Psoriasis-risk SNP rs610604 reveals nuclear IKKα-TNFAIP3 repressor axis driving autoinflammatory circuits.

Abstract

Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation and immune activation. The single nucleotide polymorphism (SNP) rs610604 within the TNFAIP3 locus is associated with increased psoriasis susceptibility and response to TNF-targeted therapies, yet its functional mechanism remained unclear. In this study, we identify, to our knowledge, previously unreported regulatory axis linking IKKα to TNFAIP3 in keratinocytes and demonstrate how genetic variation at rs610604 modulates inflammatory signaling. Genome-wide chromatin profiling revealed nuclear IKKα predominantly occupies transcriptionally inactive regions and acts as a chromatin-associated repressor. Among its targets, TNFAIP3 emerged as a key locus containing an IKKα-binding region overlapping the rs610604 variant. Functional analyses showed allele-specific recruitment of IKKα, with the psoriasis-risk G allele displaying stronger and more persistent binding compared with the protective T allele. This interaction promotes transcriptional repression of TNFAIP3, a negative regulator of NF-κB, MAPK, and IL-17 pathways, thereby sustaining pro-inflammatory signaling; consistently in psoriatic lesions nuclear IKKα is reduced. These findings identify a nuclear IKKα-TNFAIP3 axis linking genetic susceptibility to inflammatory signaling, providing a potential explanation for the paradox of chronic inflammation without frequent malignant transformation in psoriatic skin, and highlighting IKKα as a potential therapeutic target in psoriasis and related inflammatory disorders.