Table 1.
Summary of the sources of macrophages and macrophage-like cells within the plaque and their role in atherosclerosis and metabolic disease.
| Macrophage type | Resident tissue macrophages | VSMC-derived macrophage-like cells | Monocyte-derived macrophages | Monocytic MDSCs |
|---|---|---|---|---|
| Origin | Likely to ultimately originate from monocytes | Vascular smooth muscle cells | Bone marrow stem cells via medullary or extramedullary (spleen) myelopoiesis | Bone marrow stem cells via medullary or possibly extramedullary (spleen) myelopoiesis |
| Subsets and markers | CD68, Mac-2 Brdu+ following labeling |
CD68, Mac-2 | CD68, Mac-2 will incorporate Brdu |
|
| Monocytes | ||||
| Mouse: CD11b+Ly6G- and Ly6Chi or Ly6Clo | Mouse: CD11b+Ly6G-Ly6Chi
Also lack CD11c and MHC class II |
|||
| Human: HLA-DR+ and CD14++CD16−, CD14+CD16+ or CD14dimCD16+ | Human: CD14+HLA-DR-/lo | |||
| Limitations of markers | Due to shared markers, lineage tracing studies still required to confirm contribution of these cells | Due to shared markers, lineage tracing studies required to confirm contribution in metabolic diseases | Some studies lack sufficient evidence to rule out potential contributions of macrophage from other sources. Bone marrow transplant studies and monocyte labeling provide good evidence for their contribution. | Most studies in mice fail to discriminate MDSCs from monocytes and/or neutrophils |
| Function | Pro-atherogenic | Pro-atherogenic Reduced phagocytic capacity |
Pro-atherogenic | Anti-atherogenic? Immunosuppressive |
| Mouse vs. human | Minimal proliferation of macrophages identified in humans, unknown macrophage origin | Evidence of co-expression of SMC and macrophage markers. May contribute to macrophage content identified by immunohistochemistry. |
Circulating monocytes correlate with disease | Associated with ACS in humans Role in mice unclear |
| Affected by diabetes/obesity | ↑ total plaque macrophage content in diabetic mice Unknown if from resident tissue macrophages |
Promoted by hypercholesterolemia and hyperglycemia (in vitro), unknown in models of diabetes/obesity | ↑ in circulation in diabetes/obesity ↑ lesion entry in diabetes ↓ lesion egress in diabetes |
↑ in circulation in T1D patients ↑ in obese adipose tissue Not known if altered in the lesion |
VSMC, vascular smooth muscle cell; MDSC, myeloid-derived suppressor cell.