Profibrotic role of transcription factor SP1 in cross-talk between fibroblasts and M2 macrophages

Fibrosis disrupts tissue balance and links to severe illnesses, impairing organ function and, in some cases, even fatality. The interaction between M2 macrophages and fibroblasts is vital for tissue equilibrium. Transforming growth factor β1 (TGF-β1) released by M2 macrophages plays a central role in fibrosis, regulating fibroblast activity and extracellular matrix metabolism. Targeting TGF-β1 is key to fibrosis treatment. In our study using three fibroblast cell lines, we reveal that the M2 macrophage transcription factor SP1 enhances binding to the TGF-β1 promoter motif, promoting TGF-β1 transcription and activating fibroblasts (This process does not involve changes in DNA methylation levels surrounding the motif sequence). The zinc fingers in SP1's DNA-binding domain 3 are crucial for this binding. In vivo, targeting SP1 in rat ligaments significantly reduces extracellular matrix accumulation. Our findings highlight SP1 as a promising target for regulating tissue extracellular matrix and combating fibrosis.