ACT1 Is Required for Murine IL-23-Induced Psoriasiform Inflammation Potentially Independent of E3 Ligase Activity

J Invest Dermatol. 2021 Jul;141(7):1772-1779.e6. doi: 10.1016/j.jid.2020.10.029. Epub 2021 Feb 4.

Abstract

Psoriasis is a debilitating skin disease characterized by epidermal thickening, abnormal keratinocyte differentiation, and proinflammatory immune cell infiltrate into the affected skin. IL-17A plays a critical role in the etiology of psoriasis. ACT1, an intracellular adaptor protein and a putative ubiquitin E3 ligase, is essential for signal transduction downstream of the IL-17A receptor. Thus, IL-17A signaling in general, and ACT1 specifically, represent attractive targets for the treatment of psoriasis. We generated Act1 knockout and Act1 L286G knockin (ligase domain) mice to investigate the potential therapeutic effects of targeting ACT1 and its U-box domain, respectively. Act1 knockout, but not Act1 L286G knockin, mice were resistant to increases in CXCL1 plasma levels induced by subcutaneous injection of recombinant IL-17A. Moreover, in a mouse model of psoriasiform dermatitis induced by intradermal IL-23 injection, Act1 knockout, but not Act1 L286G knockin, was protective against increases in ear thickness, keratinocyte hyperproliferation, expression of genes for antimicrobial peptides and chemokines, and infiltration of monocytes and macrophages. Our studies highlight the critical contribution of ACT1 to proinflammatory skin changes mediated by the IL-23/IL-17 signaling axis and illustrate the need for further insight into ACT1 E3 ligase activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Chemokine CXCL1 / metabolism
  • Disease Models, Animal
  • Female
  • Gene Knock-In Techniques
  • Humans
  • Interleukin-17 / administration & dosage
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism
  • Interleukin-23 / administration & dosage
  • Interleukin-23 / immunology*
  • Interleukin-23 / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Psoriasis / immunology*
  • Psoriasis / pathology
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / immunology
  • Recombinant Proteins / metabolism
  • Signal Transduction / immunology
  • Skin / immunology
  • Skin / pathology

Substances

  • Adaptor Proteins, Signal Transducing
  • Chemokine CXCL1
  • Cxcl1 protein, mouse
  • Il17a protein, mouse
  • Interleukin-17
  • Interleukin-23
  • Recombinant Proteins
  • Traf3ip2 protein, mouse