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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)-1\u03b2, 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-1\u03b2 and the inflammatory IL-1\u03b2\/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.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf069","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T08:59:26Z","timestamp":1748422766000},"page":"2029-2040","source":"Crossref","is-referenced-by-count":9,"title":["Butyrate receptor HCAR2\/GPR109A controls imiquimod-induced psoriasis-like skin inflammation"],"prefix":"10.1093","volume":"214","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-0901-1375","authenticated-orcid":false,"given":"Lucija","family":"Leko","sequence":"first","affiliation":[{"name":"Immuno-Neuro Modulation, UMR7355 INEM, National Centre for Scientific Research and University of Orl\u00e9ans , Orl\u00e9ans Cedex 2,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5411-4604","authenticated-orcid":false,"given":"Darija","family":"\u0160imi\u0107","sequence":"additional","affiliation":[{"name":"Immuno-Neuro Modulation, UMR7355 INEM, National Centre for Scientific Research and University of Orl\u00e9ans , Orl\u00e9ans Cedex 2,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7939-3796","authenticated-orcid":false,"given":"Timna Valera","family":"Martins","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo , Ribeir\u00e3o Preto, SP,","place":["Brazil"]},{"name":"Center for Research in Inflammatory Diseases, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo , Ribeir\u00e3o Preto, SP,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4435-659X","authenticated-orcid":false,"given":"Gabriel Victor Lucena","family":"da Silva","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo , Ribeir\u00e3o Preto, SP,","place":["Brazil"]},{"name":"Center for Research in Inflammatory Diseases, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo , Ribeir\u00e3o Preto, SP,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7964-5978","authenticated-orcid":false,"given":"Isabelle","family":"Maillet","sequence":"additional","affiliation":[{"name":"Immuno-Neuro Modulation, UMR7355 INEM, National Centre for Scientific Research and University of Orl\u00e9ans , Orl\u00e9ans Cedex 2,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0470-422X","authenticated-orcid":false,"given":"Florence","family":"Savigny","sequence":"additional","affiliation":[{"name":"Immuno-Neuro Modulation, UMR7355 INEM, National Centre for Scientific Research and University of Orl\u00e9ans , Orl\u00e9ans Cedex 2,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara","family":"Vuksan","sequence":"additional","affiliation":[{"name":"Immuno-Neuro Modulation, UMR7355 INEM, National Centre for Scientific Research and University of Orl\u00e9ans , Orl\u00e9ans Cedex 2,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2811-6621","authenticated-orcid":false,"given":"Dorian","family":"de Moura Rodrigues","sequence":"additional","affiliation":[{"name":"Immuno-Neuro Modulation, UMR7355 INEM, National Centre for Scientific Research and University of Orl\u00e9ans , Orl\u00e9ans Cedex 2,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5945-3800","authenticated-orcid":false,"given":"Marc","family":"Le Bert","sequence":"additional","affiliation":[{"name":"Immuno-Neuro Modulation, UMR7355 INEM, National Centre for Scientific Research and University of Orl\u00e9ans , Orl\u00e9ans Cedex 2,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8676-6805","authenticated-orcid":false,"given":"Stefan","family":"Offermanns","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Max Planck Institute for Heart and Lung Research , Bad Nauheim,","place":["Germany"]},{"name":"Center for Molecular Medicine, Goethe University Frankfurt , Frankfurt,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1306-6466","authenticated-orcid":false,"given":"Nicolas","family":"Riteau","sequence":"additional","affiliation":[{"name":"Immuno-Neuro Modulation, UMR7355 INEM, National Centre for Scientific Research and University of Orl\u00e9ans , Orl\u00e9ans Cedex 2,","place":["France"]},{"name":"Immune Health Laboratory, \u201cRegulation of Host Responses and Immune Health\u201c IRL2029, French National Centre for Scientific Research and Ribeir\u00e3o Preto Medical School, S\u00e3o Paulo University , Ribeir\u00e3o Preto,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6658-414X","authenticated-orcid":false,"given":"Dieudonn\u00e9e","family":"Togbe","sequence":"additional","affiliation":[{"name":"Immuno-Neuro Modulation, UMR7355 INEM, National Centre for Scientific Research and University of Orl\u00e9ans , Orl\u00e9ans Cedex 2,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2907-7995","authenticated-orcid":false,"given":"Valerie F","family":"Quesniaux","sequence":"additional","affiliation":[{"name":"Immuno-Neuro Modulation, UMR7355 INEM, National Centre for Scientific Research and University of Orl\u00e9ans , Orl\u00e9ans Cedex 2,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1715-3834","authenticated-orcid":false,"given":"Remo Castro","family":"Russo","sequence":"additional","affiliation":[{"name":"Laboratory of Pulmonary Immunology and Mechanics, Federal University of Minas Gerais , Belo Horizonte, MG,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9918-8714","authenticated-orcid":false,"given":"Jos\u00e9 Carlos","family":"Alves-Filho","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo , Ribeir\u00e3o Preto, SP,","place":["Brazil"]},{"name":"Center for Research in Inflammatory Diseases, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo , Ribeir\u00e3o Preto, SP,","place":["Brazil"]},{"name":"Immune Health Laboratory, \u201cRegulation of Host Responses and Immune Health\u201c IRL2029, French National Centre for Scientific Research and Ribeir\u00e3o Preto Medical School, S\u00e3o Paulo University , Ribeir\u00e3o Preto,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2897-8230","authenticated-orcid":false,"given":"Bernhard","family":"Ryffel","sequence":"additional","affiliation":[{"name":"Immuno-Neuro Modulation, UMR7355 INEM, National Centre for Scientific Research and University of Orl\u00e9ans , Orl\u00e9ans Cedex 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