{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:30:02Z","timestamp":1791318602571,"version":"4.3.1"},"reference-count":50,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"683","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2023,2,15]]},"abstract":"<jats:p>Innate immunity not only shapes the way epithelial barriers interpret environmental cues but also drives adaptive responses. Therefore, modulators of innate immune responses are expected to have high therapeutic potential across immune-mediated inflammatory diseases. IRAK4 is a kinase that integrates signaling downstream of receptors acting at the interface between innate and adaptive immune responses, such as Toll-like receptors (TLRs), interleukin-1R (IL-1R), and IL-18R. Because effects of IRAK4 inhibition are stimulus, cell type, and species dependent, the evaluation of the therapeutic potential of IRAK4 inhibitors requires a highly translational approach. Here, we profiled a selective IRAK4 inhibitor, GLPG2534, in an extensive panel of models of inflammatory skin diseases, translationally expanding evidence from in vitro to in vivo and from mouse to human. In vitro, IRAK4 inhibition resulted in substantial inhibition of TLR and IL-1 responses in dendritic cells, keratinocytes, granulocytes, and T cells but only weakly affected dermal fibroblast responses. Furthermore, disease activity in murine models of skin inflammation (IL-23\u2013, IL-33\u2013, imiquimod-, and MC903-induced) was markedly dampened by IRAK4 inhibition. Last, inhibiting IRAK4 reversed pathogenic molecular signatures in human lesional psoriasis and atopic dermatitis biopsies. Over the variety of models used, IRAK4 inhibition consistently affected central mediators of psoriasis (IL-17A) and atopic dermatitis (IL-4 and IL-13). Overall, our data highlight IRAK4 as a central player in skin inflammatory processes and demonstrate the potential of IRAK4 inhibition as a therapeutic strategy in chronic inflammatory skin diseases.<\/jats:p>","DOI":"10.1126\/scitranslmed.abj3289","type":"journal-article","created":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T13:58:40Z","timestamp":1676469520000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":46,"title":["IRAK4 inhibition dampens pathogenic processes driving inflammatory skin diseases"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3390-9221","authenticated-orcid":true,"given":"St\u00e9phanie","family":"Lavazais","sequence":"first","affiliation":[{"name":"Galapagos SASU, 93230 Romainville, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manja","family":"Jargosch","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergy, Technical University of Munich, 80802 Munich, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Dupont","sequence":"additional","affiliation":[{"name":"Galapagos SASU, 93230 Romainville, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Lab\u00e9gu\u00e8re","sequence":"additional","affiliation":[{"name":"Galapagos SASU, 93230 Romainville, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christel","family":"Menet","sequence":"additional","affiliation":[{"name":"Galapagos NV, 2800 Mechelen, Belgium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6277-1711","authenticated-orcid":true,"given":"Catherine","family":"Jagerschmidt","sequence":"additional","affiliation":[{"name":"Galapagos SASU, 93230 Romainville, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frenz","family":"Ohm","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Allergy, Technical University of Munich, 80802 Munich, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3535-5496","authenticated-orcid":true,"given":"Laszlo","family":"Kupcsik","sequence":"additional","affiliation":[{"name":"Galapagos NV, 2800 Mechelen, Belgium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7947-0544","authenticated-orcid":true,"given":"Isabelle","family":"Parent","sequence":"additional","affiliation":[{"name":"Galapagos SASU, 93230 Romainville, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4883-3154","authenticated-orcid":true,"given":"C\u00e9line","family":"Cottereaux","sequence":"additional","affiliation":[{"name":"Galapagos SASU, 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Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Cl\u00e9ment-Lacroix","sequence":"additional","affiliation":[{"name":"Galapagos SASU, 93230 Romainville, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0094-2674","authenticated-orcid":true,"given":"Kilian","family":"Eyerich","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Venerology, Medical Center\u2013University of Freiburg, Freiburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3415-7124","authenticated-orcid":true,"given":"Reginald","family":"Brys","sequence":"additional","affiliation":[{"name":"Galapagos NV, 2800 Mechelen, Belgium."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3260"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/jdv.14673"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1109997"},{"key":"e_1_3_3_5_2","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1002\/art.21519","article-title":"The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment","volume":"54","author":"Breedveld F. C.","year":"2006","unstructured":"F. C.\u00a0Breedveld, M. H.\u00a0Weisman, A. F.\u00a0Kavanaugh, S. B.\u00a0Cohen, K.\u00a0Pavelka, R.\u00a0van Vollenhoven, J.\u00a0Sharp, J. L.\u00a0Perez, G. T.\u00a0Spencer-Green, The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 54, 26\u201337 (2006).","journal-title":"Arthritis Rheum."},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2010.12.005"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.05.006"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01412"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0901181106"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.37804"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1398-9995.2008.01889.x"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0906312"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2438"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.24552"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600788"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0802361"},{"key":"e_1_3_3_17_2","article-title":"Efficacy and safety of the selective interleukin-1 receptor associated kinase 4 inhibitor, PF-06650833, in patients with active rheumatoid arthritis and inadequate response to methotrexate","volume":"71","author":"Danto S. I.","year":"2019","unstructured":"S. I.\u00a0Danto, N.\u00a0Shojaee, R.\u00a0S.\u00a0P.\u00a0Singh, Z.\u00a0Manukyan, J.\u00a0Mancuso, E.\u00a0Peeva, M.\u00a0Vincent, J.\u00a0Beebe, Efficacy and safety of the selective interleukin-1 receptor associated kinase 4 inhibitor, PF-06650833, in patients with active rheumatoid arthritis and inadequate response to methotrexate. 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