Cardiovascular diseases are the leading cause of mortality worldwide. It is widely known that non-resolving inflammation results in atherosclerotic conditions, which are responsible for a host of downstream pathologies including thrombosis, myocardial infarction (MI), and neurovascular events. Macrophages, as part of the innate immune response, are among the most important cell types in every stage of atherosclerosis. In this review we discuss the principles governing macrophage function in the healthy and infarcted heart. More specifically, how cardiac macrophages participate in myocardial infarction as well as cardiac repair and remodeling. The intricate balance between phenotypically heterogeneous populations of macrophages in the heart have profound and highly orchestrated effects during different phases of myocardial infarction. In the early “inflammatory” stage of MI, resident cardiac macrophages are replaced by classically activated macrophages derived from the bone marrow and spleen. And while the macrophage population shifts towards an alternatively activated phenotype, the inflammatory response subsides giving way to the “reparative/proliferative” phase. Lastly, we describe the therapeutic potential of cardiac macrophages in the context of cell-mediated cardio-protection. Promising results demonstrate innovative concepts; one employing a subset of yolk sac-derived, cardiac macrophages that have complete restorative capacity in the injured myocardium of neonatal mice, and in another example, post-conditioning of cardiac macrophages with cardiosphere-derived cells significantly improved patient’s post-MI diagnoses.

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Objective: To determine whether overexpression of the chitin degrading enzyme, chitotriosidase (CHIT1), modulates macrophage function and ameliorates atherosclerosis. Approach and Results: Using a mouse model that conditionally overexpresses CHIT1 in macrophages (CHIT1-Tg) crossbred with the Ldlr −/− mouse provided us with a means to investigate the effects of CHIT1 overexpression in the context of atherosclerosis. In vitro, CHIT1 overexpression by murine macrophages enhanced protein expression of IL-4, IL-8, and G-CSF by BMDM upon stimulation with a combination of lipopolysaccharide (LPS) and interferon-γ (IFN-γ). Phosphorylation of ERK1/2 and Akt was also down regulated when exposed to the same inflammatory stimuli. Hyperlipidemic, Ldlr −/−-CHIT1-Tg (CHIT1-OE) mice were fed a high-fat diet for 12 weeks in order to study CHIT1 overexpression in atherosclerosis. Although plaque size and lesion area were not affected by CHIT1 overexpression in vivo, the content of hyaluronic acid (HA) and collagen within atherosclerotic plaques of CHIT1-OE mice was significantly greater. Localization of both ECM components was markedly different between groups. Conclusions: These data demonstrate that CHIT1 alters cytokine expression and signaling pathways of classically activated macrophages. In vivo, CHIT1 modifies ECM distribution and content in atherosclerotic plaques, both of which are important therapeutic targets.

Summary Although it is a member of the IL-1 family, IL-37 is unique in that it has wide-ranging anti-inflammatory characteristics. It was originally thought to prevent IL-18-mediated inflammation by binding to the IL-18-binding protein. However, upon discovery that it binds to the orphan receptor, IL-1R8, further studies have revealed an expanded role of IL-37 to include several intracellular and extracellular pathways that affect various aspects of inflammation. Its potential role specifically in cardiovascular diseases (CVD) stemmed initially from the discovery of elevated plasma IL-37 levels in human patients with acute coronary syndrome and atrial fibrillation. Other studies using mouse models of ischemia/reperfusion injury, vascular calcification and myocardial infarction have revealed that IL-37 can have a beneficial role in these conditions. This review will explore recent research on the effects of IL-37 on the pathogenesis of CVD.

Increased risk of atherosclerotic cardiovascular diseases is common in HIV+ adults on stable antiretroviral treatment (ART). A key step in the development of the atherosclerotic plaque is the transmigration of monocytes to the plaque area and their differentiation into macrophages and eventually foam cells. The objective of this study was to determine if the propensity of monocytes to transmigrate as well as their ability to take up and efflux cholesterol is affected by HIV infection. Monocytes (transmigration) and differentiated macrophages (lipid metabolism) from HIV+ ART treated patients were compared against those from matched controls as a single point cross-sectional study. Monocyte transmigration was assessed by transwell assay using MCP1 as a chemoattractant, whereas lipid uptake was measured by flow cytometry analysis of internalized acetylated LDL and cholesterol efflux by tracking tritiated cholesterol excreted from the cell after exposure to HDL. Interestingly, isolation of monocytes via negative selection with magnetic beads revealed that the yield of monocyte was significantly lower from HIV+ patients compared to controls. While no significant differences were found in cholesterol uptake or efflux parameter, the ability of monocyte to transmigrate was slightly increased in HIV patients compared to controls suggesting that the chemotactic function of monocytes may be partly responsible for the differences in the atherosclerosis risk in patients with HIV.