Membranal Expression of Calreticulin Induced by Unfolded Protein Response in Melanocytes: A Mechanism Underlying Oxidative Stress–Induced Autoimmunity in Vitiligo

Abstract

Calreticulin (CRT), a damage-associated molecular pattern molecule, is reported to translocate from endoplasmic reticulum to membrane in melanocytes under oxidative stress. To investigate the potential role of CRT in the pathogenesis of vitiligo, we analyzed the correlation between CRT and ROS in serum and lesions of vitiligo, detected CRT and protein kinase RNA-like ER kinase (PERK) expression in vitiligo lesions, and studied the production of CRT and mediators of unfolded protein response (UPR) pathway, then tested the chemotactic migration of CD8+ T cells or CD11c+ CD86+ cells. Initially, we verified the overexpression of CRT in perilesional epidermis that was positively correlated with the disease severity of vitiligo. Furthermore, the PERK branch of UPR was confirmed to be responsible for the overexpression and membranal translocation of CRT in melanocytes under oxidative stress. We also found that oxidative stress-induced membranal translocation of CRT promoted the activation and migration of CD8+ T cells in vitiligo. Additionally, dendritic cells from vitiligo patients were also prone to maturation with the co-incubation of melanocytes harboring membranal CRT. CRT could be induced on the membrane of melanocytes via UPR and might play a role in oxidative stress-triggered CD8+ T cell response in vitiligo.