Cav1.4 calcium channels control cytokine production by human peripheral TH17 cells and psoriatic skin-infiltrating T cells

Background: Type-17 inflammation characterizes psoriasis, a chronic skin disease. Because several inflammatory cytokines contribute to psoriasis pathogenesis, inhibiting the simultaneous production of these cytokines in T(H)17 cells may be beneficial in psoriasis. We found that Ca(v)1.4, encoded by CACNA1F, was the only Ca(v)1 calcium channel expressed in T(H)17 cells. Objective: We sought to investigate the role of Cav1.4 expression in early T(H)17-activation events and effector functions, as well as its association with T(H)17 signature genes in lesional psoriatic (LP) skins. Methods: Transcriptional gene signatures associated with CACNA1F expression were examined in LP skins by RT-PCR and in situ hybridization. Ca(v)1 inhibitor and/or shRNA lentivectors were used to assess the contribution of Ca(v)1.4 in T(H)17 activation and effector functions in a 3-dimensional skin reconstruction model. Results: CACNA1F expression correlated with inflammatory cytokine expression that characterizes LP skins and was preferentially associated with RORC expression in CD4(+) and CD4(-) cells from LP biopsies. Nicardipine, a Ca(v)1 channel antagonist, markedly reduced inflammatory cytokine production by T(H)17 cells from blood or LP skin. This was associated with decreased TCR-induced early calcium events at cell membrane and proximal signaling events. The knockdown of Ca(v)1.4 in T(H)17 cells impaired cytokine production. Finally, Ca(v)1 inhibition reduced the expression of the keratinocyte genes characteristic of T(H)17-mediated psoriasis inflammation in human skin equivalents. Conclusions: Ca(v)1.4 channels promote T(H)17-cell functions both at the periphery and in inflammatory psoriatic skin.