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

• Published in: Immunity (Cambridge, Mass.) Vol. 53; no. 2; pp. 384 - 397.e5
• Main Authors: Chong, Wai Po, Mattapallil, Mary J., Raychaudhuri, Kumarkrishna, Bing, So Jin, Wu, Sihan, Zhong, Yajie, Wang, WeiWei, Chen, Zilin, Silver, Phyllis B., Jittayasothorn, Yingyos, Chan, Chi-Chao, Chen, Jun, Horai, Reiko, Caspi, Rachel R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.08.2020; Elsevier Limited; Cell Press
• Subjects: Adult; Animal models; Animals; Antigens; Autocrine signalling; Autoimmune diseases; Clinical trials; Cytokines; Cytokines - genetics; Cytokines - metabolism; Disease; Disease Models, Animal; encephalomyelitis; experimental autoimmune uveitis; Experimental autoimmune uveoretinitis; Feedback; Feedback loops; Female; GM-CSF; Granulocyte-macrophage colony-stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Helper cells; Humans; IL-17; IL-24; Interleukin 24; Interleukin-17 - genetics; Interleukin-17 - metabolism; Lymphocytes; Lymphocytes T; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Monoclonal antibodies; Multiple sclerosis; Negative feedback; neuroinflammation; NF-kappa B - metabolism; NF-κB protein; Pathogenicity; Pathogens; Retina; Rheumatoid arthritis; secukinumab; T cell receptors; Th17; Th17 Cells - immunology; Th17 Cells - pathology; Transcription activation; Uveitis; Uveitis - immunology; Uveitis - pathology; Young Adult; encephalomyelitis; experimental autoimmune uveitis; GM-CSF; neuroinflammation; IL-17; secukinumab; IL-24; Th17
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2020.06.022

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. [Display omitted] •IL-17A deficiency does not reduce the pathogenicity of Th17 cells in uveitis•IL-17A binds to its own receptor on Th17 cells, activating NF-κB•NF-κB induces IL-24 production, repressing the Th17 cytokine program through SOCS1/3•Silencing or depleting IL-24 in Th17 cells exacerbates neuroinflammation Loss of IL-17A, the signature cytokine of autoreactive Th17 cells, unexpectedly did not diminish the pathogenicity of Th17 cells in neuroinflammatory disease. This report demonstrates that IL-17A represses the Th17 cytokine program, primarily IL-17F and GM-CSF, by inducing autocrine production of IL-24. Thus, IL-17A has a dual role in Th17 cells: pathogenic as well as regulatory.