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Immune Cells: The Good with the Bad

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Posted March 26, 2018

A team of Harvard Medical School investigators based at Massachusetts General Hospital has discovered, for the first time, that immune cells called macrophages contribute to a type of heart failure for which there is currently no effective treatment.

In a report published in the Journal of Experimental Medicine, the research team describes how macrophage activity can lead to the development of heart failure with preserved ejection fraction (HFpEF), which accounts for around half of all human heart failure cases, in mouse models of the condition.

“We show that macrophages—white blood cells primarily known for removing cellular debris, pathogens and other unwanted materials—are actively involved in the development of HFpEF,” said study lead author Maarten Hulsmans, an HMS research fellow in radiology at Mass General.

“These findings put macrophages on the map when it comes to HFpEF therapy and open up previously unexplored treatment options,” he said.

The concept of heart failure traditionally referred to a loss of the organ’s pumping capacity, which is called systolic heart failure. But in HFpEF the heart retains the ability to pump or eject blood into the circulation.

What is compromised is the ability of the heart muscle to relax and allow blood to flow into the left ventricle, reducing the amount of blood available to pump into the aorta. Symptoms of HFpEF are similar to those of heart failure in general, but since factors contributing to the condition are not well understood, it has been difficult to find promising therapies.

Interactions among cells within the heart, including macrophages, are essential to normal cardiac function but can also contribute to problems. For example, after the heart muscle is damaged by a heart attack, macrophages induce the cells called fibroblasts to generate the connective tissues that help reinforce damaged tissue. But excessive fibroblast activation can lead to distortion and stiffening of tissues, further reducing cardiac function.

To explore a potential role for macrophages in HFpEF, the team examined cardiac macrophages in two mouse models that develop the sort of diastolic dysfunction—impaired relaxation of the heart muscle—that characterizes HFpEF. These models were found to have increased macrophage density in the left ventricle and exhibited elevated levels of a factor called IL-10, which is known to contribute to fibroblast activation.

Deletion of IL-10 from cardiac macrophages in one model, in which the development of hypertension is induced, prevented the upregulation of macrophages and reduced the numbers and activation of cardiac fibroblasts. Levels of cardiac macrophages were also elevated in tissue biopsies from human patients with HFpEF, as were levels of circulating monocytes, precursors of macrophages.

“Not only were numbers of inflammatory cardiac macrophages increased in both the mice and in humans with HFpEF, but their characteristics and functions were also different from those in a healthy heart,” said Hulsmans.

“Through their participation in the remodeling of heart tissue, these macrophages increase the production of extracellular matrix, which reduces diastolic relaxation. Our findings regarding the cell-specific knockout of IL-10 are the first to support the contribution of macrophages to HFpEF,” he said.

“Heart muscle cells and fibroblasts have been considered the major contributors to HFpEF. Our identification of the central involvement of macrophages should give us a new focus for drug development,” added senior study author Matthias Nahrendorf, HMS professor of radiology at Mass General.

“And since macrophages naturally take up materials for disposal, inducing them to ingest drugs carried in by nanoparticles could limit their contributions to the development of HFpEF,” Nahrendorf said.

Source: HMS

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