Erythropoietin inhibits SGK1-dependent TH17 induction and TH17-dependent kidney disease.
IL-17-producing CD4+ cells (TH17) are pathogenically linked to autoimmunity including to autoimmune kidney disease. Erythropoietin's (EPO) newly recognized immunoregulatory functions and its predominant intra-renal source suggested that EPO physiologically regulates TH17 differentiation, thereby serving as a barrier to the 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 generation and promotes trans-differentiation of TH17 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 IL-17 and IL-23 receptor genes. In a murine model of TH17-dependent aristolochic acid (ArA)-induced, interstitial kidney disease associated with reduced renal EPO production, we demonstrate that transgenic EPO overexpression or recombinant EPO (rEPO) administration limits TH17 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 induction and clinical/histological expression of pristane-induced glomerulonephritis (associated with decreased intrarenal EPO). rEPO prevents spontaneous glomerulonephritis and TH17 generation in MRL-lpr mice. Together, our findings indicate that EPO physiologically and therapeutically modulate TH17 cells to limit expression of TH17-associated autoimmune kidney disease.
['Donadei|Chiara|C|', 'Angeletti|Andrea|A|', 'Cantarelli|Chiara|C|', "D'Agati|Vivette D|VD|", 'La Manna|Gaetano|G|', 'Fiaccadori|Enrico|E|', 'Horwitz|Julian K|JK|', 'Xiong|Huabao|H|', 'Guglielmo|Chiara|C|', 'Hartzell|Susan|S|', 'Madsen|Joren C|JC|', 'Maggiore|Umberto|U|', 'Heeger|Peter S|PS|', 'Cravedi|Paolo|P|']
D000818:Animals D034341:Aristolochic Acids D002478:Cells, Cultured D004195:Disease Models, Animal D000068817:Epoetin Alfa D004921:Erythropoietin D005260:Female D006801:Humans D017874:Immediate-Early Proteins D020381:Interleukin-17 D008181:Lupus Nephritis D008297:Male D051379:Mice D019463:Mice, Inbred MRL lpr D008822:Mice, Transgenic D009395:Nephritis, Interstitial D010766:Phosphorylation D061251:Primary Cell Culture D017346:Protein Serine-Threonine Kinases D017467:Receptors, Erythropoietin D018123:Receptors, Interleukin D012720:Severity of Illness Index D050378:T-Lymphocytes, Regulatory D058504:Th17 Cells
T cells Adaptive immunity Immunology Nephrology Tolerance