Innate Immunity
Innate immunity is based on the ability of PRRs to detect pathogen-associated molecular patterns (PAMPs) found in pathogens or DAMPs released by damaged cells [50]. Reactive oxygen species and iHSP70 produced by stressed melanocytes serve as DAMPs in vitiligo, and PRRs initiate the innate response [43]. Innate immune cells such as natural killer (NK) cells, macrophage and dendritic cells show aberrant activation in vitiligo skin and granzyme-B (GZMB)-expressing activated NK cells have been found [44, 46]. Vitiligo skin shows an increase in NK cells activating receptors (CD16+CD56+ and CD3+CD16+CD56+), an upregulation in CLEC2B, an activating ligand of NK cells, and a decrease in the inhibitory receptors (CD16+CD158a+). Vitiligo skin also demonstrates increased numbers of dendritic cells, which can destroy melanocytes when activated by iHSP70 [46, 51]. While chemicals can trigger vitiligo by inducing melanocyte stress, adding HSP70i alone aggravates vitiligo mouse model, probably via the activation of dendritic cells in the skin [45].
In addition, mutant HSP70i delivery, which interferes with the signaling pathway of endogenous HSP70i, could inhibit depigmentation in vitiligo mouse and swine models by interfering with dendritic cell activation [46, 52]. Thus, DAMPS, in particular HSP70i, can directly initiate vitiligo in animal models by activating dendritic cells. Activated, dendritic cells locally synthesise cytokines, inducing T cell activation and recruitment to the skin and, in local lymph nodes, recruit cytotoxic T cells, thus bridging the innate with the adaptive immunity [53]. Therefore, delivery of mutant HSP70i may offer a potential treatment for vitiligo by altering the innate immunity. The connection in vitiligo between cellular stress and cell-based immunity was illustrated when melanocytes, stressed by exposure to 4-tertiary butyl phenol, were noted to facilitate activation of dendritic cells thus rendering them melanocytotoxic in vitro [48]. Others have demonstrated that stressed melanocytes can activate melanocyte-specific CD8+ T cells, resulting in an autoimmune response and consequent pigment cell destruction [54]. Recently, perilesional keratinocytes from vitiligo skin, under oxidative stress in vitro, have been shown to exhibit increased expressions of NLR family pyrin domain containing 3 (NLRP3) and downstream cytokine IL-1β, an inflammasome regulator that may modulate innate immune attack on melanocytes [55].
NLRP3 is a cytoplasmic NLR and is an essential constituent of the inflammasome in the innate immunity. The activation of NLRP3 inflammasome requires two signals. The first signal primes cells and induces NLRP3 expression by nuclear factor kB (NF-kB)-mediated signaling [56], while the other signal requires mitochondrial reactive oxygen species (mtROS) and interaction of NLRP3 and apoptosis-associated speck-like protein containing a CARD (ASC) [57]. In addition, the NLRP3 inflammasome can also be activated through transient receptor potential cation channel subfamily M member 2 (TRPM2)-induced intracellular and mitochondrial calcium influx in H2O2-treated keratinocytes [55]. Once activated, NLRP3 inflammasome mediates caspase-1 cleavage which promotes synthesis of IL-β [58, 59]. Subsequently, the function of CD8+ and CD4+ T cell is strengthened through IL1-β/IL-1R signaling pathway [55]. IL1-β elevated the expression of CXCR6 and CXCR3 in CD8+ T cells from vitiligo patients. Also, IL1-β increased the synthesis of IL17A/F in CD4+ T cells and IFN-γ in both CD8+ and CD4+ T cells [55]. IL1-β in stressed keratinocytes also stimulated the expression of CXCL10 and CXCL16, ligands of CXCR3 and CXCR6 through NF-kB pathway, which promote the migration of cytotoxic T cells into vitiligo lesions [55] (Figure 1 ).