Interleukin-17 Cytokines Are Critical in Development of Fatal Lupus Glomerulonephritis

Abstract

SUMMARY Systemic lupus erythematosus is a potentially fatal autoimmune disease. Although interleukin-17 (IL-17) has been linked to human lupus and mouse models of this disease, it has not been addressed whether this cytokine plays a critical role in fatal lupus pathology. Here we have demonstrated that increased production of IL-17 cytokines and their signaling via the adaptor protein CIKS (a.k.a. Traf3ip2, Act1) critically contributed to lethal pathology in an FcgammaR2b-deficient mouse model of lupus. Mice lacking IL-17 and especially those lacking CIKS showed greatly improved survival and were largely protected from development of glomerulonephritis. Importantly in this model, potential effects of IL-17 cytokines on antibody production could be distinguished from critical local contributions in kidneys, including recruitment of neutrophils and monocytes. These findings provide the proof of principle that signaling by IL-17 family cytokines mediated via CIKS presents promising therapeutic targets for the treatment of systemic lupus erythematosus, especially in cases with kidney involvement.

IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms

“…heterotypic SEFIR domain association (22,23). Consistent with a pathogenic role for IL-17 cytokines in various diseases, CIKS is critical for the development of collagen-induced arthritis, lupus, and asthma in mouse models (24)(25)(26).…”

“…C57BL/6NTac Traf3ip2 −/− (CIKS-KO) mice have been described (26); they were cohoused and experimentally matched with C57BL/6NTac Traf3ip2 +/+ (WT) mice. C57BL/6J Traf3ip2 flx/flx (WT) and C57BL/6J Traf3ip2 −/− mice also have been described (25); they were cohoused and experimentally matched with C57BL/6J mice in which CIKS was conditionally ablated in epithelial cells via K5-Cre (K5-cre; Traf3ip2 −/flx ) (i.e., CIKS K5-KO mice). CIKS K5-KO mice were generated by intercrosses with C57BL/6J K5-Cre transgenic mice (40), with K5-Cre transmission via male mice only; final crosses also yielded the following littermate controls which behaved similarly: Traf3ip2 flx/+ , Traf3ip2 flx/flx , Traf3ip2 −/+ , and Traf3ip2 −/fl .…”

FcγRIIIa-Syk Co-signal Modulates CD4+ T-cell Response and Up-regulates Toll-like Receptor (TLR) Expression

“…T H 17 responses are observed both in inflammation and in autoimmunity (20,28). IL-17 cytokines are necessary for the development of severe glomerulonephritis (29). Pathogenic T H 17 cell commitment has a unique requirement of IL-23 that is elevated in serum and tissue in SLE patients (30).…”

Absence of Interleukin‐17 Receptor A Signaling Prevents Autoimmune Inflammation of the Joint and Leads to a Th2‐like Phenotype in Collagen‐Induced Arthritis

“…Its primary role is in immune responses against extracellular pathogens (3,4). In addition, IL-17A has been implicated in several autoimmune diseases, including systemic lupus erythematosus, multiple sclerosis, psoriasis, and rheumatoid arthritis (5)(6)(7)(8)(9)(10)(11). Of the other family members, IL-17F is most similar to IL-17A, suggesting that they have similar functions (12,13).…”