IRAK2 Has a Critical Role in Promoting Feed-Forward Amplification of Epidermal Inflammatory Responses

Shuai Shao; Lam C. Tsoi; William R. Swindell; Jiaoling Chen; Ranjitha Uppala; Allison C. Billi; Xianying Xing; Chang Zeng; Mrinal K. Sarkar; Rachael Wasikowski; Yanyun Jiang; Joseph Kirma; Jingru Sun; Olesya Plazyo; Gang Wang; Paul W. Harms; John J. Voorhees; Nicole L. Ward; Feiyang Ma; Matteo Pellegrini; Alexander Merleev; Bethany E. Perez White; Robert L. Modlin; Bogi Andersen; Emanual Maverakis; Stephan Weidinger; J. Michelle Kahlenberg; Johann E. Gudjonsson

doi:10.1016/j.jid.2021.03.019

IRAK2 Has a Critical Role in Promoting Feed-Forward Amplification of Epidermal Inflammatory Responses

Shuai Shao, Lam C. Tsoi, William R. Swindell, Jiaoling Chen, Ranjitha Uppala, Allison C. Billi, Xianying Xing, Chang Zeng, Mrinal K. Sarkar, Rachael Wasikowski, Yanyun Jiang, Joseph Kirma, Jingru Sun, Olesya Plazyo, Gang Wang, Paul W. Harms, John J. Voorhees, Nicole L. Ward, Feiyang Ma, Matteo PellegriniAlexander Merleev, Bethany E. Perez White, Robert L. Modlin, Bogi Andersen, Emanual Maverakis, Stephan Weidinger, J. Michelle Kahlenberg, Johann E. Gudjonsson^*

^*Corresponding author for this work

Dermatology

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Many inflammatory skin diseases are characterized by altered epidermal differentiation. Whether this altered differentiation promotes inflammatory responses has been unknown. Here, we show that IRAK2, a member of the signaling complex downstream of IL-1 and IL-36, correlates positively with disease severity in both atopic dermatitis and psoriasis. Inhibition of epidermal IRAK2 normalizes differentiation and inflammation in two mouse models of psoriasis- and atopic dermatitis-like inflammation. Specifically, we demonstrate that IRAK2 ties together proinflammatory and differentiation-dependent responses and show that this function of IRAK2 is specific to keratinocytes and acts through the differentiation-associated transcription factor ZNF750. Taken together, our findings suggest that IRAK2 has a critical role in promoting feed-forward amplification of inflammatory responses in skin through modulation of differentiation pathways and inflammatory responses.

Original language	English (US)
Pages (from-to)	2436-2448
Number of pages	13
Journal	Journal of Investigative Dermatology
Volume	141
Issue number	10
DOIs	https://doi.org/10.1016/j.jid.2021.03.019
State	Published - Oct 2021

Funding

This work was supported by NIH P30 AR075043 (JEG), NIH RO1 AR069071 (JEG), an National Psoriasis Foundation Psoriasis Prevention Initiative award (JEG, JMK, NLW, EM, LCT), the Taubman Institute Innovation Project program (JEG and JMK), the Babcock Endowment Fund (LCT, MKS, JEG), the National Institute of Arthritis and Musculoskeletal and Skin Diseases AR060802 (JEG) and AR072129 (LCT), National Psoriasis Foundation Translational Grant (MKS), National Institute of Allergy and Infectious Diseases under Award Number R01-AR06 (JEG), and the Parfet Emerging Scholar Award (JMK). LCT is supported by the Dermatology Foundation, Arthritis National Research Foundation , and National Psoriasis Foundation.

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Dermatology
Cell Biology

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Shao, S., Tsoi, L. C., Swindell, W. R., Chen, J., Uppala, R., Billi, A. C., Xing, X., Zeng, C., Sarkar, M. K., Wasikowski, R., Jiang, Y., Kirma, J., Sun, J., Plazyo, O., Wang, G., Harms, P. W., Voorhees, J. J., Ward, N. L., Ma, F., ... Gudjonsson, J. E. (2021). IRAK2 Has a Critical Role in Promoting Feed-Forward Amplification of Epidermal Inflammatory Responses. Journal of Investigative Dermatology, 141(10), 2436-2448. https://doi.org/10.1016/j.jid.2021.03.019

@article{b0da4595b5a54d379798a6750746d83d,

title = "IRAK2 Has a Critical Role in Promoting Feed-Forward Amplification of Epidermal Inflammatory Responses",

abstract = "Many inflammatory skin diseases are characterized by altered epidermal differentiation. Whether this altered differentiation promotes inflammatory responses has been unknown. Here, we show that IRAK2, a member of the signaling complex downstream of IL-1 and IL-36, correlates positively with disease severity in both atopic dermatitis and psoriasis. Inhibition of epidermal IRAK2 normalizes differentiation and inflammation in two mouse models of psoriasis- and atopic dermatitis-like inflammation. Specifically, we demonstrate that IRAK2 ties together proinflammatory and differentiation-dependent responses and show that this function of IRAK2 is specific to keratinocytes and acts through the differentiation-associated transcription factor ZNF750. Taken together, our findings suggest that IRAK2 has a critical role in promoting feed-forward amplification of inflammatory responses in skin through modulation of differentiation pathways and inflammatory responses.",

author = "Shuai Shao and Tsoi, {Lam C.} and Swindell, {William R.} and Jiaoling Chen and Ranjitha Uppala and Billi, {Allison C.} and Xianying Xing and Chang Zeng and Sarkar, {Mrinal K.} and Rachael Wasikowski and Yanyun Jiang and Joseph Kirma and Jingru Sun and Olesya Plazyo and Gang Wang and Harms, {Paul W.} and Voorhees, {John J.} and Ward, {Nicole L.} and Feiyang Ma and Matteo Pellegrini and Alexander Merleev and {Perez White}, {Bethany E.} and Modlin, {Robert L.} and Bogi Andersen and Emanual Maverakis and Stephan Weidinger and Kahlenberg, {J. Michelle} and Gudjonsson, {Johann E.}",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = oct,

doi = "10.1016/j.jid.2021.03.019",

language = "English (US)",

volume = "141",

pages = "2436--2448",

journal = "Journal of Investigative Dermatology",

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Shao, S, Tsoi, LC, Swindell, WR, Chen, J, Uppala, R, Billi, AC, Xing, X, Zeng, C, Sarkar, MK, Wasikowski, R, Jiang, Y, Kirma, J, Sun, J, Plazyo, O, Wang, G, Harms, PW, Voorhees, JJ, Ward, NL, Ma, F, Pellegrini, M, Merleev, A, Perez White, BE, Modlin, RL, Andersen, B, Maverakis, E, Weidinger, S, Kahlenberg, JM & Gudjonsson, JE 2021, 'IRAK2 Has a Critical Role in Promoting Feed-Forward Amplification of Epidermal Inflammatory Responses', Journal of Investigative Dermatology, vol. 141, no. 10, pp. 2436-2448. https://doi.org/10.1016/j.jid.2021.03.019

TY - JOUR

T1 - IRAK2 Has a Critical Role in Promoting Feed-Forward Amplification of Epidermal Inflammatory Responses

AU - Shao, Shuai

AU - Tsoi, Lam C.

AU - Swindell, William R.

AU - Chen, Jiaoling

AU - Uppala, Ranjitha

AU - Billi, Allison C.

AU - Xing, Xianying

AU - Zeng, Chang

AU - Sarkar, Mrinal K.

AU - Wasikowski, Rachael

AU - Jiang, Yanyun

AU - Kirma, Joseph

AU - Sun, Jingru

AU - Plazyo, Olesya

AU - Wang, Gang

AU - Harms, Paul W.

AU - Voorhees, John J.

AU - Ward, Nicole L.

AU - Ma, Feiyang

AU - Pellegrini, Matteo

AU - Merleev, Alexander

AU - Perez White, Bethany E.

AU - Modlin, Robert L.

AU - Andersen, Bogi

AU - Maverakis, Emanual

AU - Weidinger, Stephan

AU - Kahlenberg, J. Michelle

AU - Gudjonsson, Johann E.

PY - 2021/10

Y1 - 2021/10

N2 - Many inflammatory skin diseases are characterized by altered epidermal differentiation. Whether this altered differentiation promotes inflammatory responses has been unknown. Here, we show that IRAK2, a member of the signaling complex downstream of IL-1 and IL-36, correlates positively with disease severity in both atopic dermatitis and psoriasis. Inhibition of epidermal IRAK2 normalizes differentiation and inflammation in two mouse models of psoriasis- and atopic dermatitis-like inflammation. Specifically, we demonstrate that IRAK2 ties together proinflammatory and differentiation-dependent responses and show that this function of IRAK2 is specific to keratinocytes and acts through the differentiation-associated transcription factor ZNF750. Taken together, our findings suggest that IRAK2 has a critical role in promoting feed-forward amplification of inflammatory responses in skin through modulation of differentiation pathways and inflammatory responses.

AB - Many inflammatory skin diseases are characterized by altered epidermal differentiation. Whether this altered differentiation promotes inflammatory responses has been unknown. Here, we show that IRAK2, a member of the signaling complex downstream of IL-1 and IL-36, correlates positively with disease severity in both atopic dermatitis and psoriasis. Inhibition of epidermal IRAK2 normalizes differentiation and inflammation in two mouse models of psoriasis- and atopic dermatitis-like inflammation. Specifically, we demonstrate that IRAK2 ties together proinflammatory and differentiation-dependent responses and show that this function of IRAK2 is specific to keratinocytes and acts through the differentiation-associated transcription factor ZNF750. Taken together, our findings suggest that IRAK2 has a critical role in promoting feed-forward amplification of inflammatory responses in skin through modulation of differentiation pathways and inflammatory responses.

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U2 - 10.1016/j.jid.2021.03.019

DO - 10.1016/j.jid.2021.03.019

M3 - Article

C2 - 33864770

AN - SCOPUS:85105447387

SN - 0022-202X

VL - 141

SP - 2436

EP - 2448

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

IS - 10

ER -

IRAK2 Has a Critical Role in Promoting Feed-Forward Amplification of Epidermal Inflammatory Responses

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