Mechanisms of melanocyte death in vitiligo

Abstract

Vitiligo is an autoimmune depigment disease results from extensive melanocytes destruction. The destruction of melanocyte is thought to be of multifactorial causation. Genome-wide associated studies have identified single-nucleotide polymorphisms in a panel of susceptible loci as risk factors in melanocyte death. But vitiligo onset can't be solely attributed to a susceptive genetic background. Oxidative stress triggered by elevated levels of reactive oxygen species accounts for melanocytic molecular and organelle dysfunction, a minority of melanocyte demise, and melanocyte-specific antigens exposure. Of note, the self-responsive immune function directly contributes to the bulk of melanocyte deaths in vitiligo. The aberrantly heightened innate immunity, type-1-skewed T helper, and incompetent regulatory T cells tip the balance toward autoreaction and CD8⁺ cytotoxic T lymphocytes finally execute the killing of melanocytes, possibly alarmed by resident memory T cells. In addition to the well-established apoptosis and necrosis, we discuss several death modalities like oxeiptosis, ferroptosis, and necroptosis that are probably employed in melanocyte destruction. This review focuses on the various mechanisms of melanocytic death in vitiligo pathogenesis to demonstrate a panorama of that. We hope to provide new insights into vitiligo pathogenesis and treatment strategies by the review.

Keywords: autoimmunity; death; melanocyte; oxidative stress; vitiligo.

Figure 1

Clinical and pathological manifestation of vitiligo. A, Vitiligo is characterized by chronic depigmentation and milk‐white lesion in the skin. B, Representative images of normal melanocytes in the stratum basale of healthy control and an absence of melanocytes in vitiligo skin. The sections stained with hematoxylin and eosin (×400, black arrowheads in the inset: Melanocytes). C, Healthy skin with normal quantity of melanocytes in contrast to vitiligo lesional skin being devoid of melanocytes on account of melanocyte destruction, as detected by immunofluorescence. Melanocytes in the epidermis were stained with antibodies to Melan‐A (red). Nuclei were counterstained with 4′,6‐diamidino‐2‐phenylindole (blue) (scale bar = 100 μm) (white arrowheads in the inset: Melanocytes) [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

A road map for melanocyte in vitiligo. The figure briefly illustrates the main contents of melanocyte death triggers and the logical relation between them in vitiligo. ROS, reactive oxygen species; Th cells, T‐helper cells; Treg: regulatory T cell; T_RM, resident memory T cell [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3

Source of ROS. Accumulation of ROS can be generated by either excessive formation or inadequate scavenging. Environmental stimuli like UV, trauma, pregnancy, stress, and vaccination promote ROS formation. External phenols including monobenzone, hydroquinone and 4‐TBP also give rise to ROS as known. Melanin biosynthesis and energy metabolism in mitochondria physically yield ROS. Neighboring keratinocytes also reportedly transfer ROS to melanocytes. With respect to inadequate scavenging of ROS, downregulated Nrf2 pathway and enzymic or nonenzymic antioxidant agents should be attributable. 4‐TBP, 4‐tertiary butyl‐phenol; ARE, antioxidant response element; CAT, catalase; GPx, glutathione peroxidase; HO‐1, heme oxygenase‐1; Nrf2, nuclear factor E2‐related factor 2; ROS, reactive oxygen species; SOD, superoxide dismutase [Color figure can be viewed at wileyonlinelibrary.com]

Figure 4

Oxidative stress leads to multiple death modalities through various pathways in melanocyte. Excessive ROS hyperactivate the UPR to trigger endoplasmic‐reticulum‐associated melanocytic apoptosis. Translocation of CRT from endoplasmic reticulum under oxidative stress adds to melanocyte immunogenicity. Mitochondria also participate in ROS‐related apoptosis through forming MOMP. Besides, redundant ROS give rise to deficient Nrf2 pathway, generation of HMGB1 and E‐cadherin diminution, which underlie melanocyte apoptosis. Of note, oxidative stress also evokes other modalities of melanocytic death, like necroptosis, necrosis, oxeiptosis, and probably pyroptosis and parthanatos. Some pathways surmised to exist are drawn in dotted lines. Ac‐OPA1, acetylated optic atrophy 1; AIFM1, apoptosis‐inducing factor mitochondrion‐associated 1; ATF6, activating transcription factor 6; CASP1, caspase 1; CHOP, CAAT/enhancer‐binding protein homologous protein; CRT, calreticulin; ER, endoplasmic reticulum; GSDMD, gasdermin D; IRE1α, inositol‐requiring enzyme‐1α; KEAP1, kelch‐like ECH‐associated protein 1; MIF, macrophage migration inhibitory factor; MLKL, mixed lineage kinase domain‐like protein; MOMP, mitochondrial outer membrane permeabilization; mtROS, mitochondrial ROS; Cyto C, cytochrome c; NLRP3, NLR family pyrin domain containing 3; Nrf2, nuclear factor E2‐related factor 2; PARP1, poly(ADP‐ribose) polymerase 1; PERK, PRKR‐like ER kinase; PGAM5, PGAM family member 5; p‐JNK, phosphorylated c‐Jun N‐terminal kinase; RIDD, regulated IRE1‐dependent messenger RNA decay; RIPK1, receptor‐interacting serine/threonine kinase 1; RIPK3, receptor‐interacting serine/threonine kinase 3; SIRT3, sirtuin 3; HMGB1, high‐mobility group box 1; TRPM2, transient receptor potential cation channel subfamily M member 2; UPR, unfolded protein response; ΔΨm, the mitochondrial membrane potential [Color figure can be viewed at wileyonlinelibrary.com]

Figure 5

Overview of factors triggering melanocyte death in vitiligo. In the predisposing genetic background, environmental stimuli, aberrant metabolism and deficient antioxidants indirectly cause several possible death modalities of a fraction of melanocytes through ROS, though minor direct death‐triggering pathways exist. Outcomes of these melanocyte deaths, antigens exposure and inflammatory microenvironment, confer the majority of melanocyte demise via immune cells breaching the self‐tolerance. CD8⁺CTL, CD8⁺ cytotoxic T lymphocytes; DC, dendritic cell; ILC, innate lymphoid cells; NK, natural killer cells; Th1, T‐helper cell 1; Th17, T‐helper cell 17; Th2, T‐helper cell 2; Treg, regulatory T cell; T_RM, resident memory T cell [Color figure can be viewed at wileyonlinelibrary.com]

Figure 6

Aberrantly activated immune response in vitiligo. Outlined in the figure are members and their reciprocal relationship of the aberrantly activated innate and adaptive immunity in vitiligo pathogenesis. The interaction between innate immune cells are drawn in blue long‐tail arrow, and the interaction between adaptive immune cells in red. CCL5, CC chemokine ligand 5; CRT, calreticulin; CXCL12, C‐X‐C motif chemokine ligand 12; CXCL16, C‐X‐C motif chemokine ligand 16; CXCL9/10, C‐X‐C motif chemokine ligand 9/10; CXCR3, C‐X‐C motif chemokine receptor 3; CXCR6, C‐X‐C motif chemokine receptor 6; DAMP, damage‐associated molecular patterns molecule; DC, dendritic cell; Fas/FasL, Fas/Fas ligand; HMGB1, high‐mobility group box 1; HSP70i, inducible heat shock protein 70; IFN‐α, interferon‐α; IFN‐γ, interferon‐γ; IL‐10, interleukin‐10; IL‐15, interleukin‐15; IL‐15R, interleukin‐15 receptor; IL‐17A, interleukin‐17A; IL‐17F, interleukin‐17F; IL‐1R, interleukin‐1 receptor; IL‐1β, interleukin‐1β; IL‐8, interleukin‐18; ILC, innate lymphoid cells; MICA/MICB, major histocompatibility complex class I chain‐related protein A and B; NK, nature killer cells; NKG2D, natural killer group 2D; PRR, pattern recognition receptors; ROS, reactive oxygen species; T_EM, effector memory T cells; TGF‐β, transforming growth factor‐β; Th1, T‐helper cells; Th17, T‐helper cell 17; TLR, toll‐like receptors; T_naive, naïve T cells; Treg, regulatory T cells; T_RM, resident memory T cells [Color figure can be viewed at wileyonlinelibrary.com]