Unanchored by two hits: IFNγ and mechanical stress synergize to undermine melanocyte adhesion and promote vitiligo.

Vitiligo is a chronic depigmentation disorder caused by selective melanocyte loss. Autoreactive CD8+ T cells are known contributors, but impaired melanocyte-keratinocyte adhesion due to E-cadherin dysfunction has also been implicated. This study aimed to identify the key adhesion molecules mediating melanocyte-basement membrane interactions and to investigate their modulation in response to vitiligo-associated factors, including IFNγ and mechanical stress. Primary human epidermal melanocytes (PHEMs) and ex vivo human skin tissues were exposed to IFNγ and mechanical stress. To identify key molecules involved in melanocyte adhesion, we integrated RNA sequencing data from prior studies with antibody array profiling. The involvement of focal adhesion-associated proteins in melanocyte-basement membrane attachment was further assessed by confocal imaging of vitiligo patient skin, revealing a reduction in these molecules. Exposure to interferon gamma (IFNγ) and mechanical stress reduced focal adhesion kinase (FAK) and integrin β1 (ITGβ1) expression in melanocytes and ex vivo human skin, increasing melanocyte detachment. Both molecules were also decreased in basal keratinocytes and melanocytes from the skin of vitiligo patients compared to healthy controls. Pre-treatment with the JAK inhibitor baricitinib, used in vitiligo therapy, reduced melanocyte detachment through a cathepsin L (CTSL)-dependent mechanism. IFNγ and mechanical stress contribute to melanocyte detachment from the basement membrane via CTSL, FAK, and ITGβ1 regulation. These findings highlight the importance of melanocyte-basement membrane adhesion in vitiligo pathogenesis and offer insight into the Koebner phenomenon in disease progression.