The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions

Abstract

Healing of myocardial infarction (MI) requires monocytes/macrophages. These mononuclear phagocytes likely degrade released macromolecules and aid in scavenging of dead cardiomyocytes, while mediating aspects of granulation tissue formation and remodeling. The mechanisms that orchestrate such divergent functions remain unknown. In view of the heightened appreciation of the heterogeneity of circulating monocytes, we investigated whether distinct monocyte subsets contribute in specific ways to myocardial ischemic injury in mouse MI. We identify two distinct phases of monocyte participation after MI and propose a model that reconciles the divergent properties of these cells in healing. Infarcted hearts modulate their chemokine expression profile over time, and they sequentially and actively recruit Ly-6Chi and -6Clo monocytes via CCR2 and CX3CR1, respectively. Ly-6Chi monocytes dominate early (phase I) and exhibit phagocytic, proteolytic, and inflammatory functions. Ly-6Clo monocytes dominate later (phase II), have attenuated inflammatory properties, and express vascular–endothelial growth factor. Consequently, Ly-6Chi monocytes digest damaged tissue, whereas Ly-6Clo monocytes promote healing via myofibroblast accumulation, angiogenesis, and deposition of collagen. MI in atherosclerotic mice with chronic Ly-6Chi monocytosis results in impaired healing, underscoring the need for a balanced and coordinated response. These observations provide novel mechanistic insights into the cellular and molecular events that regulate the response to ischemic injury and identify new therapeutic targets that can influence healing and ventricular remodeling after MI.

Durable Benefits of Cellular Postconditioning: Long‐Term Effects of Allogeneic Cardiosphere‐Derived Cells Infused After Reperfusion in Pigs with Acute Myocardial Infarction

“…Mϕ have the intrinsic capacity to polarize between M1 (proinflammatory) and M2 (reparative) phenotypes; interestingly, we observed a strong shift toward an M2‐like Mϕ phenotype (Figure 9F and 9G). Taken together, these data suggest that salutary changes in Mϕ polarization from a “proinflammatory” toward a “healing” phenotype may contribute to cellular postconditioning, consistent with more‐extensive mechanistic studies in rats and in isolated macrophages 19, 20…”

“…Moreover, a subset of leukocytes (viz., neutrophils and monocytes) are associated with microvascular injury, LV remodeling, and function 34, 38. In addition, monocyte/macrophage heterogeneity post‐AMI is associated with the impairment of myocardial salvage and adverse LV remodeling 19. Here, we found that peripheral leukocyte counts are lower in CDC‐treated animals compared to placebo in the first 2 days postreperfusion.…”

Alteration of Cholinergic Anti‐Inflammatory Pathway in Rat With Ischemic Cardiomyopathy–Modified Electrophysiological Function of Heart

“…To explain the above findings, we hypothesize that regional myocardial infarction induces an accumulation of monocytes/macrophages accompanied by an increase of cytokines that, in turn, can support angiogenesis and extracellular matrix synthesis by providing vascular endothelial growth factor, transforming growth factor‐β, and profibrotic transforming growth factor‐α after acute wound 30. Takamura et al reported that regulating the activation of proinflammatory macrophages post–myocardial infarction improves cardiac remodeling 31.…”

“…Takamura et al reported that regulating the activation of proinflammatory macrophages post–myocardial infarction improves cardiac remodeling 31. Indeed, Ly‐6C low macrophage has been shown to play a crucial role in the pathogenesis and progression of the healing myocardium 30. In addition, macrophage‐induced fibrosis and several cytokines could aggravate arrhythmogenic properties 32, 33.…”

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

“…Immediately after an ischemic insult, cardiac remodeling is initiated by a transient inflammatory response triggered through danger‐associated molecular (DAMP) patterns and cytokines released from injured cardiomyocytes, attracting immune cells into the infarcted area 5, 6. Once the wound is “cleared” and the inflammatory phase is repressed, fibroblasts are activated and recruited, followed by their proliferation and differentiation into myofibroblasts 7, 8. Myofibroblasts express and deposit large amounts of collagen to renew the extracellular matrix (ECM) compartment, therefore ensuring the integrity of the heart tissue 9, 10.…”