NF-κB1 Contributes to Imiquimod-Induced Psoriasis-Like Skin Inflammation by Inducing Vγ4+Vδ4+γδT17 Cells

Abstract

Recent studies have identified NF-κB1 as a new disease susceptibility gene for psoriasis. Although accumulating evidence has shown the importance of NF-κB signaling in various cell types in the pathogenesis of psoriasis, it remains unclear how NF-κB1 contributes to the pathogenesis of psoriasis. In this study, we examined psoriasis-like skin diseases induced by topical administration of imiquimod in Nf-κb1‒deficient (Nf-κb1^-/-) mice and littermate wild-type (WT) mice. Compared with WT mice, Nf-κb1^-/- mice exhibited attenuated skin inflammation. The numbers of Vγ4⁺Vδ4⁺γδT17 cells, which cause skin inflammation in this model, were significantly reduced in the skin and draining lymph nodes in imiquimod-treated Nf-κb1^-/- mice. Nf-κb1 is preferentially phosphorylated in Vγ4⁺Vδ4⁺γδT17 cells in WT mice. In vitro proliferation of Vγ4⁺Vδ4⁺γδT17 cells but not conventional CD4⁺ T cells was significantly impaired in Nf-κb1^-/- mice compared with that in WT mice. RNA-sequencing analyses revealed that the expression of E2 factor target genes was decreased in Vγ4⁺Vδ4⁺γδT cells by the absence of NF-κB1. Consistently, the cell cycle progression of Vγ4⁺Vδ4⁺γδT cells was reduced in Nf-κb1^-/- mice compared with that in WT mice. These results suggest that Nf-κb1 plays a crucial role in the pathogenesis of imiquimod-induced psoriasis-like skin inflammation by promoting the proliferation of Vγ4⁺Vδ4⁺γδT17 cells.