Fas‐FasL interaction in cytotoxic T cell‐mediated vitiligo: The role of lesional expression of tumor necrosis factor‐α and interferon‐γ in Fas‐mediated melanocyte apoptosis

Abstract

Vitiligo is an acquired skin depigmentation disorder resulting from the selective loss of epidermal melanocytes, and previous studies have suggested that a T lymphocyte‐mediated mechanism has a role in melanocyte loss. Although Fas‐Fas ligand (FasL) interactions are important for T lymphocytes to mediate cytotoxicity, there are only few reports examining the involvement of the Fas‐FasL pathway in vitiligo using in vivo mouse models. In addition, there have been no reports concerning Fas‐mediated apoptosis in human melanocytes in vitro. In this study, we found that the Fas‐mediated pathway is involved in cytotoxic T lymphocyte (CTL)‐dependent vitiligo in a mouse model and FasL‐induced apoptosis of human melanocytes. Tumor necrosis factor (TNF)‐α and interferon (IFN)‐γ, the expression levels of which have been reported to be elevated in lesional skin of patients with vitiligo, synergistically upregulated Fas expression on human melanocytes but inhibited the Fas‐mediated apoptosis. Treatment with TNF‐α and IFN‐γ synergistically upregulated the expression of the anti‐apoptotic genes, c‐IAP2, c‐FLIP and MCL1. A siRNA knock‐down study showed that c‐FLIP and MCL1, but not c‐IAP2, were involved in inducing synergistic inhibitory effects on Fas‐mediated apoptosis. Furthermore, we found that FasL and TNF‐related apoptosis‐inducing ligand (TRAIL) synergistically induced apoptosis on human melanocytes. In conclusion, our results suggest that the Fas‐FasL pathway is involved in CTL‐dependent vitiligo and the elevated expression levels of TNF‐α and IFN‐γ in lesional skin may act synergistically on melanocytes to suppress Fas‐mediated apoptosis.

Mechanisms of melanocyte death in vitiligo

“…HSP70‐exposed TNF related apoptosis‐inducing ligand (TRAIL) + DC are lytic towards TRAIL‐receptor‐expressing melanocytes 141,142 . Cells expressing TRAIL are also found to infiltrate the papillary dermis of patients with inflammatory vitiligo 143 . Besides, upon endogenous and exogenous stress, NK, and ILC1 secret IFN‐γ to induce expression of C‐X‐C motif chemokine receptor (CXCR) 3B on melanocyte surface and release of CXCL9, CXCL10, and CXCL11 from keratinocyte and melanocyte.…”

“…Research based on a mouse model with DNA immunization against a xenogeneic form of TRP‐2 revealed that autoimmunity against normal melanocytes required perforin but Fas–FasL was dispensable 166 . Of the other three studies, depending on transgenic mice with tyrosinase‐specific T cell clone, 167 transgenic mice carrying T cells with an HLA‐A2 restricted human tyrosinase reactive T cell receptor (TCR) 168 and mice manifesting melanoma‐induced autoimmune symptoms (vitiligo‐like white coat), 143 respectively, the former two regard perforin as an unnecessary mechanism in melanocyte destruction. And the first and third affirmed the implication of the Fas–FasL system in killing melanocyte.…”

The fate of melanocyte: Mechanisms of cell death in vitiligo

“…T lymphocyte‐mediated mechanism has been strongly suggested to play a great role in the loss of MCs. Cytotoxic T lymphocytes (CTLs) can directly induce cytotoxicity in MCs through release of cytotoxic mediators such as tumor necrosis factor (TNF)‐α, interferon as well as Fas‐FasL interaction (Jimbo et al., 2019). As a death receptor interacting with FasL, Fas recruits the adaptor protein Fas‐associated protein with death domain (FADD) and procaspase‐8 to form a death‐inducing signaling complex (DISC) in which procaspase‐8 is cleaved and activated.…”

“…Activated caspase‐8 then results in the proteolytic stimulation of downstream effector caspases, such as caspases‐3 and caspases‐7, finally inducing apoptosis. One study (M. Li et al., 2008) demonstrated that polymorphisms of the FAS gene may influence the risk and clinical progression of vitiligo in Han Chinese populations and elevated level of Fas was indeed observed in vitiligo MCs (Jimbo et al., 2019). Moreover, alteration of cytokine expression has been demonstrated in vitiligo patients.…”

“…Several members of TNFRSF have been found significantly upregulated in MCs to various extent after treatment with H2O2 (Sastry et al., 2019), indicating the involvement of TNF‐α/TNFR pathway in MC apoptosis of vitiligo. Besides, the level of interferon (IFN)‐γ was also reported to be elevated in lesional skin of patients with vitiligo (Jimbo et al., 2019). In addition to CTLs, T helper 1 (Th1) cells, natural killer (NK) cells, and innate lymphoid cells (ILC)1 are able to secret IFN‐γ, as well (Tulic et al., 2019).…”