Macrophages sense ECM mechanics and growth factor availability through cytoskeletal remodeling to regulate their tissue repair program [ATAC-seq]

Tissue resident macrophages play important roles in tissue homeostasis and repair. However, how macrophages monitor and maintain tissue integrity is not well understood. The extracellular matrix (ECM) is a key structural and organizational component of all tissues. Here, we find that macrophages sense the mechanical properties of the ECM in order to regulate a specific tissue repair program. We show that macrophage mechanosensing is mediated by cytoskeletal remodeling and can be performed in three-dimensional environments through a non-canonical, integrin-independent mechanism analogous to amoeboid migration. We find that these cytoskeletal dynamics also integrate biochemical signaling by CSF1 and ultimately regulate chromatin accessibility to control the mechanosensitive gene expression program. This study suggests a distinct mode of ECM mechanosensing and growth factor signaling through which macrophages may regulate tissue repair and fibrosis. ATAC-seq of unstimulated, IL-4 stimulated, IL-4 stimulated+MCSF, and IL-4 stimulated+LatA murine bone-marrow derived macrophages (BMDMs).