Cardiac macrophage biology in the steady-state heart, the aging heart, and following myocardial infarction

Abstract

Macrophages play critical roles in homeostatic maintenance of the myocardium under normal conditions and in tissue repair after injury. In the steady-state heart, resident cardiac macrophages remove senescent and dying cells and facilitate electrical conduction. In the aging heart, the shift in macrophage phenotype to a proinflammatory subtype leads to inflammaging. Following myocardial infarction (MI), macrophages recruited to the infarct produce both proinflammatory and anti-inflammatory mediators (cytokines, chemokines, matrix metalloproteinases, and growth factors), phagocytize dead cells, and promote angiogenesis and scar formation. These diverse properties are attributed to distinct macrophage subtypes and polarization status. Infarct macrophages exhibit a proinflammatory M1 phenotype early and become polarized toward an anti-inflammatory M2 phenotype later post- MI. Although this classification system is oversimplified and needs to be refined to accommodate the multiple different macrophage subtypes that have been recently identified, general concepts on macrophage roles are independent of subtype classification. This review summarizes current knowledge about cardiac macrophage origins, roles, and phenotypes in the steady state, with aging, and after MI, as well as highlights outstanding areas of investigation.

Fibroblast polarization over the myocardial infarction time continuum shifts roles from inflammation to angiogenesis

“…Integrin switching includes Itga5 , the major fibronectin-binding integrin, at MI day 3, and Itga11 , the major collagen-binding integrin, at MI day 7 [1]. Inflammation mediated by chemokine/cytokine signaling was enriched in the basal phenotype and at MI days 1 and 7, indicating that fibroblasts cross talk with resident immune cells regardless of injury state [29]. The day 0 secretome stimulated tube formation in vitro, indicating that fibroblasts in the uninjured heart play an active role in promoting a healthy vasculature.…”

Inflammatory cells and their non-coding RNAs as targets for treating myocardial infarction

“…Classical human and Mon1 mouse monocytes induce pro-inflammatory responses and exhibit high phagocytosis, whereas non-classical/Mon3 monocytes express anti-inflammatory mediators [155, 159]. In the steady state, the inflammatory circulating forms account for 50–60% of the total circulating monocytes in mice (Ly6C hi CCR2 high CX3CR1 low CD62 L + ) and 80–90% in humans (CD14 high CD16 − ) [116]. MI stimulates adrenergic signaling that triggers the bone marrow and spleen to produce new monocytes that are recruited into the heart [42].…”

“…MI stimulates adrenergic signaling that triggers the bone marrow and spleen to produce new monocytes that are recruited into the heart [42]. Within 24 h post-MI, the weight of the spleen decreases by 50% accompanied by a depletion of monocyte numbers as a result of their departure from the spleen’s monocyte reservoir [116, 171]. Chemokine receptors induce the recruitment of monocytes into the infarct region; inflammatory Ly6c hi monocytes are recruited early on post-MI in a CCR2-dependent manner, whereas anti-inflammatory Ly6c low monocyte recruitment is dependent on Cx3cr1 and occurs later.…”

Cadherin-11 Blockade Reduces Inflammation-Driven Fibrotic Remodeling and Improves Outcomes After Myocardial Infarction

“…As such, there has been an increasing interest in the role of Ms in the process of healing and cardiac remodeling after MI. [25][26][27][28] We hypothesized that CDH11 regulates the interactions between CFs and Ms in the heart after MI, noting that M activity has been shown to alter CF function in the ischemic heart independent of CDH11. 29 Interactions between Ms and CFs have been reported to regulate IL-6 expression in response to TGF-β1 signaling and fibrosis.…”