Cytosolic dsDNA triggers apoptosis and pro‐inflammatory cytokine production in normal human melanocytes

Abstract

Considerable evidence implicates that viral infection might be a participant factor in the pathogenesis of vitiligo. However, it is still unclear how viral infection leads to the melanocyte destruction. To elucidate the effects of viral dsDNA on the viability and cytokine synthesis of normal human melanocytes and to explore the underlying mechanisms, primary cultured normal human melanocytes were transfected with poly (dA:dT). The results demonstrated that poly(dA:dT) triggered apoptosis instead of pyroptosis in melanocytes. Knocking down AIM2 or RIG-I by RNA interference partially reduced the poly (dA:dT)-induced LDH release, suggesting the involvement of both nucleic acid sensors in the process of melanocyte death. Poly(dA: dT) induced the expression of pro-inflammatory cytokine genes including IFN-b, TNF-a, IL-6 and IL-8 as well, whereas the pro-inflammatory cytokine production was suppressed by RIG-I siRNA, but not by AIM2 siRNA. Poly(dA:dT) treatment increased the phosphorylation of p38 and JNK and NFjB. Accordingly, NFjB inhibitor Bay 11-7082 and JNK inhibitor SP600125 blocked the induction of the cytokine genes except IFN-b. The production of IL6 and IL8 was also suppressed by p38 inhibitor SB203580. On the contrary, the Poly(dA:dT)-induced melanocyte death was only decreased by SP600125. This study provides the possible mechanism of melanocyte destruction and immuno-stimulation in vitiligo by innate immune response following viral infection.

The immunology and inflammatory responses of human melanocytes in infectious diseases

“…A C C E P T E D ACCEPTED MANUSCRIPT 11 The innate immune signaling pathways are intimately linked to apoptosis through the mobilization of TRADD, RIP and FADD molecules. The intrinsic apoptosis pathway is initiated by the release of cytochrome C from the mitochondria which promotes the formation of the apoptosome, including APAF-1 (apoptotic protease activating factor) and caspase 9 which in turn activates the effector caspase 3.…”

“…Tyrosinase activity is inhibited by IL-1 and possibly contributing to hypopigmentation (60); (61); (11) Tumor necrosis factor-α Inhibit the growth of MC. enhances the expression of VLA-2, ICAM-1 and HLA class I antigens and strongly induced HLA-DR. May decrease pigmentation by reducing melanocortin-1 receptor expression on MC.…”

“…MC apoptotic or necrotic debris could be perceived as autoantigens by T cells (bystander activation mechanism). (11,42) HMGB1 Nuclear protein released either by infected-, stressed-or necrotic (e.g. MC) cells.…”

“…The initial factor(s) that triggers the autoimmune vitiligo response is still elusive. However, it has been proposed that the appearance of scattered skin/hair depigmentation accompanied with viral infection and the discovery of the causative link between herpes viral infection and vitiligo in a chicken model are plausible links between the onset of vitiligo and viral infection of melanocytes (9)(10)(11).…”

Comment: the mystery of melanocyte demise in vitiligo

“…To link melanocyte loss in vitiligo and melanocyte responses to viral infection, Wang et al. in this issue demonstrate in vitro that a viral dsDNA analog poly(dA:dT) induces apoptosis and pro‐inflammatory cytokine production including interferon (IFN)‐ β , tumor necrosis factor (TNF)‐ α , interleukin (IL)‐6 and IL‐8 in normal human melanocytes . Viral infections are a constant threat to higher organisms.…”