Oxidative Stress–Induced HMGB1 Release from Melanocytes: A Paracrine Mechanism Underlying the Cutaneous Inflammation in Vitiligo

Abstract

Vitiligo is a cutaneous depigmentation disorder caused by the destruction of epidermal melanocytes. The generation and the skin infiltration of autoreactive CD8 þ cytotoxic T cells triggered by oxidative stress play a critical role in vitiligo. High-mobility group protein B1 (HMGB1) is a classic damage-associated molecular pattern molecule with strong proinflammatory effects in inflammatory reactions. A previous study reported an enhanced expression of HMGB1 in vitiligo lesions, but the role of HMGB1 in cutaneous inflammation of vitiligo is still unknown. In the present study, we initially found that HMGB1 was released from the nucleus of melanocytes in vitiligo perilesional skin. Furthermore, cultured normal human melanocytes could release HMGB1 under treatment with hydrogen peroxide. Moreover, HMGB1 facilitated the secretion of CXCL16 and IL-8 from keratinocytes by binding to the receptor for advanced glycation end products and activating NF-kB and extracellular signaleregulated kinase signaling pathways. Subsequently, HMGB1 led to the formation of chemotaxis for the migration of CD8 þ T cells from patients with vitiligo by increasing the release of CXCL16 from keratinocytes. Additionally, HMGB1 promoted the maturation of dendritic cells from patients with vitiligo. Altogether, our study demonstrates that HMGB1 released from melanocytes contributes to the formation of oxidative stresseinduced autoimmunity in vitiligo.

SnapshotDx Quiz: June 2020

“…2. According to the paper by Cui et al(2019), HMGB1 mRNA is highly expressed in ______________ cells after oxidative stress.…”

“…to the paper byCui et al(2019), HMGB1 mRNA is highly expressed in ____________ cells after oxidative stress. expression from oxidatively stressed melanocytes facilitates maturation of _____________ cells, which likely promotes the development of autoimmunity in vitiligo.a.…”

“…In this monthly online-only quiz, the first question ("What is your diagnosis?") relates to the clinical image shown, while additional questions concern the findings reported in the JID article by Cui et al (2019) (https://doi.org/10.1016/ j.jid.2019.03.1148).…”

Vitiligo, From Physiopathology to Emerging Treatments: A Review

“…The secretion of DAMPs in the extracellular environment may be accountable for bridging cellular stress to the autoimmune response against melanocytes in vitiligo [7] and, therefore, could represent highly interesting potential targets to prevent initiation of autoimmunity at the onset of the disease. Indeed, HMGB1 can induce the production of chemokine ligands, such as (C-X-C motif) ligand (CXCL1)6 or interleukin (IL)-8 by keratinocytes, which is important for the recruitment of immune cells [8]. For its part, CRT has been reported to induce melanocyte apoptosis and the release of membrane-debris important for immunogenecity [9].…”

Meeting Report of the 4th Annual Meeting of the Chinese Society for Investigative Dermatology: Reflections on the Rise of Cutaneous Biology Research in China

“…A paracrine mechanism underlying the oxidative stress-induced cutaneous inflammation in vitiligo. Cui et al, 2019;Jian et al, 2014;Li et al, 2017;Quan et al, 2010 (continued ) J Uitto et al Ge et al, 2016;Guo et al, 2016Guo et al, ,2011Hu et al, 2019Lin et al, 2018 Autoimmune bullous diseases…”