Figure 1. Activated NLRP3 inflammasome in keratinocytes
promotes T cell responses in vitiligo. NLRP3 inflammasome in stressed
keratinocytes is activated by NF-kB-mediated signaling as well as the
interaction between mtROS and of NLRP3. NLRP3 inflammasome can also be
activated through TRPM2-mediated intracellular and mitochondrial calcium
influx. Once activated, NLRP3 inflammasome mediates caspase-1 cleavage
which provoke synthesis of IL-β, resulting in the activation of D8+ and
CD4+ T cells through IL1-β/IL-1R signaling pathway. IL1-β augments CXCR6
and CXCR3 expression in CD8+ T cells, IL17A/F synthesis in CD4+ T cells
and IFN-γ production in both CD8+ and CD4+ T cells. IL1-β also promotes
the expression of CXCL10 and CXCL16. TRPM2-facilitated NLRP3
inflammasome activation in keratinocytes stimulates T-cell function in
vitiligo patients as demonstrated by upregulation of T cell activation
markers CD69 and CD137 (Adapted from Li et al., 2020)[55].
Furthermore, perilesional infiltrating self-reactive CD8+ T cells in
vitiligo patients recognise Melan-A/MART, tyrosinase (TYR) and
melanocyte-specific protein, all of which are antigens involved in the
melanogenic pathway [66].
Vitiligo patients showed elevated numbers of CD8+ T cells in their blood
compared to healthy individuals [64].
Moreover, peri-lesional skin of vitiligo patients are highly infiltrated
by melanocyte-specific CD8+ T cells [62], and these cells have the
ability to kill melanocytes in vitro [62, 67, 68]. CD8+ T
cells isolated from peri-lesional skin of vitiligo patients infiltrate
explants of autologous healthy pigmented vitiligo skin and eliminate
melanocytes in a way similar to the clinical pathology of vitiligo
[68]. Importantly, isolated CD4+ T cells were incapable of inducing
melanocyte apoptosis in autologous skin explants [68]. In
vitro culture of CD8+ and CD4+ T cells derived from peri-lesional
vitiligo skin secrete high levels interferon-γ (IFN-γ), a
pro-inflammatory cytokine required for melanocyte-specific autoreactive
CD8+ T cell recruitment [69]. These findings provide robust evidence
that CD8+ T cells are equally essential and sufficient for destruction
of melanocytes in vitiligo lesions.