The involvement of ERK1/2 and p38 MAPK in the premature senescence of melanocytes induced by HO through a p53-independent p21 pathway.

Background: The pathogenesis of vitiligo is still unknown and oxidative stress is an important factor that can damage or incapacitate melanocytes.

Objective: To investigate the role of oxidative stress in the premature senescence of melanocytes and their transfer of melanosomes.

Methods: Cultured human melanocytes were treated with HO after which cell viability and apoptosis were assessed. We investigated whether exposure to HO induces premature senescence. RNA sequencing was used to screen aging-related signaling pathways. The expression of dendritic regulatory proteins, adhesion molecules and cell cytoskeletal proteins, as well as melanosome distribution were characterized. The ROS scavenger NAC was used to study the role of ROS in cell senescence and in melanosome transfer.

Results: Cell viability decreased progressively and cell apoptosis increased after treatment with HO. HO treatment tended to induce premature senescence in melanocytes through a p53-independent p21 pathway. RNA sequencing analysis showed that HO treatment induced the differential expression of MAPK signaling pathway components. Western blotting and qRT-PCR confirmed that HO treatment increased the phosphorylation of ERK1/2 and p38 MAPK, which are involved in inducing the senescence of melanocytes, but not JNK. The expression of cell cytoskeleton and adhesion molecules decreased after HO treatment. p21 siRNA treatment reversed these changes. Treatment with NAC improved the premature senescence and the impaired melanosome transfer induced by HO.

Conclusion: HO increases ROS levels, which activates the ERK1/2 and p38 MAPK pathways to induce the premature senescence of melanocytes through p21 via a p53-independent pathway and consequently disrupts melanosome transfer.