Psoriasis pathogenesis involves dysregulated immune responses, yet the role of protein prenylation (particularly PGGT1B-mediated geranylgeranylation) in macrophage-driven inflammation remains poorly understood. This study aims to explore the role and molecular mechanism of protein geranylgeranyltransferase type I subunit beta (PGGT1B) in the development of psoriasis. Myeloid cell-specific PGGT1B gene knockout mice were generated, and a mouse psoriasis model was established with imiquimod to study the role and mechanism of PGGT1B gene downregulation-induced macrophage activation in the pathogenesis of psoriasis. Bone marrow-derived macrophages (BMDMs) from wild-type and PGGT1B knockout mice were cultured and stimulated with resiquimod (R848) to simulate the immune microenvironment of psoriasis. In addition, the differentially expressed genes induced by PGGT1B knockout were analyzed using RNA-seq, and bioinformatics analysis was carried out to study the possible biological process of PGGT1B regulation. Finally, PMA-THP-1 was co-cultured with HaCaT cells to study the effect of PGGT1B deletion in macrophages on the proliferation and differentiation of keratinocytes. Bone marrow PGGT1B deficiency aggravated the psoriasis-like lesions induced by imiquimod in mice. In BMDMs with PGGT1B deficiency, the NF-κB signaling pathway was over-activated by R848, and the expressions of proinflammatory cytokines IL-1β, IL-6, and TNF-α were significantly increased. Activation of cell division cycle 42 (CDC42) may mediate the activation of the NF-κB pathway in PGGT1B-deficient BMDMs. PGGT1B deletion can promote the proliferation and inhibit the differentiation of HaCaT cells. Reduced PGGT1B levels can increase the expression of CDC42, which further activates NLRP3 inflammation in macrophages through NF-κB signaling, further aggravating the inflammatory state of psoriasis. Psoriasis-like lesions induced by IMQ are aggravated when PGGT1B expression is reduced in mouse bone marrow cells. A possible mechanism for this is that PGGT1B-deficient macrophages migrate to the epidermis more easily during psoriasis, which leads to the activation of Cdc42, NF-κB signaling, and NLRP3 inflammatory corpuscles.
