Oxidative stress impairs the expansion of regulatory T cells in active vitiligo via dysregulated CGRP-RAMP1-Gαi3 signaling

The Koebner phenomenon is a hallmark of active vitiligo, yet its underlying mechanisms remain unclear. Here, we investigated whether Calcitonin gene-related peptide (CGRP), which is released from transient receptor potential vanilloid 1 (TRPV1)⁺ nociceptive neurons following skin injury, impairs the expansion of regulatory T cells (Tregs) and amplifies the melanocyte (MC)-directed autoimmune cascade. Dual immunofluorescence staining revealed increased CGRP expression and TRPV1⁺ innervation in human vitiligo lesions and in traumatized mouse skin. Flow cytometry of circulating skin-homing cutaneous lymphocyte-associated antigen (CLA)⁺ Tregs showed a higher proportion of receptor activity-modifying protein 1 (RAMP1)⁺ cells in patients with active vitiligo than in patients with stable disease. Tregs from active vitiligo exhibited reduced proliferation responsiveness to CGRP in vitro, and intradermal injection of CGRP exacerbated depigmentation in a mouse vitiligo model. Mechanistically, hydrogen peroxide (H₂O₂) and CGRP upregulated inhibitory guanine nucleotide-binding protein α subunit 3 (Gαi3) while suppressing phosphorylated cAMP response element-binding protein (p-CREB) and proliferating cell nuclear antigen (PCNA) in Treg-like MT-2 cells. Given the clinical challenges in managing the exacerbation of active vitiligo lesions following trauma, targeting the dysregulated CGRP-RAMP1-Gαi3 signaling axis in vitiligo offers a novel mechanism-based preventive strategy to mitigate or control disease progression.

Calcitonin gene-related peptide; Isomorphic response; Receptor activity-modifying protein 1; Regulatory; T-lymphocytes; Vitiligo.