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Br. J. Dermatol., Mar 31 2026, ljag113 | https://doi.org/10.1093/bjd/ljag113 Unanchored by two hits: IFNγ and mechanical stress synergize to undermine melanocyte adhesion and promote vitiligo

Eun Jung Lee^{1 †}, Il Joo Kwon^{1 †}, Ji Young Kim ¹, Seohyun Park ¹, Hui-Ting Han ², Shinwon Hwang ¹, Yu Jeong Bae ¹, A-Ram Kim ³, Jamal Mohammed Alqahtani ⁴, Dong Hyun Kim ^{3 5}, Jinu Lee ⁶, Si-Hyung Lee², Sang Ho Oh ^{1 *}

¹Department of Dermatology and Cutaneous Biology Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
²Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea.
³Department of Dermatology, School of Medicine, CHA University, Pocheon, Korea.
⁴Department of Dermatology, Imam Abdulrahman Bin Faisal University, Saudi Arabia.
⁵Department of Dermatology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea.
⁶College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Korea.

^†E.J.L. and I.J.K. contributed equally to this study.

^*Corresponding author: correspondence to Sang Ho Oh

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
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.

Methods
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.

Results
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.

Conclusions
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.

논문소개전체 설명

백반증은 마찰이 잘 되는 부위에 발생하는 쾨브너 현상의 특징이 있다. 이러한 현상에 대한 설명으로 Keratinocyte와 Melanocyte 사이의 E cadherin의 결합이 중요한 역할을 하며 이 결합의 결손이 발생의 원인으로 생각되어 왔다. 하지만 melanocyte는 basement membrane 위에 위치하면서 keratinocyte가 분화되는 것과 달리 항상 그 위치에 위치하는 특성이 있다. 따라서 KC, MC사의 결합도 중요할수 있지만 basal layer (epidermis)에 위치하는 결합이 더 중요할수 있다. 이런 결합으로 integrin의 중요성을 이 논문에서는 제시하였고 특히 백반증의 발생에 중요한 IFN gamma가 integrin 결합에 영향을 주는 것을 실험적으로 증명하여 이 연구논문을 출간하게 되었다.

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