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

Wai Po Chong; Mary J. Mattapallil; Kumarkrishna Raychaudhuri; So Jin Bing; Sihan Wu; Yajie Zhong; Wei Wei Wang; Zilin Chen; Phyllis B. Silver; Yingyos Jittayasothorn; Chi Chao Chan; Jun Chen; Reiko Horai; Rachel R. Caspi

doi:10.1016/j.immuni.2020.06.022

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

Wai Po Chong, Mary J. Mattapallil, Kumarkrishna Raychaudhuri, So Jin Bing, Sihan Wu, Yajie Zhong, Wei Wei Wang, Zilin Chen, Phyllis B. Silver, Yingyos Jittayasothorn, Chi Chao Chan, Jun Chen, Reiko Horai, Rachel R. Caspi^*

^*Corresponding author for this work

Chinese Medicine - Teaching and Research Division

Research output: Contribution to journal › Journal article › peer-review

116 Citations (Scopus)

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.

Original language	English
Pages (from-to)	384-397.e5
Number of pages	19
Journal	Immunity
Volume	53
Issue number	2
DOIs	https://doi.org/10.1016/j.immuni.2020.06.022
Publication status	Published - 18 Aug 2020

User-Defined Keywords

IL-17
IL-24
GM-CSF
Th17
experimental autoimmune uveitis
encephalomyelitis
neuroinflammation
secukinumab

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.immuni.2020.06.022

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Chong, W. P., Mattapallil, M. J., Raychaudhuri, K., Bing, S. J., Wu, S., Zhong, Y., Wang, W. W., Chen, Z., Silver, P. B., Jittayasothorn, Y., Chan, C. C., Chen, J., Horai, R., & Caspi, R. R. (2020). The Cytokine IL-17A Limits Th17 Pathogenicity via a Negative Feedback Loop Driven by Autocrine Induction of IL-24. Immunity, 53(2), 384-397.e5. https://doi.org/10.1016/j.immuni.2020.06.022

@article{0bea3f4483a647639e53502c575c7c3f,

title = "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-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.",

keywords = "IL-17, IL-24, GM-CSF, Th17, experimental autoimmune uveitis, encephalomyelitis, neuroinflammation, secukinumab",

author = "Chong, {Wai Po} and Mattapallil, {Mary J.} and Kumarkrishna Raychaudhuri and Bing, {So Jin} and Sihan Wu and Yajie Zhong and Wang, {Wei Wei} and Zilin Chen and Silver, {Phyllis B.} and Yingyos Jittayasothorn and Chan, {Chi Chao} and Jun Chen and Reiko Horai and Caspi, {Rachel R.}",

note = "Funding information: We thank Dr. Yoichiro Iwakura for Il17a−/−, Il17f−/−, and Il17a−/− Il17f−/− mice and Dr. Renee de Waal Malefyt of Merck (formerly DNAX) for his gift of Il24−/− mice. We are grateful to Matthew Brooks, BS, of N-NRL, NEI, for performing RNA-seq. We thank the staff of the Zhongshan Ophthalmic Center Flow Cytometry Core and the NEI Flow Cytometry Core for flow cytometry support. This study was funded by NIH/National Eye Institute (NEI) intramural funding (project number EY000184); the Fundamental Research Funds of the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center; and the Natural Science Foundation of Guangdong Province (grants 201604020082, 2017A030313836, 2018A030313877 and 2019A1515010956). Publisher copyright: Published by Elsevier Inc.",

year = "2020",

month = aug,

day = "18",

doi = "10.1016/j.immuni.2020.06.022",

language = "English",

volume = "53",

pages = "384--397.e5",

journal = "Immunity",

issn = "1074-7613",

publisher = "Cell Press",

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}

Chong, WP, Mattapallil, MJ, Raychaudhuri, K, Bing, SJ, Wu, S, Zhong, Y, Wang, WW, Chen, Z, Silver, PB, Jittayasothorn, Y, Chan, CC, Chen, J, Horai, R & Caspi, RR 2020, 'The Cytokine IL-17A Limits Th17 Pathogenicity via a Negative Feedback Loop Driven by Autocrine Induction of IL-24', Immunity, vol. 53, no. 2, pp. 384-397.e5. https://doi.org/10.1016/j.immuni.2020.06.022

TY - JOUR

T1 - The Cytokine IL-17A Limits Th17 Pathogenicity via a Negative Feedback Loop Driven by Autocrine Induction of IL-24

AU - Chong, Wai Po

AU - Mattapallil, Mary J.

AU - Raychaudhuri, Kumarkrishna

AU - Bing, So Jin

AU - Wu, Sihan

AU - Zhong, Yajie

AU - Wang, Wei Wei

AU - Chen, Zilin

AU - Silver, Phyllis B.

AU - Jittayasothorn, Yingyos

AU - Chan, Chi Chao

AU - Chen, Jun

AU - Horai, Reiko

AU - Caspi, Rachel R.

N1 - Funding information: We thank Dr. Yoichiro Iwakura for Il17a−/−, Il17f−/−, and Il17a−/− Il17f−/− mice and Dr. Renee de Waal Malefyt of Merck (formerly DNAX) for his gift of Il24−/− mice. We are grateful to Matthew Brooks, BS, of N-NRL, NEI, for performing RNA-seq. We thank the staff of the Zhongshan Ophthalmic Center Flow Cytometry Core and the NEI Flow Cytometry Core for flow cytometry support. This study was funded by NIH/National Eye Institute (NEI) intramural funding (project number EY000184); the Fundamental Research Funds of the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center; and the Natural Science Foundation of Guangdong Province (grants 201604020082, 2017A030313836, 2018A030313877 and 2019A1515010956). Publisher copyright: Published by Elsevier Inc.

PY - 2020/8/18

Y1 - 2020/8/18

N2 - 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.

AB - 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.

KW - IL-17

KW - IL-24

KW - GM-CSF

KW - Th17

KW - experimental autoimmune uveitis

KW - encephalomyelitis

KW - neuroinflammation

KW - secukinumab

UR - https://www.scopus.com/inward/record.uri?eid=2-s2.0-85089097954&doi=10.1016%2fj.immuni.2020.06.022&partnerID=40&md5=bef111fc95ab694390d3cabeae04fab2

U2 - 10.1016/j.immuni.2020.06.022

DO - 10.1016/j.immuni.2020.06.022

M3 - Journal article

SN - 1074-7613

VL - 53

SP - 384-397.e5

JO - Immunity

JF - Immunity

IS - 2

ER -

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

Abstract

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