Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Erythropoietin inhibits SGK1-dependent Th17 cell induction and Th17 cell–dependent kidney disease
Chiara Donadei, … , Peter S. Heeger, Paolo Cravedi
Chiara Donadei, … , Peter S. Heeger, Paolo Cravedi
Published April 23, 2019
Citation Information: JCI Insight. 2019;4(10):e127428. https://doi.org/10.1172/jci.insight.127428.
View: Text | PDF
Research Article Immunology Nephrology

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

  • Text
  • PDF
Abstract

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.

Authors

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

×

Figure 1

EPO inhibits Th17 cell induction in vitro.

Options: View larger image (or click on image) Download as PowerPoint
EPO inhibits Th17 cell induction in vitro.
Enriched human naive CD4+ T c...
Enriched human naive CD4+ T cells were cultured in the presence of Th17 cell–polarizing conditions (see Methods) in control media or in media with 20–40 mM NaCl or 40–80 mM urea added in the presence of EPO (1000 IU/ml) or vehicle control. (A) RORC and (B) IL17 gene expression (n = 3 donors) after 24 hours of culture. *P < 0.05, paired t test. (C) Representative plots and (D) normalized data quantification of IL-17+CD4+ Th17 cells after 5 days of culture (5 experiments from 7 different donors). (E) Quantification of annexin V staining (normalized to vehicle controls) of the cultures in C and D. Naive CD44loCD62LhiCD4+ T cells were enriched through negative magnetic isolation from EPO-Rfl/flCD4-Cre+ mice and Cre– controls and were cultured in Th17 cell–polarizing conditions. (F) Representative plots and (G) data quantification of IL-17+ cells after 5 days of culture (n = 6 mice per group). *P < 0.05 vs. vehicle; #P < 0.05 vs. media (no NaCl or urea), paired t test or 2-way ANOVA with Tukey test. Data represent mean ± SEM.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts