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

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Item Type:Article
Title:A growth factor-expressing macrophage subpopulation orchestrates regenerative inflammation via GDF-15
Creators Name:Patsalos, A. and Halasz, L. and Medina-Serpas, M.A. and Berger, W.K. and Daniel, B. and Tzerpos, P. and Kiss, M. and Nagy, G. and Fischer, C. and Simandi, Z. and Varga, T. and Nagy, L.
Abstract: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-β 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/PPARγ. 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]).
Keywords:Cell Differentiation, Cultured Cells, Gene Expression Profiling, Growth Differentiation Factor 15, Inbred C57BL Mice, Inflammation, Intercellular Signaling Peptides and Proteins, Knockout Mice, Macrophages, Muscle Cells, Muscles, Myeloid Cells, RNA-Seq, Regeneration, Animals, Mice
Source:Journal of Experimental Medicine
Publisher:Rockefeller University Press
Page Range:e20210420
Date:3 January 2022
Official Publication:https://doi.org/10.1084/jem.20210420
PubMed:View item in PubMed

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