A growth factor–expressing macrophage subpopulation orchestrates regenerative inflammation via GDF-15
Open Access
- 30 November 2021
- journal article
- research article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 219 (1)
- https://doi.org/10.1084/jem.20210420
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 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]).Keywords
Funding Information
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institutes of Health (R01-DK115924, R01-DK124782)
- Hungarian Scientific Research Fund (OTKA PD124843)
- Hungarian Academy of Sciences
- Ministry of Human Capacities (ÚNKP-19-4-DE-173)
- European Access Sequencing Infratructure-Genomics (824110)
This publication has 133 references indexed in Scilit:
- Pax7 is critical for the normal function of satellite cells in adult skeletal muscleProceedings of the National Academy of Sciences of the United States of America, 2013
- Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosisProceedings of the National Academy of Sciences of the United States of America, 2012
- An integrated encyclopedia of DNA elements in the human genomeNature, 2012
- STAT6 Transcription Factor Is a Facilitator of the Nuclear Receptor PPARγ-Regulated Gene Expression in Macrophages and Dendritic CellsImmunity, 2010
- Distribution and Function of Macrophage Galactose-type C-type Lectin 2 (MGL2/CD301b)Online Journal of Public Health Informatics, 2010
- Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell IdentitiesMolecular Cell, 2010
- A CREB-C/EBPβ cascade induces M2 macrophage-specific gene expression and promotes muscle injury repairProceedings of the National Academy of Sciences of the United States of America, 2009
- Analysis of PPARα-dependent and PPARα-independent transcript regulation following fenofibrate treatment of human endothelial cellsAngiogenesis, 2009
- Oxidative metabolism and PGC-1β attenuate macrophage-mediated inflammationCell Metabolism, 2006
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005