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Inflammatory Macrophages are Found to Contribute to Harmful Ventricular Remodeling in Heart Failure

It is already well known that the immune cells called macrophages are involved in the mechanisms of heart failure, and in the research noted here the details of that role are further explored. Macrophages are important in processes of regeneration and tissue growth throughout the body, but also in the propagation of inflammation in response to damaging circumstances. A growing theme in the research of past years is the polarization of macrophages, meaning their division into several subtypes based on behavior. Some are inflammatory and aggressive, attacking pathogens but also hindering regeneration, while others are not inflammatory and undertake a variety of activities to directly aid tissue regeneration. A useful response to injury requires both behaviors in some proportion, and at different times, but later life and many age-related conditions are characterized by the presence of far too many inflammatory macrophages. Removing these macrophages or adjusting their state shows promise as a basis for therapy.

The researchers here find macrophages displaying a CCR2 receptor, which correlates fairly well with the inflammatory polarization, are necessary for much of the harmful growth of the heart that takes place in later life, as the cardiovascular system becomes damaged and dysfunctional. One of the more important components of heart failure is this hypertrophy of heart tissue. The muscle grows larger and weaker, initially in response to the failure of blood pressure feedback mechanisms that takes place alongside the development of hypertension, but later a range of other mechanisms are also involved. Clearly, inflammatory macrophages are doing their part to generate an unhelpful growth response - and so selectively removing them could be a useful form of therapy.

Prevention of blood pressure issues is probably a better first option for those not already old, however. If rejuvenation therapies can (a) prevent the processes that lead to the stiffening of blood vessels, such as cross-linking and calcification, and (b) prevent the atherosclerotic plaque that narrows blood vessels, such as by clearing out the harmful lipid compounds that cells cannot effectively break down, then hypertension and other blood pressure issues could be largely eliminated. Given a life-long normal blood pressure, the impact of inflammatory processes on the heart will be that much less severe. They must still be dealt with, as the secondary consequence of fibrosis remains an issue, but that can happen in a context of better overall health and physical robustness.

Immune cell target identified that may prevent or delay heart failure after pressure overload

Researchers have found that preventing the early infiltration of CCR2+ macrophages into the heart, after experimental pressure overload in a mouse model, significantly lessened the heart's enlargement and reduced pumping ability that leads to later heart failure. Thus, this infiltration is a required step in the path toward heart failure. Macrophages are immune cells that engulf and remove damaged or dead cells in response to tissue injury or infection. They also may present antigens to other immune cell types. The most common forms of pressure overload are aortic stenosis - a narrowing of the aortic valve of the heart that forces the heart muscle to overwork - and high blood pressure.

The researchers used two different methods to prevent early macrophage infiltration - an inhibitor of the macrophage cell-surface CCR2 chemokine receptor, and an antibody that selectively removes CCR2+ macrophages. Migrating macrophages use the CCR2 receptor to home in on damaged tissues in the body that are releasing chemokines. Preventing early macrophage infiltration may offer a therapeutic target in human disease. Researchers had previously known that pressure-overload heart failure is associated with inflammation caused by activated T-cells. The present study showed the link between infiltrating macrophages and the T-cell response during pressure overload of the heart.

One week after inducing pressure load, that the heart showed increased expression of three attractant chemokines that are able to bind to the CCR2 receptor on macrophages. The researchers also found an increased number of monocytes with the cell-surface markers Ly6C and CCR2 circulating in the blood, and they saw an eightfold increase in CCR2+ macrophages infiltrating into the heart. Those macrophages are derived from the circulating monocytes. Thus increased circulating monocytes might serve as an easily measurable biomarker that reflects cardiac tissue CCR2+ macrophage expansion. The circulating monocytes - along with other clinical, imaging and biochemical biomarkers - could guide patient selection for a prospective clinical trial to find out whether modulating CCR2 macrophages in humans with pressure-overload hypertrophy will delay or prevent later transition to heart failure.

CCR2+ Monocyte-Derived Infiltrating Macrophages Are Required for Adverse Cardiac Remodeling During Pressure Overload

Inflammation is a hallmark of chronic heart failure (HF) initially triggered by nonimmune modes of cardiac injury, such as myocardial infarction, genetic mutations, and mechanical stress (e.g., pressure overload). Moreover, the systemic and myocardial immune cell profiles underlying the inflammatory response in the various etiologies of HF are of considerable importance for disease progression. For example, in chronic ischemic HF, expanded populations of both innate immune cells (e.g., macrophages) and T cells in the heart promote tissue injury and pathological remodeling. Chronic nonischemic HF due to pressure overload is characterized by CD4+ T-cell activation, which has been shown to play a critical role in promoting adverse cardiac remodeling. We recently demonstrated that during cardiac pressure overload, proinflammatory macrophage expansion in the heart occurs early, before sustained systolic dysfunction, but resolves during the chronic stage.

Importantly, although pressure-overload HF is characterized by T-cell activation, prior work also indicates that such activation is dependent on antigen presentation, because the progression of HF is ameliorated upon blockade of T-cell costimulatory molecules on antigen presenting cells (APCs). The requirement for specific antigen recognition implies an essential pathogenetic role for macrophages and other APCs, although their specific function in the development of pressure-overload HF remains poorly defined. Recent studies have characterized cardiac macrophage populations in the heart with disparate functions, including tissue-resident, embryonically derived macrophages and infiltrating monocyte-derived macrophages. The normal heart is seeded with resident macrophages that are not replenished by circulating monocytes under steady-state conditions. Resident cardiac macrophages are minimally inflammatory and promote angiogenesis and tissue repair. However, cardiac injury and aging stimulate the infiltration of monocyte-derived macrophages that are proinflammatory, promote tissue injury, and the death and substitution of resident cells.

Monocyte-derived macrophages can be distinguished by the expression of C-C chemokine receptor 2 (CCR2). Although we and others have documented expansion of cardiac macrophages during the early phase of pressure overload, it is unknown whether the macrophages are monocyte-derived, and whether these cells play an important role in subsequent T-cell recruitment and activation, and associated long-term adverse cardiac remodeling. Accordingly, here we tested the hypothesis that CCR2+ monocyte-derived macrophages infiltrate the heart early following pressure-overload-induced hemodynamic stress, and that this macrophage population plays a critical role in the activation of T cells and the ensuing transition to failure.

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