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

J Invest Dermatol. 2021 Oct;141(10):2436-2448. doi: 10.1016/j.jid.2021.03.019. Epub 2021 Apr 15.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation
  • Cells, Cultured
  • Dermatitis, Atopic / etiology
  • Epidermis / pathology*
  • Humans
  • Inflammation / etiology*
  • Interleukin-1 Receptor-Associated Kinases / physiology*
  • NF-kappa B / physiology
  • Psoriasis / etiology
  • Severity of Illness Index
  • Signal Transduction
  • Transcription Factors / physiology
  • Tumor Suppressor Proteins / physiology

Substances

  • NF-kappa B
  • Transcription Factors
  • Tumor Suppressor Proteins
  • ZNF750 protein, human
  • Interleukin-1 Receptor-Associated Kinases