Suppression of CSF2RA macrophage polarisation impacts pathological cardiac remodelling in mice

TL;DR

Blocking CSF2RA in mice reduces harmful inflammation and improves heart recovery after injury by changing macrophage and fibroblast behavior.

Contribution

First demonstration that CSF2RA inhibition promotes pro-fibrotic macrophages and improves cardiac repair through CXCL10/CXCR3 signaling and CTSZ reduction.

Findings

Pharmacological CSF2RA inhibition limits border zone fibrosis and encourages scar maturation after cardiac injury.

Loss of CSF2 signaling promotes pro-fibrotic macrophages that facilitate myofibroblast dedifferentiation via decreased CTSZ and increased CXCL10/CXCR3 signaling.

CSF2RA inhibition modulates macrophage and fibroblast function to enhance cardiac remodelling and recovery.

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.

The online version contains supplementary material available at 10.1038/s41598-025-33936-1.

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