Unanchored by two hits: interferon-γ and mechanical stress synergize to undermine melanocyte adhesion and promote vitiligo

Abstract

Background 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.Objectives To identify the key adhesion molecules mediating melanocyte-basement membrane interactions and to investigate their modulation in response to vitiligo-associated factors, including interferon (IFN)-gamma and mechanical stress.Methods Primary human epidermal melanocytes and ex vivo human skin tissues were exposed to IFN-gamma 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 skin from patients with vitiligo, revealing a reduction in these molecules.Results Exposure to IFN-gamma and mechanical stress reduced focal adhesion kinase (FAK) and integrin beta 1 (ITG beta 1) 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 patients with vitiligo compared with healthy controls. Pretreatment with the Janus kinase inhibitor baricitinib, used in vitiligo therapy, reduced melanocyte detachment through a cathepsin L (CTSL)-dependent mechanism.Conclusions IFN-gamma and mechanical stress contribute to melanocyte detachment from the basement membrane via CTSL, FAK and ITG beta 1 regulation. These findings highlight the importance of melanocyte-basement membrane adhesion in vitiligo pathogenesis and offer insight into the Koebner phenomenon in disease progression. Vitiligo is a persistent condition that affects the pigmentation (colour) of skin. Areas of skin become very pale or white. This is caused by the loss of skin cells called melanocytes. These cells produce a pigment called melanin. Melanin is responsible for skin, hair and eye colour.In vitiligo, melanocytes are mistakenly attacked by the body's own immune system. Melanocytes can be destroyed altogether or damaged, so that they no longer function correctly.We studied whether melanocyte damage is caused by a molecule called 'interferon gamma'. We combined this molecule with mechanical stress. Mechanical stress involved repeatedly stretching the skin cells in the lab. We found that the combination of interferon gamma and mechanical stress reduced the ability of melanocytes to work properly. The cells also produced fewer of the molecules they need to attach to skin ('attachment molecules'). When this was reversed, the melanocytes were able to attach properly.In conclusion, interferon gamma and mechanical stress may be important in vitiligo. This finding could help us develop new treatment strategies for vitiligo. Interferon-gamma and mechanical stress reduce focal adhesion between melanocytes and the basement membrane. This finding not only advances our understanding of vitiligo pathogenesis, but also highlights a novel therapeutic avenue and provides mechanistic insight into the Koebner phenomenon.