Activation of NF-κB signaling in tissue-resident memory T cells promotes recurrent psoriasis in mice.

Abstract

BACKGROUND: Recurrence triggered by immunological memory is a critical challenge in the treatment of psoriasis. Tissue-resident memory T (Trm) cells are the primary pacemakers in recurrent psoriasiform dermatitis following stimulation and infection by previous pathogens. However, the mechanisms underlying Trm cell activation remain unclear. METHODS: In this study, imiquimod-induced recurrent psoriatic mice were established to characterize the phenotypes of different Trm cell subsets. CD8/CD4Tcm cell injection and NF-κB inhibitor or agonist treatment were then used to investigate the role and mechanisms of Trm cells in recurrent psoriasis. Finally, CD8T cells and keratinocyte co-culture systems were established to investigate the effects of activating NF-κB activation in Trm cells. RESULTS: Mice displayed severe psoriatic dermatitis after repeated imiquimod treatment. The CD8Trm cells, but not CD4Trm cells, were elevated in the skin of recurrent psoriatic mice. Injection of CD8Tcm cells injection elicited more severe psoriatic symptoms than imiquimod treatment alone, indicating that CD8Trm cells are critical participants in psoriatic recurrence. Phosphorylation of NF-kB p65 (RELA), p-IKKa, p-RelB and NF-kB p100/p52 was enhanced in the skin of imiquimod-induced recurrent psoriatic mice. NF-κB inhibitor/agonist treatment significantly suppressed or restored the dermatitis severity and CD8Trm cell levels in recurrent psoriatic mice. Meanwhile, NF-κB inhibition also restored the expression of DLAT in Trm cells. Finally, NF-κB inhibitors directly suppressed Trm cell activation and inflammation of Trm cells. CONCLUSION: Together, these findings suggest that canonical and non-canonical NF-κB signaling directly activates Trm cell differentiation, inhibits cellular cuproptosis, and promotes recurrent psoriasis.