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.
N1 - Funding Information:
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.
Publisher Copyright:
© 2021 The Authors
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 -