IL-17C/IL-17 Receptor E Signaling in CD4+ T Cells Promotes TH17 Cell-Driven Glomerular Inflammation

Abstract

The IL-17 cytokine family and the cognate receptors thereof have a unique role in organ-specific autoimmunity. Most studies have focused on the founding member of the IL-17 family, IL-17A, as the central mediator of diseases. Indeed, although pathogenic functions have been ascribed to IL-17A and IL-17F in the context of immune-mediated glomerular diseases, the specific functions of the other IL-17 family members in immunity and inflammatory kidney diseases is largely unknown. Here, we report that compared with healthy controls, patients with acute Anti-neutrophil cytoplasmatic antibody (ANCA)-associated crescentic glomerulonephritis (GN) had significantly elevated serum levels of IL-17C (but not IL-17A, F, or E). In mouse models of crescentic GN (nephrotoxic nephritis) and pristane-induced lupus nephritis, deficiency in IL-17C significantly ameliorated the course of GN in terms of renal tissue injury and kidney function. Deficiency of the unique IL-17C receptor IL-17 receptor E (IL-17RE) provided similar protection against crescentic GN. These protective effects associated with a reduced T17 response. Bone marrow transplantation experiments revealed that IL-17C is produced by tissue-resident cells, but not by lymphocytes. Finally, IL-17RE was highly expressed by CD4 T17 cells, and loss of this expression prevented the T17 responses and subsequent tissue injury in crescentic GN. Our findings indicate that IL-17C promotes T17 cell responses and immune-mediated kidney disease IL-17RE expressed on CD4 T17 cells. Targeting the IL-17C/IL-17RE pathway may present an intriguing therapeutic strategy for T17-induced autoimmune disorders.

IL-17C/IL-17RE: Emergence of a Unique Axis in TH17 Biology

“…We showed the proinflammatory role of IL-17C in established mouse models for lupus nephritis and crescentic glomerulonephritis. In accordance with the mentioned previous studies, our experiments showed expression of Il17re by T H 17 cells and significantly less T H 17 cells in inflamed kidneys of both Il17c −/− and Il17re −/− mice (24).…”

“…Validating this finding, our group found strong Il17re expression IL-17A + YFP + cells from IL-17A YFP + fate reporter mice and in T H 17 polarized cells (compared to T H 0, T H 1, and Treg cells) (24). Similar to IL17C, we reported that Il17re was upregulated 24 h after induction of NTN (24).…”

“…This expression is strongly enhanced when the cells are stimulated with a cytokine cocktail of IL-6, TGF-β, IL-1, and IL-23 and IL-17C also induced expression of the receptor on T H 17 cells (40). Validating this finding, our group found strong Il17re expression IL-17A + YFP + cells from IL-17A YFP + fate reporter mice and in T H 17 polarized cells (compared to T H 0, T H 1, and Treg cells) (24). Similar to IL17C, we reported that Il17re was upregulated 24 h after induction of NTN (24).…”

“…Several groups confirmed this IL17C expression in keratinocytes (20)(21)(22)(23). Other epithelial cells producing the cytokine include colonic epithelial cells (9), resident kidney cells (24,25), and respiratory epithelial cells (26)(27)(28).…”

“…In the DSS-colitis model, the authors found induction of Il17c expression after 2 days in colons and mesenteric lymph nodes, but upregulation of I17a and Il17f mRNA transcripts was not detected before day 6 (19). In the nephrotoxic nephritis (NTN) mouse model for crescentic glomerulonephritis, we showed that Il17c is upregulated as early as 12 h after induction of the disease, while Il17a and Il17f expression starts after a couple of days (24).…”