Immunology of the eye

Thematic

IL-17A Dampens Autoimmune Disease by Inhibiting the Expression of IL-17 Lineage Cytokines through a Negative Feedback Loop Involving IL-24

Saturday, June 17
1:25 PM - 1:40 PM

The Th17 response has been associated with autoimmune diseases in patients and in animal models, including autoimmune uveitis and its experimental counterpart, EAU. Paradoxically, however, IL-17A treatment given to EAU-challenged mice was reported to ameliorate the disease (PMID: 19234216) and clinical trials targeting IL-17A in uveitis have been largely disappointing (PMID: 25648267). Here, we investigated susceptibility to uveitis of spontaneously uveitic R161H mice (IRBP T cell receptor transgenic, PMID: 23810578) crossed onto the IL-17A-/- background. Surprisingly, IL-17A-/- R161H mice developed essentially undiminished uveitis. Moreover, IL-17A-/- R161H T cells, polarized to Th17 and infused into wild type recipients, induced similar disease to IL-17A-sufficient R161H T cells. These Th17-polarized IL-17A-/- R161H T cells produced elevated amounts of other Th17 lineage cytokines, namely, IL-17F, GM-CSF and IL-22, and this was reversed by supplementing the cultures with recombinant IL-17A. RNAseq analysis revealed that the IL-17A-/- T cells expressed lower levels of IL-24 compared to their IL-17A sufficient counterparts. Mechanistic studies in vitro indicated a negative feedback loop where IL-17A induces Th17 cells to produce IL-24, which subsequently suppresses production of Th17 lineage cytokines. Studies in vivo showed that injection of recombinant IL-24 ameliorated adoptive Th17-induced EAU, and conversely, silencing IL-24 expression in the adoptively transferred Th17 cells increased their pathogenicity and enhanced disease severity. Our data suggest that IL-17A exerts a negative feedback on Th17 cells by inducing IL-24, which limits the expression of Th17-related cytokines and dampens Th17 effector pathogenicity.

Wai Po Chong

NIE/NIH, Bethesda, MD, USA and ZOC, Guangzhou, China

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Kumarkrishna Raychoudhuri

NEI/NIH , Bethesda, MD, USA

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Reiko Horai

NIE/NIH, Bethesda, MD, USA

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Phyllis B. Silver

NIE/NIH, Bethesda, MD, USA

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Yingyos Jittayasothorn

NIE/NIH, Bethesda, MD, USA

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Chi Chao Chan

NIE/NIH, Bethesda, MD, USA

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Jun Chen

NIE/NIH, Bethesda, MD, USA and ZOC, Guangzhou, China

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Rachel R. Caspi

NIE/NIH, Bethesda, MD, USA

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IL-17A Dampens Autoimmune Disease by Inhibiting the Expression of IL-17 Lineage Cytokines through a Negative Feedback Loop Involving IL-24



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