Fibroblast-derived MMP2 drives tissue-resident memory T cell formation via TGF-β1 activation and remodels the immune microenvironment in psoriasis

Abstract Psoriasis is an immune-mediated chronic inflammatory skin disease characterized by a high recurrence rate, presenting a significant challenge for clinical treatment. Tissue-resident memory T cells (TRM) are considered crucial drivers of psoriasis relapse, with fibroblasts playing a pivotal role in regulating this process. Previous studies have shown that fibroblasts with high expression of matrix metalloproteinase 2 ( MMP2 ) exacerbate inflammation, yet the mechanisms by which they remodel the immune microenvironment and regulate TRM residency remain unclear. In this study, we constructed a fibroblast-specific MMP2 overexpression transgenic mouse model (FB-Mmp2KI) and employed various techniques, including single-cell transcriptomics, spatial transcriptomics, immunofluorescence, ELISA, and in vitro co-culture. Our results demonstrate that inflammation in FB-Mmp2KI mice is significantly aggravated. Single-cell analyses revealed that MMP2 overexpression remodels the immune microenvironment: the proportion of inflammatory fibroblasts increases, accompanied by epithelial-mesenchymal transition (EMT), while keratinocyte proliferation and metabolic activity are elevated. Additionally, there is significant infiltration of monocyte-derived macrophages (MDMac) and dendritic cells, which express high levels of IL-1β . Importantly, we found that MMP2 activates latent TGF-β1 , leading to the upregulation of CD69 and CD103 on T cells, thereby enhancing TRM cell residency. In vitro experiments confirmed that MMP2 inhibitors could reverse this process. In summary, fibroblast-derived MMP2 promotes TRM residency by inducing EMT, remodeling innate immunity, and activating TGF-β signaling, thereby collaboratively driving inflammation and recurrence. This establishes MMP2 as a central molecular hub linking fibroblast abnormalities to immune memory, suggesting that targeting the MMP2-TGF-β1 -TRM axis may provide a novel approach to simultaneously control inflammation and prevent recurrence.