p38α signaling in Langerhans cells promotes the development of IL-17-producing T cells and psoriasiform skin inflammation.

Dendritic cells (DCs) contribute to psoriasis pathogenesis. In a mouse model of imiquimod-induced psoriasiform skin inflammation, we found that p38 alpha activity in Langerhans cells (LCs), a skin-resident subset of DCs, promoted the generation of T cells that produce IL-17, a proinflammatory cytokine that is implicated in autoimmune disease. Deletion of p38 alpha in LCs, but not in other skin or circulating DC subsets or T cells, decreased T cell-mediated psoriasiform skin inflammation in mice. The activity of p38 alpha in LCs specifically promoted IL-17 production from gamma delta and CD4(+) T cells by increasing the abundance of IL-23 and IL-6, two cytokines that stimulate IL-17 secretion. Inhibition of p38 activity through either pharmacological inhibition or genetic deletion also reduced the severity of established psoriasiform skin inflammation. Together, our findings indicate a critical role for p38 alpha signaling in LCs in promoting inflammatory responses in the skin and suggest that targeting p38 alpha signaling in LCs may offer an effective therapeutic approach to treat psoriasis.