Platelet-instructed SPP1+ macrophages drive myofibroblast activation in fibrosis in a CXCL4-dependent manner.

Fibrosis represents the common end stage of chronic organ injury independent of the initial insult, destroying tissue architecture and driving organ failure. Here we discover a population of profibrotic macrophages marked by expression of Spp1 , Fn1 , and Arg1 (termed Spp1 macrophages), which expands after organ injury. Using an unbiased approach, we identify the chemokine (C-X-C motif) ligand 4 (CXCL4) to be among the top upregulated genes during profibrotic Spp1 macrophage differentiation. In vitro and in vivo studies show that loss of Cxcl4 abrogates profibrotic Spp1 macrophage differentiation and ameliorates fibrosis after both heart and kidney injury. Moreover, we find that platelets, the most abundant source of CXCL4 in vivo , drive profibrotic Spp1 macrophage differentiation. Single nuclear RNA sequencing with ligand-receptor interaction analysis reveals that macrophages orchestrate fibroblast activation via Spp1 , Fn1 , and Sema3 crosstalk. Finally, we confirm that Spp1 macrophages expand in both human chronic kidney disease and heart failure. [Display omitted] • ECM regulator scoring identifies a SPP1 ⁺ macrophage subset in myocardial infarction • Chemokine CXCL4 drives SPP1 ⁺ macrophage activation and macrophage-fibroblast crosstalk • Platelet-derived CXCL4 mediates SPP1 ⁺ macrophage activation and organ fibrosis • SPP1 ⁺ macrophages expand in human heart failure and chronic kidney disease By ranking immune cells after myocardial infarction based on ECM regulator expression, Hoeft et al. find an SPP1 ⁺ macrophage subset. They identify the chemokine CXCL4 as critical for SPP1 ⁺ macrophage activation, macrophage-fibroblast crosstalk, and organ fibrosis. They confirm expansion of SPP1 ⁺ macrophages in human heart failure and chronic kidney disease. [ABSTRACT FROM AUTHOR]