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

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
JournalJournal of Investigative Dermatology
DOIs
StateAccepted/In press - 2021

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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