Cutaneous Calcium/Calmodulin-Dependent Protein Kinase II--Positive Sympathetic Nerves Secreting Norepinephrine Dictate Psoriasis

Cutaneous sympathetic nerve is a crucial part of neuropsychiatric factors contributing to skin immune response, but its role in the psoriasis pathogenesis remains unclear. It is found that cutaneous calcium/calmodulin-dependent protein kinase II-gamma (CAMK2 gamma), expressed mainly in sympathetic nerves, is activated by stress and imiquimod in mouse skin. Camk2g-deficient mice exhibits attenuated imiquimod-induced psoriasis-like manifestations and skin inflammation. CaMK2 gamma regulates dermal gamma delta T-cell interleukin-17 production in imiquimod-treated mice, dependent on norepinephrine production following cutaneous sympathetic nerve activation. Adrenoceptor beta 1, the primary skin norepinephrine receptor, colocalises with gamma delta T cells. CaMK2 gamma aggravates psoriasiform inflammation via sympathetic nerve-norepinephrine-gamma delta T cell-adrenoceptor beta 1-nuclear factor-kappa B and -p38 axis activation. Application of alcaftadine, a small-molecule CaMK2 gamma inhibitor, relieves imiquimod-induced psoriasis-like manifestations in mice. This study reveals the mechanisms of sympathetic-nervous-system regulation of gamma delta T-cell interleukin-17 secretion, and provides insight into neuropsychiatric factors dictating psoriasis pathogenesis and new potential targets for clinical psoriasis treatment.