The Integrin-Mediated Focal Adhesion Is Critically Involved in the Macrophage-to-Myofibroblast Transition in Subretinal Fibrosis.

Fibrosis, a common endpoint of chronic inflammatory diseases across organs, remains a major therapeutic challenge. Macrophages are central regulators of fibrotic remodeling, with evidence suggesting their direct role through macrophage-to-myofibroblast transition (MMT). However, the upstream mechanisms governing macrophage fibrogenic reprogramming remain unclear. Using a laser-induced mouse model of subretinal fibrosis, we investigated whether adhesion-dependent mechanotransduction regulates macrophage-driven fibrosis. Bulk RNA-seq of retinal pigment epithelium (RPE)-choroid tissues revealed significant enrichment of adhesion-related genes and focal adhesion pathways, with upregulation of integrins such as Itgb2, Itgal, and Itgax. Increased integrin expression and focal adhesion kinase phosphorylation (pFAK) were detected in infiltrating F4/80+ macrophages within fibrotic lesions. Bone marrow-derived macrophages under high-adherence conditions expressed higher levels of fibrosis-related genes and focal adhesion kinases-related genes such as Ptk2 and Ptk2b. FAK inhibitor PF562271 suppressed TGF-β1-induced upregulation of fibrosis-related genes (Col1a1, Fn1, Acta2) and α-SMA in macrophages. Intraperitoneal administration PF562271 reduced adhesion molecules ITGB2 and ITGAL expression on circulating monocytes and alleviated subretinal fibrosis. These findings identify integrin-FAK-mediated mechanotransduction as a key regulator of macrophage fibrogenic reprogramming and MMT, highlighting adhesion-dependent signaling as a conserved pathway linking tissue remodeling to fibrotic macrophage activation and FAK as a potential therapeutic target.