Systems level identification of a matrisome-associated macrophage polarisation state in multi-organ fibrosis.

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 (SPP1MAM) 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.