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. 2025 Aug 1;214(8):2029-2040.
doi: 10.1093/jimmun/vkaf069.

Butyrate receptor HCAR2/GPR109A controls imiquimod-induced psoriasis-like skin inflammation

Lucija Leko  1 , Darija Šimić  1 , Timna Valera Martins  2   3 , Gabriel Victor Lucena da Silva  2   3 , Isabelle Maillet  1 , Florence Savigny  1 , Lara Vuksan  1 , Dorian de Moura Rodrigues  1 , Marc Le Bert  1 , Stefan Offermanns  4   5 , Nicolas Riteau  1   6 , Dieudonnée Togbe  1 , Valerie F Quesniaux  1 , Remo Castro Russo  7 , José Carlos Alves-Filho  2   3   6 , Bernhard Ryffel  1
Affiliations

Butyrate receptor HCAR2/GPR109A controls imiquimod-induced psoriasis-like skin inflammation

Lucija Leko et al. J Immunol. .

Abstract

Psoriasis is a chronic inflammatory skin disorder characterized by aberrant keratinocyte proliferation and immune cell infiltration with upregulation of inflammatory cytokines. Here, we examined the contribution of HCAR2 encoding for the short-chain fatty acid receptor GPR109A. Human and mouse RNA sequencing public datasets reveal elevated HCAR2 gene expression in psoriatic as compared with healthy skin, both in keratinocytes and myeloid cells. Immunostaining and flow cytometry of imiquimod-induced psoriatic-like lesions in Hcar2-mRFP reporter mice showed increased GPR109A expression by keratinocytes and inflammatory cells. GPR109A-deficient mice demonstrated a more severe imiquimod-induced psoriasis-like response than wild-type mice, with exacerbated epidermal hyperplasia, dermal inflammatory cell infiltration, and increased inflammatory mediators myeloperoxidase, CXCL5, LCN2, interleukin (IL)-1β, IL-6, IL-23, and IL-17A. Conversely, topical administration of sodium butyrate reduced imiquimod-induced skin inflammation in wild-type mice, but not in GPR109A-deficient mice. Mechanistically, GPR109A agonist butyrate inhibits histone deacetylase 3, thus inhibiting IL-1β and the inflammatory IL-1β/IL-23/IL-17A axis in imiquimod-induced skin inflammation. Therefore, GPR109A may have a protective role in psoriasis pathogenesis, supporting a potential therapeutic benefit of sodium butyrate administration or other GPR109A agonists for treating psoriasis.

Keywords: autoimmunity; inflammation; monocytes/macrophages; neutrophils; skin.

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