Phenotypic transitions of macrophages orchestrate tissue repair

Abstract

Macrophages are essential for the efficient healing of numerous tissues, and they contribute to impaired healing and fibrosis. Tissue repair proceeds through overlapping phases of inflammation, proliferation, and remodeling, and macrophages are present throughout this progression. Macrophages exhibit transitions in phenotype and function as tissue repair progresses, although the precise factors regulating these transitions remain poorly defined. In efficiently healing injuries, macrophages present during a given stage of repair appear to orchestrate transition into the next phase and, in turn, can promote debridement of the injury site, cell proliferation and angiogenesis, collagen deposition, and matrix remodeling. However, dysregulated macrophage function can contribute to failure to heal or fibrosis in several pathological situations. This review will address current knowledge of the origins and functions of macrophages during the progression of tissue repair, with emphasis on skin and skeletal muscle. Dysregulation of macrophages in disease states and therapies targeting macrophage activation to promote tissue repair are also discussed.

Figure 1

Models of monocyte recruitment during tissue repair. Left panel: In mouse skeletal muscle, circulating Ly6C^hi monocytes are recruited via CCL2/CCR2, then converted to Ly6C^lowin situ. Right panel: After myocardial infarction in mice, the heart sequentially recruits Ly6C^hi, then Ly6C^low, blood monocytes via CCL2/CCR2 and CX3CL1/CX3CR1, respectively. The mechanisms of monocyte recruitment in skin remain to be determined.

Figure 2

Phases of tissue repair. Efficient tissue repair occurs in overlapping phases of inflammation, proliferation, and remodeling. Monocytes/macrophages (Mps) are present during all phases of repair and orchestrate timely progression of healing. Macrophages of the inflammatory phase phagocytose dead tissue and promote proliferation of endothelial cells (ECs) and skeletal muscle myoblasts (Mbs). Effects on fibroblast (Fb) proliferation and collagen production appear to be tissue dependent. Macrophages of the proliferative phase promote vascular maturation, myofiber hypertrophy, and collagen production and remodeling.