Interleukin 17 signaling drives Type I Interferon induced proliferative crescentic glomerulonephritis in lupus-prone mice

Abstract

Crescentic glomerulonephritis (cGN) is a severe clinical manifestation in a subset of patients with Systemic lupus erythematosus. Lack of understanding of the pathogenesis of cGN act as a major constraint in treating these patients. Emerging evidence suggest a critical role of IL-17 in the pathogenesis of membranoproliferative glomerulonephritis in lupus. However, the role of IL-17 receptor (IL-17RA) signaling in cGN is unknown. Here, we developed a model of poly I:C-induced Type I Interferon (IFN-I)-dependent cGN in B6.MRL-Faslpr/J (B6.lpr) mice. B6.lpr mice deficient in IL-17RA were protected from IFN-I-dependent cGN. While systemic response was unabated, renal infiltration of alternatively activated macrophages was severely impaired in IL-17RA(-/-) mice. Finally, we show that IL-17 differentially regulates the expression of macrophage chemo-attractant genes in renal tubular epithelial cells and macrophages in association with IFN-I. These results suggest that neutralization IL-17 may confer better protection in SLE patients with high IFN-I gene signature and cGN.

Keywords: Crescentic glomerulonephritis; IL-17; Lupus; Systemic lupus erythematosus; Type I Interferon.