Intracellular virus sensor MDA5 exacerbates vitiligo by inducing the secretion of chemokines in keratinocytes under virus invasion

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.

Melanogenesis Connection with Innate Immunity and Toll-Like Receptors

“…In 1996, cytomegalovirus, a type of herpesvirus with double-stranded DNA as its genome, was identified in a skin biopsy specimen of vitiligo patients [67]. Anti-CMV levels in sera of patients with advanced vitiligo are significantly higher than in healthy individuals [68]. Furthermore, a strong association between turkey herpesvirus and vitiligo was suggested in the Smyth line chicken vitiligo model [69].…”

Functional Interfaces, Biological Pathways, and Regulations of Interferon-Related DNA Damage Resistance Signature (IRDS) Genes

“…Virus invasion significantly activated MDA5 as well as promoted the secretion of CXCL10 and CXCL16 in keratinocytes, which are the two vital chemokines for the cutaneous infiltration of CD8+ T cells in vitiligo. Under virus invasion, IFNβ mediated by the MDA5-MAVS-NF-κB/IRF3 signalling pathway, induced the secretion of CXCL10 via the JAK/STAT1 pathway and MDA5-mediated IRF3 transcriptionally activated the production of CXCL16 in keratinocytes [ 170 ]. Furthermore, the IFITMs are restriction factors conferring potent antiviral activity to the cell host, and IFITM1/2/3 proteins inhibit the replication of a wide range of viruses.…”

Targeting Innate Immunity to Combat Cutaneous Stress: The Vitiligo Perspective

“…There is some evidence that viral infections in a genetically predisposed host may induce excessive ROS production by recruited lymphocytes leading to destruction of epidermal melanocytes (29). Furthermore, IFIH1, encoding intracellular virus sensor MDA5, has been identified as a vitiligo susceptibility gene capable of inducing secretion of CXCL10 and CXCL16 from keratinocytes and inducing infiltration of CD8 + T cells in vitiligo (30).…”