IRAK4 inhibition dampens pathogenic processes driving inflammatory skin diseases

Autor: Stéphanie Lavazais, Manja Jargosch, Sonia Dupont, Frédéric Labéguère, Christel Menet, Catherine Jagerschmidt, Frenz Ohm, Laszlo Kupcsik, Isabelle Parent, Céline Cottereaux, Florence Marsais, Line Oste, An Van de Water, Thierry Christophe, Steve De Vos, Padraic Fallon, Felix Lauffer, Philippe Clément-Lacroix, Kilian Eyerich, Reginald Brys
Rok vydání: 2023
Předmět:
Zdroj: Science Translational Medicine. 15
ISSN: 1946-6242
1946-6234
Popis: 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–, IL-33–, 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.
Databáze: OpenAIRE
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