Unknown

Dataset Information

0

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


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-?B 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.

SUBMITTER: Chong WP 

PROVIDER: S-EPMC7362799 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

altmetric image

Publications


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 reveal  ...[more]

Similar Datasets

2020-07-22 | GSE152534 | GEO
| PRJNA639596 | ENA
| S-EPMC9280194 | biostudies-literature
| S-EPMC4302761 | biostudies-literature
| S-EPMC3916096 | biostudies-literature
| S-EPMC3818355 | biostudies-literature
| S-EPMC5350071 | biostudies-literature
| S-EPMC3533283 | biostudies-literature
| S-EPMC6393183 | biostudies-literature
| S-EPMC8394206 | biostudies-literature