TNFSF14‐HVEM/LTβR Exacerbates Keratinocyte Abnormalities and IMQ‐Induced Psoriatic Skin Inflammation via Activating NF‐κB/TWIST1 Signalling Pathway

Psoriasis (PS) is a chronic autoimmune skin disease that poses a serious threat to over 100 million patients worldwide. An increasing number of studies have indicated that keratinocytes (KCs) play an essential role in the inflammatory progression of PS. The present study found that tumour necrosis factor superfamily member 14 (TNFSF14) and its two receptors were up-regulated in IMQ-primed KCs and psoriatic skin sections. It also revealed that blocking TNFSF14 signalling (via gene knockout or injections) with its receptors' soluble fusion proteins lymphotoxin beta receptor (LTβR)-immunoglobulin G Fc domain (LTβR-IgGFc) and herpesvirus entry mediator-IgGFc (HVEM-IgGFc) significantly alleviated imiquimod (IMQ)-induced psoriatic skin inflammation by attenuating epidermal hyperplasia, decreasing cellular proliferation, keratinisation, apoptosis, and inflammatory response. Accordingly, direct stimulation with recombinant TNFSF14 markedly enhanced KC abnormalities as evidenced by aggravated cell proliferation and keratinisation, increased cellular apoptosis, and up-regulated inflammatory cytokine expression. Mechanistic studies demonstrated that TNFSF14 mediates KC abnormalities via the nuclear factor-kappa B (NF-κB)/TWIST1 pathway. Taken together, our study findings indicate that TNFSF14-HVEM/LTβR promotes KC dysfunction and IMQ-induced psoriatic skin inflammation via enhancing NF-κB/TWIST1 signalling and suggest that TNFSF14 is a promising therapeutic strategy for the clinical treatment of PS.