Macrophage heterogeneity governs the balance between fibrosis and tissue protection in systemic sclerosis

Systemic sclerosis (SSc), especially its life-threatening interstitial lung disease (SSc-ILD), urgently requires targeted therapies. This review highlights how macrophage heterogeneity, transcending the obsolete M1/M2 paradigm, acts as a central orchestrator of the pathogenic "fibro-immune axis" linking vascular injury, immune dysregulation, and fibroblast-mediated fibrosis. Single-cell RNA sequencing and spatial multi-omics reveal distinct, context-dependent macrophage subsets with specialised roles across SSc tissues: secreted phosphoprotein-1 (SPP1+) macrophages dominate SSc-ILD, promoting fibrosis via epithelialmesenchymal transition and reciprocal activation of fibroblasts through IL-6/ERK signalling; FCGR3A+ macrophages drive skin inflammation and fibrosis via NF-κB and TGF-β pathways; while TREM2+ macrophages exhibit protective lipid clearance functions in skin. These subsets primarily originate from monocytes recruited through pathways such as CCL2-SPP1-ARG1 and CXCL4. Crucially, spatial analyses uncover "fibrotic niches" where macrophages and fibroblasts engage in pathogenic crosstalk, explaining the efficacy of IL-6 blockade (tocilizumab) in early SSc-ILD. Despite these advances, challenges remain in resolving temporal dynamics and spatial signalling resolution. This integrated perspective establishes macrophage heterogeneity as a fundamental determinant of SSc progression and a critical frontier for mechanism-based therapeutics.