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

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]).

Retinoids Promote Mouse Bone Marrow-Derived Macrophage Differentiation and Efferocytosis via Upregulating Bone Morphogenetic Protein-2 and Smad3

“…Circulating monocytes scan for pathogens and respond to inflammatory signals needed to perform their phagocytic functions, or monocytes can tissue migrate to become macrophages. The resulting macrophages are not a uniform cell population; and there is significant macrophage heterogeneity determined by the immune environment [ 51 ]. In mice, monocyte derived macrophages are typically classified as either pro-inflammatory M1 (Ly6C Hi ) or M2 (Ly6C Lo ) pro-reparative cells generated following efferocytosis.…”

“…In mice, monocyte derived macrophages are typically classified as either pro-inflammatory M1 (Ly6C Hi ) or M2 (Ly6C Lo ) pro-reparative cells generated following efferocytosis. The Ly6C Lo macrophages can be divided into three further groups participating in the resolution of inflammation, antigen presentation, and tissue repair, and the later are known to release growth factors and pro-angiogenic and tissue repair factors, such as VEGFA, growth differentiation-factor 3 (GDF3), or insulin-like growth factor-1 (IGF-1) [ 51 ].…”

Coping With Stress: The Mitokine GDF-15 as a Biomarker of COVID-19 Severity

“…In the same animal model, the expression of GDF-15 was induced in the skeletal muscles via PPARβ/δ agonist, mitigating inflammation and improving glucose tolerance ( 39 ). In another mouse model, GDF-15 induction through the PPARγ pathway plays a key role in tissue regeneration ( 40 ). In summary, hindbrain GFRAL acts as a receptor for GDF-15 and may explain part of its metabolic effects, however the mechanisms of its immunomodulatory effect remain to be determined.…”

Involvement of phosphatidylserine receptors in the skeletal muscle regeneration: therapeutic implications

“…A recent detailed analysis of these macrophages by determining their mRNA expressions on a single cell level demonstrated the complexity of this transformation process. 7 The timed switch between the two main subsets of macrophages, the inflammatory ones that produce proinflammatory cytokines and the healing ones that produce growth and angiogenic factors and anti-inflammatory mediators, is a key to the proper regeneration process, and it is thought to be induced by the efferocytosis process itself. This idea came from many previous observations that demonstrated that uptake of apoptotic cells induces an anti-inflammatory phenotype in macrophages.…”

“…A recent detailed analysis of these macrophages by determining their mRNA expressions on a single cell level demonstrated the complexity of this transformation process. 7 …”