Erythropoietin inhibits SGK1-dependent Th17 cell induction and Th17 cell- dependent kidney disease

被引:27
|
作者
Donadei, Chiara [1 ,2 ]
Angeletti, Andrea [1 ,2 ]
Cantarelli, Chiara [1 ,3 ]
D'Agati, Vivette D. [4 ]
La Manna, Gaetano [2 ]
Fiaccadori, Enrico [3 ]
Horwitz, Julian K. [1 ]
Xiong, Huabao [1 ]
Guglielmo, Chiara [1 ]
Hartzell, Susan [1 ]
Madsen, Joren C. [5 ,6 ]
Maggiore, Umberto [3 ]
Heeger, Peter S. [1 ]
Cravedi, Paolo [1 ]
机构
[1] Icahn Sch Med Mt Sinai, Dept Med, Precis Inst Immunol, Translat Transplant Res Ctr, New York, NY 10029 USA
[2] S Orsola Univ Hosp, Nephrol Dialysis & Renal Transplantat Unit, Bologna, Italy
[3] Univ Parma, UO Nefrol, Dipartimento Med & Chirurg, Azienda Osped, Parma, Italy
[4] Columbia Univ, Coll Phys & Surg, Dept Pathol, New York, NY USA
[5] Massachusetts Gen Hosp, Ctr Transplantat Sci, Boston, MA 02114 USA
[6] Massachusetts Gen Hosp, Dept Surg, Div Cardiac Surg, Boston, MA 02114 USA
基金
美国国家卫生研究院;
关键词
SYSTEMIC-LUPUS-ERYTHEMATOSUS; ARISTOLOCHIC ACID NEPHROPATHY; T-REG-CELLS; ANEMIA; PROGRESSION; RECEPTOR; AUTOANTIBODIES; ACTIVATION; GENERATION; TOLERANCE;
D O I
10.1172/jci.insight.127428
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 SCK1 phosphorylation, thereby inhibiting RORC-mediated transcription of IL17and 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.
引用
收藏
页数:19
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