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

J Exp Med. 2022 Jan 3;219(1):e20210420. doi: 10.1084/jem.20210420. Epub 2021 Nov 30.


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 Ly6Chigh, infiltrating inflammatory Ly6Chigh, and reparative Ly6Clow 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]).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Gene Expression Profiling / methods*
  • Growth Differentiation Factor 15 / genetics*
  • Growth Differentiation Factor 15 / metabolism
  • Inflammation / genetics*
  • Inflammation / metabolism
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Macrophages / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle Cells / metabolism
  • Muscles / injuries
  • Muscles / metabolism
  • Muscles / physiopathology
  • Myeloid Cells / metabolism
  • RNA-Seq / methods
  • Regeneration / genetics*


  • Growth Differentiation Factor 15
  • Intercellular Signaling Peptides and Proteins