A growth factor-expressing macrophage subpopulation orchestrates regenerative inflammation via GDF-15

Regenerative inflammation in skeletal muscle drives macrophage specification via a regeneration-promoting program. A growth factor-expressing macrophage population develops, producing GDF-15 under the control of RXR and PPAR gamma. GDF-15 acts as an autocrine and paracrine factor coordinating myoblast proliferation and myeloid cell invasion and activity. Muscle regeneration is the result of the concerted action of multiple cell types driven by the temporarily controlled phenotype switches of infiltrating monocyte-derived macrophages. Pro-inflammatory macrophages transition into a phenotype that drives tissue repair through the production of effectors such as growth factors. This orchestrated sequence of regenerative inflammatory events, which we termed regeneration-promoting program (RPP), is essential for proper repair. However, it is not well understood how specialized repair-macrophage identity develops in the RPP at the transcriptional level and how induced macrophage-derived factors coordinate tissue repair. Gene expression kinetics-based clustering of blood circulating Ly6C(high), infiltrating inflammatory Ly6C(high), and reparative Ly6C(low) macrophages, isolated from injured muscle, identified the TGF-beta superfamily member, GDF-15, as a component of the RPP. Myeloid GDF-15 is required for proper muscle regeneration following acute sterile injury, as revealed by gain- and loss-of-function studies. Mechanistically, GDF-15 acts both on proliferating myoblasts and on muscle-infiltrating myeloid cells. Epigenomic analyses of upstream regulators of Gdf15 expression identified that it is under the control of nuclear receptors RXR/PPAR gamma. Finally, immune single-cell RNA-seq profiling revealed that Gdf15 is coexpressed with other known muscle regeneration-associated growth factors, and their expression is limited to a unique subpopulation of repair-type macrophages (growth factor-expressing macrophages [GFEMs]).

Automated summary

Regenerative inflammation in skeletal muscle drives macrophage specification through a regeneration-promoting program. The orchestrated sequence of events involves multiple cell types and temporarily controlled phenotype switches of infiltrating macrophages, transitioning from pro-inflammatory to tissue repair phenotypes through the production of growth factors. The transcriptional identity of repair-macrophages develops through specialized factors like GDF-15, which coordinates proper tissue repair by acting on both myoblasts and muscle-infiltrating myeloid cells.