GPR108 Negatively Regulates TLR7 Signaling in Imiquimod‐Induced Psoriasiform Dermatitis

Objective Psoriasis, a common chronic inflammatory skin disease, is characterized by epidermal hyperplasia and inflammatory cell infiltration. While endosomal Toll‐like receptors (TLRs), particularly TLR7, are key drivers of psoriatic exacerbations, the regulatory mechanisms governing TLR7 activity in psoriasis remain incompletely understood. This study aims to investigate the role of G protein‐coupled receptor 108 (GPR108) in regulating TLR7 activity during imiquimod (IMQ)‐induced psoriasiform dermatitis. Methods We established IMQ‐induced psoriasiform lesions in Gpr108 ‐null mice, as well as IMQ‐treated GPR108‐deficient keratinocyte and macrophage models. The psoriasis‐like phenotype was assessed in vivo using PASI scoring and H&E staining. Protein expression was examined by Western blotting, immunohistochemistry, and immunofluorescence. Additionally, RNA‐seq and flow cytometric analyses were performed to verify the involvement of the TLR7/NF‐κB signaling in regulating GPR108‐deficient macrophage polarization. Results We found that Gpr108 deficiency exacerbates IMQ‐induced psoriatic lesions in mice. Mechanistically, GPR108 deficiency enhances TLR7/MyD88/NF‐κB signaling in both keratinocytes and macrophages following imiquimod stimulation. This increased TLR7 activation promotes keratinocyte hyperproliferation and dysregulated differentiation, and alters the M1/M2 macrophage balance, leading to elevated production of cytokines, including TNF‐α and IL‐6. Conclusion GPR108 functions as a negative regulator of TLR7 signaling in psoriasis.