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

• DOI: 10.1084/jem.20210420
• Publication Date: 2021-11-30T14:23:02Z
• Authors: Andreas Patsalos; Laszlo Halasz; Miguel A. Medina-...; Wilhelm K. Berger; Bence Daniel; Petros Tzerpos; Máté Kiss; Gergely Nagy; Cornelius Fischer; Zoltan Simandi; Tamas Varga; Laszlo Nagy
• Keywords: Inflammation; Male; Mice, Knockout; 0301 basic medicine; Muscle Cells; 0303 health sciences; Growth Differentiation Factor 15; Gene Expression Profiling; Macrophages; Muscles; Cell Differentiation; Article; Mice, Inbred C57BL; 03 medical and health sciences; Animals; Intercellular Signaling Peptides and Proteins; Regeneration; Myeloid Cells; RNA-Seq; Technology Platforms; Genes, Cells and Cell-Based Medicine [Topic 1]; Cells, Cultured

Muscle regeneration is the result of concerted action multiple cell types driven by temporarily controlled phenotype switches infiltrating monocyte-derived macrophages. Pro-inflammatory macrophages transition into a that drives tissue repair through production effectors such as growth factors. This orchestrated sequence regenerative inflammatory events, which we termed regeneration-promoting program (RPP), essential for proper repair. However, it not well understood how specialized repair-macrophage identity develops in RPP at transcriptional level and induced macrophage-derived factors coordinate Gene expression kinetics-based clustering blood circulating Ly6Chigh, reparative Ly6Clow macrophages, isolated from injured muscle, identified TGF-β superfamily member, GDF-15, component RPP. Myeloid GDF-15 required muscle following acute sterile injury, revealed gain- loss-of-function studies. Mechanistically, acts both on proliferating myoblasts muscle-infiltrating myeloid cells. Epigenomic analyses upstream regulators Gdf15 under control nuclear receptors RXR/PPARγ. Finally, immune single-cell RNA-seq profiling coexpressed with other known regeneration-associated factors, their limited to unique subpopulation repair-type (growth factor-expressing [GFEMs]).