Cytosolic mtDNA-cGAS-STING axis mediates melanocytes pyroptosis to promote CD8+ T-cell activation in vitiligo.

Abstract

Background: The cGAS-STING axis, a DNA sensor pathway, has recently emerged as a key hub in sensing stress signals and initiating the immune cascade in several diseases. However, its role in the pathogenesis of vitiligo remains unclear.

Objective: To explore the pathogenic role of the cGAS-STING axis in linking oxidative stress and CD8⁺ T-cell-mediated anti-melanocytic immunity in vitiligo.

Methods: The expression status of the cGAS-STING axis and cytosolic mtDNA were evaluated in the oxidatively stressed epidermal cells and vitiligo perilesional skin, respectively. Then, we investigated the activation of cGAS-STING axis in mtDNA-treated melanocytes, and the influence of cGAS or STING silencing on mtDNA-induced melanocytes pyroptosis. Finally, the paracrine effects of melanocytes pyroptosis on CD8⁺ T cell activation were explored.

Results: We initially demonstrated that the cGAS-STING axis in melanocytes was highly susceptible to oxidative stress and activated in the vitiliginous melanocytes of perilesional skin, accompanied by enhanced cytosolic mtDNA accumulation. Our mechanistic in vitro experiments confirmed that oxidative stress-induced mitochondrial damage in epidermal cells led to cytosolic mtDNA accumulation, which served as a trigger in activating the cGAS-STING axis in melanocytes. Furthermore, the cytosolic mtDNA-cGAS-STING axis was verified to mediate melanocytes pyroptosis. More importantly, we found that IL-1β and IL-18 produced by pyroptotic melanocytes promoted the activation of CD8⁺ T cells from patients with vitiligo.

Conclusion: The present study confirmed that the cytosolic mtDNA-cGAS-STING axis of melanocytes played an important role in oxidative stress-triggered CD8⁺ T-cell response, providing novel insights into mechanisms underlying vitiligo onset.