Inflammation modulates intercellular adhesion and mechanotransduction in human epidermis via ROCK2

Summary

Aberrant mechanotransduction and compromised epithelial barrier function are associated with numerous human pathologies including inflammatory skin disorders. However, the cytoskeletal mechanisms regulating inflammatory responses in the epidermis are not well understood. By inducing psoriatic phenotype in human keratinocytes and reconstructed human epidermis, the authors of the current study, led by GCIR member Professor Wolf-Henning Boehncke, show that psoriasis-related inflammatory cytokines induce the activation of the Rho pathway associated with destabilization of epidermal adherens junctions and the nuclear translocation of mechanoresponsive transcription co-activator YAP. These effects are largely dependent on the function of Rho-associated kinase ROCK2, however, not on the canonical myosin-II activation mechanism. Using a specific small molecule inhibitor KD025, the authors demonstrate that ROCK2 executes its effects via cytoskeletal and transcription-dependent mechanisms to shape the inflammatory response in the epidermis.

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Why is it important?

Cutaneous inflammation in general and psoriasis in particular is still an underestimated problem in clinical medicine. The current study demonstrates that the integration of cytoskeleton-dependent mechanotransduction pathways is critical in skin inflammation response and for the first time describes cytoskeletal phenotype in the inflamed keratinocytes and the epidermis. Moreover, the study shows that the ROCK2 small molecule inhibitor KD025 (SLx-2119, belumosudil) can partially rescue the keratinocyte inflammatory phenotype, including epidermal barrier function. In the context of inflammation, KD025 has been previously shown to suppress the production of IL-17A, IL-10 and IL-21 cytokines by human T-cells via the STAT3-dependent mechanism, and a phase two clinical trial for its systemic application for psoriasis vulgaris has been recently completed (clinicaltrials.gov NCT02317627). The current work reveals another function principle of this inhibitor, namely, by acting directly on human epidermal keratinocytes regulating their adhesion, barrier function and mechanosignaling. Therefore, KD025 may be considered for a topical treatment in psoriatic inflammation.

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