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 ).