubMed Scopus (70) Google Scholar, 24Holdsworth S.R. Kitching A.R. Tipping P.G. Th1 and Th2 T helper cell subsets affect patterns of injury and outcomes in glomerulonephritis.Kidney Int. 1999; 55: 1198-1216Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar, 25Kurts C. Heymann F. Lukacs-Kornek V. et al.Role of T cells and dendritic cells in glomerular immunopathology.Semin Immunopathol. 2007; 29: 317-335Crossref PubMed Scopus (54) Google Scholar To date, many studies support a central role for T lymphocytes in the generation of renal lesions.4Tipping P.G. Holdsworth S.R. T cells in crescentic glomerulonephritis.J Am Soc Nephrol. 2006; 17: 1253-1263Crossref PubMed Scopus (150) Google Scholar, 26Tan D.S. Gan P.Y. O’Sullivan K.M. et al.Thymic deletion and regulatory T cells prevent antimyeloperoxidase GN.J Am Soc Nephrol. 2013; 24: 573-585Crossref PubMed Scopus (34) Google Scholar Because renal lesions are observed despite the absence of B and T lymphocytes in mice, we propose that intrinsic renal cells play a central role in the development of anti-GBM-GN.27Akagi Y. Isaka Y. Arai M. et al.Inhibition of TGF-beta 1 expression by antisense oligonucleotides suppressed extracellular matrix accumulation in experimental glomerulonephritis.Kidney Int. 1996; 50: 148-155Abstract Full Text PDF PubMed Scopus (214) Google Scholar, 28Couser W.G. Basic and translational concepts of immune-mediated glomerular diseases.J Am Soc Nephrol. 2012; 23: 381-399Crossref PubMed Scopus (146) Google Scholar, 29Huang X.R. Tipping P.G. Apostolopoulos J. et al.Mechanisms of T cell-induced glomerular injury in anti-glomerular basement membrane (GBM) glomerulonephritis in rats.Clin Exp Immunol. 1997; 109: 134-142Crossref PubMed Scopus (98) Google Scholar, 30Le Hir M. Histopathology of humorally mediated anti-glomerular basement membrane (GBM) glomerulonephritis in mice.Nephrol Dial Transplant. 2004; 19: 1875-1880Crossref PubMed Scopus (11) Google Scholar Our findings are also in agreement with those of earlier studies that evaluated passive anti-GBM-GN lesions in nude animals.19Kusuyama Y. Nishihara T. Saito K. Nephrotoxic nephritis in nude mice.Clin Exp Immunol. 1981; 46: 20-26PubMed Google Scholar, 20Sato T. Oite T. Nagase M. Shimizu F. Nephrotoxic serum nephritis in nude rats: the roles of host immune reactions.Clin Exp Immunol. 1991; 84: 139-144Crossref PubMed Scopus (8) Google Scholar Similar observations regarding glomerular injury in the absence of T cells were also made in Rag1-/- mice in another experimental model (Alport syndrome) in which inflammatory cells are believed to contribute to renal lesions. In this latter study, T cells were not required for the emergence of glomerular injury, but may have contributed to the development of tubular lesions.31Lebleu V.S. Sugimoto H. Miller C.A. et al.Lymphocytes are dispensable for glomerulonephritis but required for renal interstitial fibrosis in matrix defect-induced Alport renal disease.Lab Invest. 2008; 88: 284-292Crossref PubMed Scopus (41) Google Scholar In our study, we find similar results in the passive anti-GBM-GN model, as tubulointerstitial lesions appear to be less severe in Rag2-/- mice than in those observed in WT mice. When reexamining the role of T lymphocytes during the generation of anti-GBM-GN lesions, it appears that several points could in fact reconcile our findings with previous studies. First, active and passive experimental anti-GBM-GN models are often unintentionally scrambled. The passive form, used in our study, results from the injection of a heterologous anti-GBM serum, whereas the active model is the result of the “active” immunization of the host against glomerular extracts or specific GBM epitopes breaking self-tolerance.32Arends J. Wu J. Borillo J. et al.T cell epitope mimicry in antiglomerular basement membrane disease.J Immunol. 2006; 176: 1252-1258Crossref PubMed Scopus (48) Google Scholar, 33Reynolds J. Strain differences and the genetic basis of experimental autoimmune anti-glomerular basement membrane glomerulonephritis.Int J Exp Pathol. 2011; 92: 211-217Crossref PubMed Scopus (15) Google Scholar, 34Steblay R.W. Glomerulonephritis induced in sheep by injections of heterologous glomerular basement membrane and Freund’s complete adjuvant.J Exp Med. 1962; 116: 253-272Crossref PubMed Scopus (136) Google Scholar The active model is largely dependent on cell-mediated immunity (CMI), but our work demonstrates that the passive model is not dependent in this way. Second, the very first studies demonstrating the role of CMI during passive anti-GBM-GN were made using either depleting antibodies, with potential off-target effects, or an unstable genetic background.35Kitching A.R. Tipping P.G. Huang X.R. et al.Interleukin-4 and interleukin-10 attenuate established crescentic glomerulonephritis in mice.Kidney Int. 1997; 52: 52-59Abstract Full Text PDF PubMed Scopus (78) Google Scholar, 36Kitching A.R. Tipping P.G. Mutch D.A. et al.Interleukin-4 deficiency enhances Th1 responses and crescentic glomerulonephritis in mice.Kidney Int. 1998; 53: 112-118Abstract Full Text PDF PubMed Scopus (62) Google Scholar, 37Tipping P.G. Huang X.R. Qi M. et al.Crescentic glomerulonephritis in CD4- and CD8-deficient mice: requirement for CD4 but not CD8 cells.Am J Pathol. 1998; 152: 1541-1548PubMed Google Scholar, 38Tipping P.G. Neale T.J. Holdsworth S.R. T lymphocyte participation in antibody-induced experimental glomerulonephritis.Kidney Int. 1985; 27: 530-537Abstract Full Text PDF PubMed Scopus (104) Google Scholar Third, some passive anti-GBM-GN phenotypes, acquired in mutant mice engineered with defective CMI effectors, could be explained by a defect in renal cells per se or the unsuspected direct action of immunosuppressive drugs on renal epithelial cells.39Faul C. Donnelly M. Merscher-Gomez S. et al.The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A.Nat Med. 2008; 14: 931-938Crossref PubMed Scopus (758) Google Scholar This defect in intrarenal CMI effectors would be evident only during the disease state and has been observed in signal transducer and activator of transcription 3 (STAT3) or B7-1 knockout animals. STAT3 signaling has been shown to be engaged in the immune process and during experimental anti-GBM-GN.40Dai Y. Gu L. Yuan W. et al.Podocyte-specific deletion of signal transducer and activator of transcription 3 attenuates nephrotoxic serum-induced glomerulonephritis.Kidney Int. 2013; 84: 950-961Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar B7-1/CD80 was first demonstrated to be an important CMI effector expressed on immune cells acting as costimulatory molecules. Later, B7-1 was found expressed on podocytes and regulating the filtration barrier in immune-mediated kidney diseases.41Reiser J. von Gersdorff G. Loos M. et al.Induction of B7-1 in podocytes is associated with nephrotic syndrome.J Clin Invest. 2004; 113: 1390-1397Crossref PubMed Scopus (460) Google Scholar Our work also illustrates this point. Indeed, we demonstrate that γC plays an important role in epithelial cells only during GN. Using double knockout animals (Rag2-/-Il2rg-/-) and bone marrow graft experiments, we demonstrate that the expression of γC in the kidney plays a major role in the development of passive anti-GBM-GN. To our knowledge, ours is the first study to show a role of a tissue-expressed γC chain. This result is obtained in the absence of lymphocytes. Several IL receptor complexes (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21) share the γC subunit.21Ring A.M. Lin J.X. Feng D. et al.Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15.Nat Immunol. 2012; 13: 1187-1195Crossref PubMed Scopus (149) Google Scholar As with γC, IL-2Rβ is also part of the coreceptor complex that signals only for IL-2 and IL-15.42Lin J.X. Leonard W.J. The role of Stat5a and Stat5b in signaling by IL-2 family cytokines.Oncogene. 2000; 19: 2566-2576Crossref PubMed Scopus (303) Google Scholar But IL-2 or IL-15 signaling requires an additional α subunit leading to functional receptor complexes formed with IL-2Rα/IL-2Rβ/γ, or IL-15Rα/IL-2Rβ/γ. To date, γC or IL-2Rβ expressions have been reported in primary cultured tubular epithelial cells or renal tumoral cells but not in glomerular cells (e.g., endothelial, mesangial, or even visceral epithelial cells) in mice or humans.43Giron-Michel J. Azzi S. Ferrini S. et al.Interleukin-15 is a major regulator of the cell-microenvironment interactions in human renal homeostasis.Cytokine Growth Factor Rev. 2013; 24: 13-22Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 44Tejman-Yarden N. Zlotnik M. Lewis E. et al.Renal cells express a functional interleukin-15 receptor.Nephrol Dial Transplant. 2005; 20: 516-523Crossref PubMed Scopus (24) Google Scholar Given either their absence or very low level of expression during anti-GBM-GN, we did not consider that IL-2, IL-4, IL-7, IL-9—or even IL-21—played an important role during anti-GBM-GN. These results and the severity of the anti-GBM-GN observed in Rag2-/-Il2rb-/- mice pointed to IL-15 in particular. We demonstrate that IL-15 per se confers a powerful protective effect against anti-GBM-GN in the absence of lymphocytes. These results are partially in line with the original study by Shinozaki et al.23Shinozaki M. Hirahashi J. Lebedeva T. et al.IL-15, a survival factor for kidney epithelial cells, counteracts apoptosis and inflammation during nephritis.J Clin Invest. 2002; 109: 951-960Crossref PubMed Scopus (76) Google Scholar Using Il15-/- mice in the same model, this study demonstrated that IL-15 produces an important antiapoptotic effect in epithelial cells. However, as opposed to the hypothesis of Shinozaki et al.,23Shinozaki M. Hirahashi J. Lebedeva T. et al.IL-15, a survival factor for kidney epithelial cells, counteracts apoptosis and inflammation during nephritis.J Clin Invest. 2002; 109: 951-960Crossref PubMed Scopus (76) Google Scholar our study highlights that the IL-15 epithelial protective effect appears to be marginally T-cell driven. Our in vitro data suggest that podocytes use the classical IL-15/JAK/SYK signaling pathways described in immune cells.21Ring A.M. Lin J.X. Feng D. et al.Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15.Nat Immunol. 2012; 13: 1187-1195Crossref PubMed Scopus (149) Google Scholar," @default.
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