In recent years innate immunity has moved into focus of therapeutically approaches due to its ability to drive downstream adaptive responses. Modulators of innate immune responses are expected to have high therapeutic potential across immune-mediated inflammatory diseases (IMIDs). The kinase IRAK4 integrates signaling downstream of receptors acting at the interface between innate and adaptive immune responses (e.g. TLRs, IL-1R, IL-18R). Here, we profiled a novel, selective IRAK4 inhibitor, GLPG2534, in an extensive series of in vitro, ex vivo, and in vivo models of inflammatory skin diseases (ISD). In vitro, IRAK4 inhibition resulted in substantial inhibition of TLR and IL-1 responses in primary keratinocytes, granulocytes, and T cells. Furthermore, disease activity in murine models of psoriasis and atopic dermatitis (AD) skin inflammation (Il-23-, Il-33-, imiquimod- and MC903-induced) was markedly dampened by IRAK4 inhibition. Finally, neutralizing IRAK4 reversed pathogenic molecular signatures in human lesional psoriasis and AD biopsies. The variety of models highlighted IRAK4 as central mediator of psoriasis and atopic dermatitis by regulating cytokines (e.g. IL-17A, IL-22, IL-23, IL-4, IL-13, IL-5, TNF-α), chemoattractant chemokines (e.g. CXCL8, CXCL5, MCP1) and antimicrobial peptides (e.g. S100A7, DEFB4A). Overall, our data demonstrate the potential of IRAK4 inhibition as a therapeutic strategy in ISD.

ESDR350 - IRAK4 drives pathogenic processes in inflammatory skin diseases

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.