Membranal Expression of Calreticulin Induced by Unfolded Protein Response in Melanocytes: A Mechanism Underlying Oxidative Stress- Induced Autoimmunity in Vitiligo
Membranal Expression of Calreticulin Induced by Unfolded Protein Response in Melanocytes: A Mechanism Underlying Oxidative Stress- Induced Autoimmunity in Vitiligo
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DOI：
10.1016/j.jid.2024.01.007
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发表时间：
2024-06-20
影响因子：
6.5
通讯作者：
Liu，Ling
中科院分区：
文献类型：
--
作者：
Song，Pu;Zhang，Weigang;Liu，Ling
钙网蛋白（CRT）是一种损伤相关的分子模式分子，据报道，在氧化应激下，黑素细胞从内质网转移到膜上。为了探讨CRT在白癜风发病机制中的潜在作用，我们分析了白癜风病变血清中CRT与ROS的相关性，检测了白癜风病变中CRT和蛋白激酶rna样内质网激酶（PERK）的表达，研究了CRT和未展开蛋白反应（UPR）通路介质的产生，并检测了CD8+T细胞或CD11c+CD86+细胞的趋化迁移。最初，我们证实了CRT在病变周围表皮的过表达与白癜风的疾病严重程度呈正相关。此外，UPR的PERK分支被证实与氧化应激下黑素细胞中CRT的过表达和膜易位有关。我们还发现氧化应激诱导的CRT膜易位促进了白癜风CD8+T细胞的活化和迁移。此外，白癜风患者的树突状细胞也容易与含有膜CRT的黑素细胞共孵卵成熟。CRT可通过UPR在黑素细胞膜上诱导，并可能在白癜风氧化应激引发的CD8+ t细胞应答中发挥作用。
Calreticulin (CRT), a damage-associated molecular pattern molecule, is reported to translocate from the endoplasmic reticulum to the 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 endoplasmic reticulum kinase (PERK) expression in vitiligo lesions, and studied the production of CRT and mediators of unfolded protein response (UPR) pathway and 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. In addition, dendritic cells from patients with vitiligo were also prone to maturation with the coincubation of melanocytes harboring membranal CRT. CRT could be induced on the membrane of melanocytes through UPR and might play a role in oxidative stress–triggered CD8+T-cell response in vitiligo.