Occludin Promotes Adhesion of CD8+ T Cells and Melanocytes in Vitiligo via the HIF-1α Signaling Pathway

Abstract

Loss of melanocytes induced by activated CD8+ T cells is the pathological hallmark of vitiligo. Melanocyte-specific CD8+ T cells are recruited to the skin via chemokines, thereby releasing perforin, granzyme, and other cytotoxic substances that destroy the melanocytes. However, the mechanism of CD8+ T cells to adhere to melanocytes is unknown. Previous transcriptome sequencing results published by our group showed that the occluding (OCLN) gene was significantly upregulated in CD8+ T cells from skin lesions of vitiligo. Occludin is a crucial component of the tight junction between cells; in cells without tight junction, occludin mediates the adhesion of two cells in the form of a self-ligand. This study demonstrated that OCLN gene expression was elevated in the CD8+ T cells of vitiligo patients, and occludin mediates the adherence of CD8+ T cells to melanocytes. Besides, pathological changes in vitiligo skin lesions reveal that CD8+ T cells continuously persist in the skin lesions, which is related to the persistence of the disease. In this regard, we found that fibroblasts from vitiligo patients significantly express occludin, which may participate in the continuous retention of CD8+ T cells in the skin lesions. The pathogenesis of vitiligo is closely related to oxidative stress, and our data suggest that overexpression of hypoxia-inducible factor-1α (HIF-1α) increases the expression of occludin. Besides, ChIP-qPCR of CD8+ T cells revealed that HIF-1α directly binds to the OCLN promoter. Thus, occludin upregulation promotes the adhesion of CD8+ T cells and melanocytes via the HIF-1α signaling pathway. Our study results suggested a critical role for OCLN in the occurrence, progression, and maintenance of vitiligo. Therefore, inhibiting the expression of OCLN gene may be a potential targeted treatment strategy.

The role of dermal fibroblasts in autoimmune skin diseases

“…Zou et al. found that fibroblasts from vitiligo patients significantly express occludin, suggesting its potential function in the continuous retention of CD8 + T cells within the lesions ( 62 ). Consequently, the secretion of ECM by fibroblasts exhibits regional variations, potentially contributing to the disparate incidence of vitiligo across different anatomical regions.…”

“…Instead, the expression of collagen type IV, fibronectin, elastin, and adhesion components was considerably lower in the lesional skin of non-segmental vitiligo (NSV) patients (61). Zou et al found that fibroblasts from vitiligo patients significantly express occludin, suggesting its potential function in the continuous retention of CD8 + T cells within the lesions (62). Consequently, the secretion of ECM by fibroblasts exhibits regional variations, potentially contributing to the disparate incidence of vitiligo across different anatomical regions.…”