A classical lay summary by Siddarth Dasari and Shyam S. Bansal, PhD, Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center
The immune system is very complex, with many cells that affect other organ systems. Of course, the main role of immune cells is to act as the body’s line of defense against infections and diseases, but some immune cells also have more roles in the body that help other organ systems operate effectively.
Macrophages are immune cells that specialize in phagocytosis (ingestion and digestion of other cells or organisms) as their role in the immune response. However, as more and more research has been done on their roles, macrophages have been discovered to be present in all tissues in the body, carrying out functions that are specific to that organ. Macrophages perform a variety of these tissue-specific roles like regulating the production of heat in fat tissue and playing a role in iron recycling in the liver and spleen.
The way the heart works is through electrical impulses that are generated at the sinoatrial node (or the SA node) at the top of the left atrium, which activates the atria to beat, followed by the impulse travelling to the atrioventricular node (AV), then causing the ventricles to beat. Put together, this is how one heartbeat occurs. While resident macrophages are present in the wall of the heart, the specific roles of macrophages in the function of the cardiac conduction system are unknown, and this is what the researchers hoped to answer.
By using a specific strain of mice where cardiac macrophages can fluoresce as green, the researchers found that the mouse AV node had a higher concentration of these cardiac macrophages when compared to another part of the heart like the left ventricle1. This is significant because the AV node provides the only electrical pathway from the atria to the ventricles, so this discovery implicates that cardiac macrophages have some role in the electrical conduction of the heart.
The researchers then sought out to answer the question of how cardiac muscle cells (cardiomyocytes) and cardiac macrophages communicate by using classical biophysical tools. First, it is important to consider how cardiomyocytes communicate amongst themselves. This is done through gap junctions, which connect the cytoplasm of two touching cells through connexin proteins to enable communication. Connexin-43 (Cx43) has been shown to create gap junctions between cardiomyocytes to coordinate synchronous contraction. After purifying cardiac macrophages, their Cx43 levels were analyzed, and the researchers discovered that Cx43 is expressed by all cardiac macrophages. This, along with microscopic images that showed Cx43 joining cardiac macrophages with cardiomyocytes, demonstrated that there are gap junctions formed between cardiomyocytes and cardiac macrophages to facilitate intercellular communication. Researchers also discovered that macrophages coupled to cardiomyocytes through the Cx43 mediated gap junctions have a synchronous action potential as the coupled cardiomyocyte. Moreover, specifically through the Cx43 mediated gap junctions, coupling macrophages to cardiomyocytes decreases cardiomyocyte action potential duration and increases the resting membrane potential. Both allow for AV conduction to happen at higher frequencies.
In short, cardiomyocytes cause coupled macrophages to have simultaneous action potentials as themselves, and these simultaneous action potentials in cardiac macrophages affect the electrical physiology of the cardiomyocytes that they are coupled to. This research is important, and this discovery is crucial because AV block, a condition where the electrical signal cannot travel from the atria to the ventricles effectively is one of the most common reasons a surgical pacemaker must be implanted in a patient. However, many AV block cases occur for unknown reasons. The reason that AV block arises might, in fact, have some cause in the malfunction of cardiac macrophages during some heart disease or injury. Understanding how cardiac macrophages function and interact with cardiomyocytes might be useful in determining how cardiac conduction is damaged following a heart injury or disease, which can possibly lead to new treatment methods that target cardiac macrophages.
Reference
1) Hulsmans M, Clauss S, Xiao L, Aguirre AD, King KR, Hanley A, Hucker WJ, Wulfers EM, Seemann G, Courties G, Iwamoto Y, Sun Y, Savol AJ, Sager HB, Lavine KJ, Fishbein GA, Capen DE, Da Silva N, Miquerol L, Wakimoto H, Seidman CE, Seidman JG, Sadreyev RI, Naxerova K, Mitchell RN, Brown D, Libby P, Weissleder R, Swirski FK, Kohl P, Vinegoni C, Milan DJ, Ellinor PT and Nahrendorf M. Macrophages Facilitate Electrical Conduction in the Heart. Cell. 2017;169:510-522 e20.