Per2 deficiency exacerbates IL-17-driven psoriasiform dermatitis in a diurnal-dependent manner.

Circadian clock genes regulate immune cell homeostasis, yet their contribution to inflammatory skin disorders remains incompletely understood. Here, we investigated the role of Period2 (Per2), a core circadian repressor, in shaping T cell-driven psoriasiform inflammation. Per2-/- and wild-type mice (WT) were subjected to imiquimod (IMQ) -induced psoriasiform dermatitis. Disease severity, cutaneous pathology, immune cell subsets, cytokines, melatonin, and circadian regulators were assessed at ZT2 and ZT14 to evaluate diurnal variations. Per2 deficiency exacerbated IMQ-induced psoriasiform dermatitis, with higher PASI scores, epidermal hyperplasia, and parakeratosis, most pronounced at ZT14. It was also associated with increased serum melatonin, expansion of splenic Th17 and γδT cells, and elevated IL-17A, IL-17F, and TNF-α in serum and lesional skin. Mechanistically, Per2 loss resulted in a nocturnal surge of NFIL3 and RORγt expression, which mirrored the elevation of IL-17A even in the absence of increased IL-23. These findings indicate that Per2 loss aggravates psoriatic inflammation in a diurnal-dependent manner by enhancing IL-17-dominated immune responses, potentially involving the derepression of the NFIL3/RORγt axis.