A major target autoantigen in anti-neutrophil cytoplasmic antibody–associated vasculitis is myeloperoxidase (MPO). Although MPO-specific CD4⁺ Th cells seem to orchestrate renal injury, the role of the Th17 subset is unknown. We hypothesized that Th17 cells direct injurious anti-MPO autoimmunity in experimental murine anti-MPO–induced glomerulonephritis (GN). We immunized mice with MPO to establish autoimmunity, resulting in systemic IL-17A production with MPO-specific dermal delayed-type hypersensitivity. We triggered disease using antibodies to the glomerular basement membrane to induce glomerular deposition of MPO by neutrophils. Wild-type mice developed necrotizing GN with an influx of glomerular leukocytes and albuminuria. In contrast, mice deficient in the key Th17 effector cytokine IL-17A were nearly completely protected. The protective effects resulted partly from reduced neutrophil recruitment, which led to less disposition of glomerular MPO. To test whether IL-17A also drives autoimmune delayed-type hypersensitivity in the kidney, we injected MPO into the kidneys of MPO-sensitized mice. IL-17A deficiency reduced accumulation of renal macrophages and renal CCL5 mRNA expression. In conclusion, IL-17A contributes to the pathophysiology of autoimmune anti-MPO GN, suggesting that it may be a viable therapeutic target for this disease.

Cytokines play an important role in host defense against microorganisms. They orchestrate innate immunity by inducing protective local inflammation and systemic acute phase responses. Cytokines are important in initiating, amplifying, directing, mediating, and regulating adaptive immunity. Unfortunately, they may also direct tissue damage if excessive responses occur or if they are involved in directing and mediating autoimmunity. Under these circumstances, cytokines are potential therapeutic targets. Over the last 20 years, we have seen the successful development and clinical implementation of biologic strategies that target key cytokines in specific inflammatory diseases with efficacy, specificity, and toxicity profiles challenging conventional drug therapies. These therapies are finding new applications and many new agents show promise. Unfortunately, these new cytokine-based therapies have had little effect on renal disease. This review provides evidence that common renal diseases, including those causing AKI and the autoimmune proliferative and crescentic forms of GN, have cytokine mediation profiles that suggest they would be susceptible to cytokine-targeting therapeutic strategies.

Although Th17 responses may contribute to the pathogenesis of glomerulonephritis, whether the key transcription factor in Th17 cell development, RORγt, also promotes glomerulonephritis is unknown. Here, we induced crescentic glomerulonephritis in wild-type and RORγt-deficient (RORγt^−/−) mice. RORγt^−/− mice were protected from disease, with reduced histologic and functional injury and decreased leukocyte infiltration. Because RORγt^−/− mice lack lymph nodes, which may influence the development of nephritis, we performed cell-transfer studies. We reconstituted Rag1^−/− mice, which lack adaptive immunity but otherwise have normal architecture of the lymphatic system, with splenocytes from naïve wild-type or RORγt^−/− mice. Mice receiving wild-type splenocytes exhibited high mortality from renal failure after induction of nephritis whereas mice receiving RORγt^−/− cells were protected. To determine the effect of RORγt deficiency specifically in T helper cells, we isolated naïve CD4⁺ T cells from wild-type and RORγt^−/− mice and transferred them into Rag1^−/− animals. Recipients of wild-type CD4⁺ T cells developed severe glomerulonephritis whereas recipients of RORγt^−/− cells developed less severe disease. To exclude effects of altered regulatory T cell (Treg) development caused by RORγt deficiency, we transferred naïve CD4⁺ T cells depleted of Tregs into Rag1^−/− mice. Recipients of wild-type, Treg-depleted, CD4⁺ T cells developed severe glomerulonephritis whereas recipients of RORγt^−/−, Treg-depleted CD4⁺ T cells did not. Taken together, this study demonstrates that RORγt promotes the development of crescentic glomerulonephritis by directing nephritogenic Th17 responses.

In acute kidney injury, which is a significant cause of morbidity and mortality, cytokines and leukocytes promote inflammation and injury. We examined the pathogenic role of IL-17A in cisplatin-induced acute kidney injury. Intrarenal IL-17A mRNA transcription and protein expression were increased in wild-type mice after cisplatin-induced renal injury. An important role for IL-17A in the nephrotoxicity of cisplatin was demonstrated by observing protection from cisplatin-induced functional and histological renal injury in Il17a(-/-) and Rorγt(-/-) mice, as well as in mice treated pre-emptively with anti-IL-17A antibodies. Both renal injury and renal IL-1β and IL-17A production were attenuated in Asc(-/-) and Tlr2(-/-) mice, suggesting that cisplatin induces endogenous TLR2 ligand production and activates the ASC-dependent inflammasome complex, resulting in IL-1β and injurious IL-17A production. Neutrophils and natural killer cells are the likely targets of these pathways, because combined depletion of these cells was strongly protective; anti-IL-17A antibodies had no additional effect in this setting. Although IL-17A can also be produced by CD4(+) and γδ T cells, IL-17A from those cells does not contribute to renal injury. Cisplatin-induced injury was unchanged in γδ T-cell-deficient mice, whereas Il17a(-/-) CD4(+) T cells induced similar injury as did wild-type CD4(+) T cells on transfer to cisplatin-injected Rag1(-/-) mice. These studies demonstrate an important role for TLR2, the ASC inflammasome, and IL-17A in innate leukocytes in cisplatin-induced renal injury.