The Cytokine IL-17A Limits Th17 Pathogenicity via a Negative Feedback Loop Driven by Autocrine Induction of IL-24

Wai Po Chong, Mary J. Mattapallil, Kumarkrishna Raychaudhuri, So Jin Bing, Sihan Wu, Yajie Zhong, Wei Wei Wang, Zilin Chen, Phyllis B. Silver, Yingyos Jittayasothorn, Chi Chao Chan, Jun Chen, Reiko Horai, Rachel R. Caspi*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

102 Citations (Scopus)

Abstract

Dysregulated Th17 cell responses underlie multiple inflammatory and autoimmune diseases, including autoimmune uveitis and its animal model, EAU. However, clinical trials targeting IL-17A in uveitis were not successful. Here, we report that Th17 cells were regulated by their own signature cytokine, IL-17A. Loss of IL-17A in autopathogenic Th17 cells did not reduce their pathogenicity and instead elevated their expression of the Th17 cytokines GM-CSF and IL-17F. Mechanistic in vitro studies revealed a Th17 cell-intrinsic autocrine loop triggered by binding of IL-17A to its receptor, leading to activation of the transcription factor NF-κB and induction of IL-24, which repressed the Th17 cytokine program. In vivo, IL-24 treatment ameliorated Th17-induced EAU, whereas silencing of IL-24 in Th17 cells enhanced disease. This regulatory pathway also operated in human Th17 cells. Thus, IL-17A limits pathogenicity of Th17 cells by inducing IL-24. These findings may explain the disappointing therapeutic effect of targeting IL-17A in uveitis.
Original languageEnglish
Pages (from-to)384-397.e5
Number of pages19
JournalImmunity
Volume53
Issue number2
DOIs
Publication statusPublished - 18 Aug 2020

User-Defined Keywords

  • IL-17
  • IL-24
  • GM-CSF
  • Th17
  • experimental autoimmune uveitis
  • encephalomyelitis
  • neuroinflammation
  • secukinumab

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