Abstract
Tissue fibrosis affects multiple organs and involves a master-regulatory role of macrophages which respond to an initial inflammatory insult common in all forms of fibrosis. The recently unravelled multi-organ heterogeneity of macrophages in healthy and fibrotic human disease suggests that macrophages expressing osteopontin (SPP1) associate with lung and liver fibrosis. However, the conservation of this SPP1(+) macrophage population across different tissues and its specificity to fibrotic diseases with different etiologies remain unclear. Integrating 15 single-cell RNA-sequencing datasets to profile 235,930 tissue macrophages from healthy and fibrotic heart, lung, liver, kidney, skin, and endometrium, we extended the association of SPP1(+) macrophages with fibrosis to all these tissues. We also identified a subpopulation expressing matrisome-associated genes (e.g., matrix metalloproteinases and their tissue inhibitors), functionally enriched for ECM remodelling and cell metabolism, representative of a matrisome-associated macrophage (MAM) polarisation state within SPP1(+) macrophages. Importantly, the MAM polarisation state follows a differentiation trajectory from SPP1(+) macrophages and is associated with a core set of regulon activity. SPP1(+) macrophages without the MAM polarisation state (SPP1(+)MAM(-)) show a positive association with ageing lung in mice and humans. These results suggest an advanced and conserved polarisation state of SPP1(+) macrophages in fibrotic tissues resulting from prolonged inflammatory cues within each tissue microenvironment.