Forward genetics and functional analysis highlight Itga11 as a modulator of murine psoriasiform dermatitis

Katja Bieber*, Siegfried Bezdek, Yask Gupta, Artem Vorobyev, Tanya Sezin, Natalie Gross, Jasper Prüssmann, Jean Paul Sayegh, Mareike Becker, Sadegh Mousavi, Ashref Hdnah, Sven Künzel, Saleh M. Ibrahim, Ralf J. Ludwig, Donald Gullberg, Christian D. Sadik

*Corresponding author for this work

Abstract

Psoriasis is a chronic inflammatory skin condition. Repeated epicutaneous application of Aldara® (imiquimod) cream results in psoriasiform dermatitis in mice. The Aldara®-induced psoriasiform dermatitis (AIPD) mouse model has been used to examine the pathogenesis of psoriasis. Here, we used a forward genetics approach in which we compared AIPD that developed in 13 different inbred mouse strains to identify genes and pathways that modulated disease severity. Among our primary results, we found that the severity of AIPD differed substantially between different strains of inbred mice and that these variations were associated with polymorphisms in Itga11. The Itga11 gene encodes the integrin α11 subunit that heterodimerizes with the integrin β1 subunit to form integrin α11β1. Less information is available about the function of ITGA11 in skin inflammation; however, a role in the regulation of cutaneous wound healing, specifically the development of dermal fibrosis, has been described. Experiments performed with Itga11 gene-deleted (Itga11−/−) mice revealed that the integrin α11 subunit contributes substantially to the clinical phenotype as well as the histopathological and molecular findings associated with skin inflammation characteristic of AIPD. Although the skin transcriptomes of Itga11−/− and WT mice do not differ from one another under physiological conditions, distinct transcriptomes emerge in these strains in response to the induction of AIPD. Most of the differentially expressed genes contributed to extracellular matrix organization, immune system, and metabolism of lipids pathways. Consistent with these findings, we detected a reduced number of fibroblasts and inflammatory cells, including macrophages, T cells, and tissue-resident memory T cells in skin samples from Itga11−/− mice in response to AIPD induction. Collectively, our results reveal that Itga11 plays a critical role in promoting skin inflammation in AIPD and thus might be targeted for the development of novel therapeutics for psoriasiform skin conditions.

Original languageEnglish
JournalJournal of Pathology
Volume261
Issue number2
Pages (from-to)184-197
Number of pages14
ISSN0022-3417
DOIs
Publication statusPublished - 10.2023

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)
  • Centers: Center for Research on Inflammation of the Skin (CRIS)

DFG Research Classification Scheme

  • 204-05 Immunology
  • 205-19 Dermatology
  • 205-22 Clinical Immunology and Allergology

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