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

Abstract

Summary 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.

Airway Microbiota-Host Interactions Regulate Secretory Leukocyte Protease Inhibitor Levels and Influence Allergic Airway Inflammation

“…Because anti-IL-17A treatment results in increased Bph titers, this worsened infection may offset the effects of IL-17A blockade by further stimulating a bacterial Th17 immune response, which is consistent with our observation that Th17 cells were not reduced in colonized mice treated with anti-IL-17A ( Figure 4I ). Alternatively, recent advances have shown that blocking IL-17A may lead to a compensatory upregulation of other Th17-related cytokines in some types of Th17 cells, which could also mitigate the effects of anti-IL-17A antibodies ( Chong et al, 2020 ). Together, our data support previously described protective roles for Th17 in blunting allergic effector responses ( Schnyder-Candrian et al, 2006 ) but additionally implicate immune responses to airway commensals as a potential source for this Th17 response.…”

Skin Immunity to Dermatophytes: From Experimental Infection Models to Human Disease

“…In the skin, fungal recognition by PRR on myeloid cells (DC, macrophages, neutrophils) and, probably, keratinocytes and fibroblasts trigger the production of cytokines like IL-23, IL-6, IL-1β, and IL-21 ( 51 , 53 , 90 ). Cytokine binding to its receptor on lymphocytes selectively triggers intracellular Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation, Retinoic-acid-receptor-related orphan nuclear receptor gamma (RORγt) transcription factor activation and, eventually, leads to the induction of Th17 lineage or the synthesis of type 17-cytokines (IL-17, GM-CSF, IL-22) ( 92 ). Noteworthily, IL-17A can also activate STAT3 in keratinocytes and amplify IL-6 production ( 80 ) ( Figure 2 ).…”

The role of interleukin-24 in atopic dermatitis

“…IL-17A upregulated IL-24 expression in normal human keratinocytes [15,36]. Chong et al [37] found that IL-17A induced IL-24 production in Th17 cells. Considering that IL-17A signals through the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway [38] and two potential NF-κB binding sites are present in the IL-24 gene, the researchers proposed that the binding of IL-17A to its receptor activates NF-κB signaling, leading to the transcription of IL-24 in Th17 cells [37].…”