IL‐17 induces cellular stress microenvironment of melanocytes to promote autophagic cell apoptosis in vitiligo

Abstract

Vitiligo is a depigmentary disorder that develops as a result of the progressive disappearance of epidermal melanocytes. Stress can precipitate or exacerbate a skin disease through psychosomatic mechanisms. Stress exposure induces vitiligo-like symptoms in mice, as cellular damage to melanocytes causes synthetic pigment loss. Stress also increases IL-17, IL-1β, and antimelanocyte IgG in model mouse serum. Up-regulation of the IL-1β transcript in patients suggests its possible role in autoimmune pathogenesis of vitiligo. We demonstrate that IL-17 promoted IL-1β secretion from keratinocytes. Mitochondrial dysfunction, which can induce the excessive production of reactive oxygen species (ROS), is emerging as a mechanism that underlies various inflammatory and autoimmune diseases. In this study, we demonstrate that IL-17 inhibits melanogenesis of zebrafish, normal human epidermal melanocytes, and B16F10 cells. IL-17 increased mitochondrial dysfunction and ROS accumulation, which was related to autophagy induction. Autophagy is needed for autophagic apoptosis of B16F10 cells induced by IL-17. To inhibit ROS generation, B16F10 cells were pretreated with N-acetyl-l-cysteine (NAC), which inhibited autophagy. 3-Methyladenine (3-MA) also had an inhibiting effect on autophagy. NAC or 3-MA pretreatments inhibited IL-17-mediated cell apoptosis. In summary, IL-17 induces the cellular stress microenvironment in melanocytes to promote autophagic cell apoptosis in vitiligo.-Zhou, J., An, X., Dong, J., Wang, Y., Zhong, H., Duan, L., Ling, J., Ping, F., Shang, J. IL-17 induces cellular stress microenvironment of melanocytes to promote autophagic cell apoptosis in vitiligo.

Critical role of metabotropic glutamate receptor 4 in bone marrow-derived dendritic cells in the Th17 cell differentiation and the melanogenesis of B16 cells

“…Therefore, we concluded that the Th17 cell-related cytokines environment modulated by downregulation or upregulation of mGluR4 in BMDC affected the expression of MITF and its downstream genes, along with the morphology and melanin production in B16 cells, leading to the local pigment abnormity. Recently Zhou et al (36) found that IL-17 promoted the autophagymediated apoptotic process, which contributed to the pathology of vitiligo. In a future study, it is suggested to probe into whether the conditioned media for CD4 coculture experiment would impact cell cytotoxicity, cell cycle, etc., of B16 cells, to determine how the Th17 cytokines would destroy B16 cells.…”

GPNMB is expressed in human epidermal keratinocytes but disappears in the vitiligo lesional skin

“…www.nature.com/scientificreports www.nature.com/scientificreports/ There have also been many reports confirming elevated levels of circulating IL-17 and increased numbers of Th17 lymphocytes in patients with non-segmental vitiligo [33][34][35] . Furthermore, IL-17 has been reported to damage melanocytes 36 .…”

Epigenetic treatment of dermatologic disorders

“…Skin epidermis, a self‐regenerating organ, constantly sheds and replaces damaged and worn‐out skin cells (Orioli & Dellambra, ; Yang & Kang, ; Zhang et al, ). Although mitochondrial dysfunction adversely affects primarily nonregenerative tissue, the neuromuscular system, and internal organs, cells in every tissue type, including skin, require a continuous and adequate supply of mitochondrial energy for their survival and proper function (Baeeri et al, ; Dinkova‐Kostova, Kostov, & Kazantsev, ; Joshi & Mochly‐Rosen, ; Martinelli et al, ; Naidoo, Hanna, & Birch‐Machin, ; Wlaschek, Singh, Sindrilaru, Crisan, & Scharffetter‐Kochanek, ; Zhou et al, ). Representing the outermost surface of the body, skin is uniquely vulnerable to a plethora of environmental insults.…”

“…muscular system, and internal organs, cells in every tissue type, including skin, require a continuous and adequate supply of mitochondrial energy for their survival and proper function(Baeeri et al, 2019;Dinkova-Kostova, Kostov, & Kazantsev, 2018;Joshi & Mochly-Rosen, 2018;Martinelli et al, 2017;Naidoo, Hanna, & Birch-Machin, 2018; Wlaschek, Singh, Sindrilaru, Crisan, & Scharffetter-Kochanek, 2019;Zhou et al, 2018). Representing the outermost surface of the body, skin is uniquely vulnerable to a plethora of environmental insults.Exposure to harmful chemicals, xenobiotics, oxidative stress, and solar UV-radiation is mitigated by various protective mechanisms that rely on signaling networks and the expression of proteins involved in the detoxification of compounds or reactive oxygen speciesDodson et al, 2019;Hiebert et al, 2018;Jadkauskaite et al, 2017;Raghunath et al, 2018;Siegenthaler et al, 2018;Sivandzade, Prasad, Bhalerao, & Cucullo, 2019;Tonelli, Chio, & Tuveson, 2018;Vega, Krajisnik, Zhang, & Wondrak, 2017;Yamamoto, Kensler, & Motohashi, 2018).…”