Double‐stranded RNA induces melanocyte death via activation of Toll‐like receptor 3

  As cutaneous pigment‐producing cells, melanocytes can become targets of primary and secondary immune response as can be seen in diseases like vitiligo and Vogt–Koyanagi–Harada (VKH) syndrome. Viral infections have previously been implicated as a possible precipitating factor in the destruction of melanocytes in these disorders. During viral replication, double‐stranded RNA (dsRNA) is produced as an intermediate metabolite, which induces antiviral and inflammatory responses through Toll‐like receptor 3 (TLR3) in cells of innate immune system. The functional responses of melanocytes to dsRNA, however, remain unclear. Herein, we demonstrated that human melanocytes expressed TLR3 at a constitutive and inducible level. Stimulation with poly(I:C), a synthetic dsRNA analogue, triggered apoptosis of melanocytes. The apoptosis‐inducing effect was shown by RNA interference to be largely dependent on TLR3, but occurred independently of NF‐κB activation since treatment with specific NF‐κB inhibitor Bay 11‐7082 failed to prevent the process. In contrast, IFN‐β neutralizing Ab blocked the apoptosis‐inducing effect of dsRNA, indicating the involvement of IFN‐β autocrine signalling. Furthermore, studies on the intracellular signal transduction pathways revealed that dsRNA induces the activation of p38, ERK1/2 and JNK1/2 in melanocytes. Using specific inhibitors, we demonstrated that activation of p38 and ERK1/2 controlled both IFN‐β secretion and IFN‐β mediated cell death. Taken together, these data suggest that viral dsRNA stimulates TLR3 in human melanocytes and triggers the cellular apoptosis through autocrine of IFN‐β.