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-kappa B activation since treatment with specific NF-kappa B inhibitor Bay 11-7082 failed to prevent the process. In contrast, IFN-beta neutralizing Ab blocked the apoptosis-inducing effect of dsRNA, indicating the involvement of IFN-beta 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-beta secretion and IFN-beta 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-beta.