Macrophages, immune cells known for their PAC-MAN-like ingestion of microbial intruders and biological waste, have a previously unrecognized role in helping the mammalian heart beat in rhythm. Massachusetts General Hospital researchers discovered that macrophages aggregate around central cardiac cells that regulate electrical impulses within the mouse heart, helping the cells conduct electricity. Mice that were genetically engineered to lack macrophages have irregular heartbeats, hinting that these immune cells may also play a role in heart disease. The findings appear April 20 in the journal Cell.
"This work opens up a completely new view on electrophysiology; now, we have a new cell type on the map that is involved in conduction," says senior author Matthias Nahrendorf, a systems biologist at Massachusetts General Hospital, Harvard Medical School. "Macrophages are famous for sensing their environment and changing their phenotype very drastically, so you can think about a situation where there is inflammation in the heart that may alter conduction, and we now need to look at whether these cells are causally involved in conduction abnormalities."
Researchers have known for decades that macrophages are in high abundance around inflamed or diseased hearts, but Nahrendorf's investigation began when he asked what the immune cells were doing in a healthy heart. After sending a mouse model depleted of macrophages for a heart MRI and electrocardiogram, the technician reported back that something was wrong; the mouse's heart was beating too slowly. Tests in a healthy rodent revealed a high density of resident macrophages at the heart's atrioventricular node, which passes electricity from the atria to the ventricles.
Nahrendorf showed the results to his colleagues, David Milan and Patrick Ellinor, both electrophysiologists at Massachusetts General Hospital, who responded by opening the doors to their labs. Together, the teams found that macrophages extend their cell membranes between cardiac cells and create pores, also called gap junctions, for the electrical current to flow through. The macrophages contribute by preparing the conducting heart cells for the next burst of electricity so conducting cells are able to keep up with a fast contraction rhythm.
"When we got the first patch clamp data that showed the macrophages in contact with cardiomyoctes were rhythmically depolarizing, that was the moment I realized they weren't insulating, but actually helping to conduct," Nahrendorf says. "This work was very exciting because it was an example of how team science can help to connect fields that are traditionally separated--in this case, immunology and electrophysiology."
The group will follow up by looking at whether macrophages are involved in common conduction abnormalities. There are also potential connections between macrophages and anti-inflammatory drugs, which are widely reported to help with heart disease. If macrophages do play a role in disease, the researchers say it can open up a new line of therapeutics, as these immune cells naturally consume foreign molecules in their presence and are easy to target as a result.
This work was funded in part by the National Institutes of Health. The General Hospital Corporation has filed a patent application based on the research.
Cell, Hulsmans, Clauss, and Xiao et al.: "Macrophages Facilitate Electrical Conduction in the Heart" http://www.cell.com/cell/fulltext/S0092-8674(17)30412-9
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