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

Immunity
Wai Po ChongRachel R Caspi

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.

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Citations

Sep 30, 2020·Annals of the Rheumatic Diseases·Pankti MehtaAmita Aggarwal
Jan 1, 2021·The New England Journal of Medicine·John T Chang
Dec 22, 2020·Frontiers in Immunology·Verónica L BursteinLaura S Chiapello
Apr 7, 2021·The Journal of Experimental Medicine·Rami BecharaSarah L Gaffen
Jul 20, 2021·Frontiers in Immunology·Di WuRajeev Aurora
Oct 13, 2021·Trends in Immunology·Ritesh KumarK Venuprasad
Oct 7, 2021·International Immunology·Soo-Hyun ChungYoichiro Iwakura

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Datasets Mentioned

BETA
GM-CSF
GSE152534

Methods Mentioned

BETA
fluorescence-activated cell sorting
PCR
RNA-seq
ELISA
flow cytometry
immunoprecipitation
RNaseq
FCS
PMA
transfection

Software Mentioned

SAMtools
Integrative Genomics Viewer
EdgeR
SCS
FastQC
eXpress
Graphpad Prism
Bowtie2
TopHat2
Genomatix

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