IL-17–producing CD4+ (Th17) cells are pathogenically linked to autoimmunity and, specifically, to autoimmune kidney disease. The newly recognized immunoregulatory functions of erythropoietin (EPO) and its predominant intrarenal source suggested that EPO physiologically regulates Th17 cell differentiation, thereby serving as a barrier to development of autoimmune kidney disease. Using in vitro studies of human and murine cells and in vivo models, we show that EPO ligation of its receptor (EPO-R) on CD4+ T cells directly inhibits Th17 cell generation and promotes transdifferentiation of Th17 cells into IL-17–FOXP3+CD4+ T cells. Mechanistically, EPO/EPO-R ligation abrogates upregulation of SGK1 gene expression and blocks p38 activity to prevent SGK1 phosphorylation, thereby inhibiting RORC-mediated transcription of IL17 and IL23 receptor genes. In a murine model of Th17 cell–dependent aristolochic acid–induced interstitial kidney disease associated with reduced renal EPO production, we demonstrate that transgenic EPO overexpression or recombinant EPO (rEPO) administration limits Th17 cell formation and clinical/histological disease expression. EPO/EPO-R ligations on CD4+ T cells abrogate, while absence of T cell–expressed EPO-R augments, Th17 cell induction and clinical/histological expression of pristane-induced glomerulonephritis (associated with decreased intrarenal EPO). rEPO prevents spontaneous glomerulonephritis and Th17 cell generation in MRL-lpr mice. Together, our findings indicate that EPO physiologically and therapeutically modulates Th17 cells to limit expression of Th17 cell–associated autoimmune kidney disease.
Chiara Donadei, Andrea Angeletti, Chiara Cantarelli, Vivette D. D’Agati, Gaetano La Manna, Enrico Fiaccadori, Julian K. Horwitz, Huabao Xiong, Chiara Guglielmo, Susan Hartzell, Joren C. Madsen, Umberto Maggiore, Peter S. Heeger, Paolo Cravedi