GPR108 Negatively Regulates TLR7 Signaling in Imiquimod-Induced Psoriasiform Dermatitis

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.

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.

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.

GPR108 functions as a negative regulator of TLR7 signaling in psoriasis.