Abstract
Vitiligo is a disfiguring disease featuring chemokines-mediated cutaneous infiltration of autoreactive CD8+ T cells that kill melanocytes. Copious studies have indicated that virus invasion participates in the pathogenesis of vitiligo. IFIH1, encoding MDA5 which is an intracellular virus sensor, has been identified as a vitiligo susceptibility gene. However, the specific role of MDA5 in melanocyte death under virus invasion is not clear. In this study, we first showed that the expression of anti-CMV IgM and MDA5 was higher in vitiligo patients than healthy controls. Then, by using Poly(I:C) to imitate virus invasion, we clarified that virus invasion significantly activated MDA5 and further potentiated the keratinocyte-derived CXCL10 and CXCL16 which are the two vital chemokines for the cutaneous infiltration of CD8+ T cells in vitiligo. More importantly, IFN-β mediated by the MDA5-MAVS-NF-κB/IRF3 signaling pathway orchestrated the secretion of CXCL10 via the JAK1-STAT1 pathway and MDA5-meidiated IRF3 transcriptionally induced the production of CXCL16 in keratinocytes under virus invasion. In summary, our results demonstrate that MDA5 signaling orchestrates the aberrant skin immunity engaging in melanocyte death via mediating CXCL10 and CXCL16 secretion, which supports MDA5 as a potential therapeutic target for vitiligo under virus invasion.
Highlights
Vitiligo is a disfiguring disease characterized by melanocyte death which is caused by autoreactive melanocytespecific CD8+ T cells with the attraction of excessive chemokines[1,2], which underlines the autoimmunity dominantly participates in the pathogenesis of vitiligo
We initially manifested that the expression of melanoma differentiation-associated 5 protein (MDA5) and anti-CMV IgM was upregulated in some progressive vitiligo, which was accompanied by the increment of the mRNA levels of CXCL10, CXCL16 in the epidermis and the infiltration quantity of CD8+ T in the skin tissues
We found that the positive rate of anti-CMV IgM was 8.92% in 56 progressive vitiligo patients, while that in 26 healthy controls was 3.84%, and the anti-CMV IgM levels were significantly higher in vitiligo patients than that in healthy controls (Fig. 1a)
Summary
Vitiligo is a disfiguring disease characterized by melanocyte death which is caused by autoreactive melanocytespecific CD8+ T cells with the attraction of excessive chemokines[1,2], which underlines the autoimmunity dominantly participates in the pathogenesis of vitiligo. Multiple studies showed that vitiligo is caused by specific environmental factors in the population with genetic predisposition[3]. As an important environmental factor, has been determined to play profound parts in the. The case-control study based on the large sample size determines that hepatitis C virus (HCV)[15] is associated with vitiligo. Many cases embody the correlation between virus infection and vitiligo[17,18,19,20,21,22], the inflammatory raised borders in vitiligo with HCV infection[19], the reactivation of herpes simplex virus in lesions of vitiligo after excimer laser treatment[20] and vitiligo occurrence after the Official journal of the Cell Death Differentiation Association
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