Suppression of CSF2RA macrophage polarisation impacts pathological cardiac remodelling in mice

Abstract

Abstract Granulocyte-macrophage colony-stimulating factor (GM-CSF; CSF2) has emerged as an important regulator of pro-inflammatory macrophage polarisation, with pro-inflammatory responses recognised to influence cardiac remodelling and repair after cardiac injury. We hypothesised that selective inhibition of CSF2RA, responsible for mediating CSF2 signalling in monocyte/macrophages, could promote reparative responses after cardiac injury through modulating macrophage/fibroblast communication. We demonstrate for the first time that pharmacological CSF2RA inhibition alters the inflammatory response and cardiac remodelling in response to injury, through promoting pro-fibrotic macrophages and beneficial effects upon cardiac fibroblast differentiation, limiting border zone fibrosis, and encouraging scar maturation, culminating in improved cardiac function. Proteomic and in vitro analyses revealed that loss of CSF2-mediated signalling promotes pro-fibrotic macrophages, which facilitate myofibroblast dedifferentiation, in part through decreased CTSZ expression and concomitant augmented CXCL10/CXCR3 signalling. Providing translational potential, we establish that pharmacological CSF2RA inhibition modulates macrophage responses and associated fibroblast function to promote cardiac remodelling, repair, and recovery. These actions may also be applicable to other inflammatory conditions, non-resolving fibrosis, and wound healing.