Group 1 innate lymphoid cells are involved in the progression of experimental anti-glomerular basement membrane glomerulonephritis and are regulated by peroxisome proliferator-activated receptor α.

Abstract

Innate lymphoid cells play an important role in the early effector cytokine-mediated response. In Wistar Kyoto rats, CD8⁺ non-T lymphocytes (CD8⁺Lym) infiltrate into glomeruli during the development of anti-glomerular basement membrane (anti-GBM) glomerulonephritis. Here, we examined the profiles and roles of CD8⁺Lym in anti-GBM glomerulonephritis. The regulation of CD8⁺Lym by peroxisome proliferator-activated receptor (PPAR)-α in anti-GBM glomerulonephritis was also evaluated. Glomerular infiltrating CD8⁺Lym were lineage-negative cells that showed markedly high expression of IFN-γ and T-bet mRNAs but not Eomes, indicating these cells are group 1 innate lymphoid cells. In anti-GBM glomerulonephritis, the glomerular mRNAs of innate lymphoid cell-related cytokines (IFN-γ and TNF-α) and chemokines (CXCL9, CXCL10, and CXCL11) are significantly increased. Treatment with a PPARα agonist ameliorated renal injury, with reduced expression of these mRNAs. In vitro, enhanced IFN-γ production from innate lymphoid cells upon IL-12 and IL-18 stimulation was reduced by the PPARα agonist. Moreover, CXCL9 mRNA in glomerular endothelial cells and CXCL9, CXCL10, and CXCL11 mRNAs in podocytes and macrophages were upregulated by IFN-γ, whereas the PPARα agonist downregulated their expression. We also detected the infiltration of innate lymphoid cells into glomeruli in human anti-GBM glomerulonephritis. Thus, innate lymphoid cells are involved in the progression of anti-GBM glomerulonephritis and regulated directly or indirectly by PPARα. Our findings suggest that innate lymphoid cells could serve as novel therapeutic targets for anti-GBM glomerulonephritis.