by Giulia Notarangelo
figures by Rebecca Clements
The human body fights off noxious intruders on a daily basis to maintain our health and prevent disease. The army of cells that is responsible for leading this fight is called the immune system. The immune system is comprised of a myriad of cells, each having their own defense strategy. Among these cells are the macrophages. As their name suggests (from Greek makros = large, and phagein = to eat), macrophages are specialized cells that keep us safe by “eating” foreign material and unwanted cells through a process known as phagocytosis. However, no war hero does it all alone. Macrophages also help to fight infections by recruiting an alliance of other immune or non-immune cells to the site of injury and by secreting molecules that promote bacterial and viral clearance. And yet, as if they weren’t already doing enough to keep us alive, recent data show that these cells might play an even more vital role than we suspected.
An exciting new study published in Cell on April 20 describes a novel role for macrophages that goes well beyond their established functions in host-defense. Researchers in the laboratory of Matthias Nahrendorf at Harvard Medical School showed that macrophages play a role in supporting something even more essential than the immune system: our heartbeats! This discovery upends what we know about the heart’s rhythm and opens the door to new potential therapies for diseases in which the heart beats irregularly, like cardiac arrhythmias. This class of conditions affects millions of people and contributes to more than 500,000 deaths in the US each year.
The Electrical Sequence of a Heartbeat
To understand what leads to irregular heartbeats, we need to first understand how the heart normally functions. The heart is divided into two upper chambers, called atria, and two lower chambers, called ventricles (Figure 1). The atria and the ventricles work together, alternately contracting and relaxing to pump blood out of the heart. Cardiac contractions are driven by electrical impulses within the heart. These electrical signals originate in the heart’s physiological pacemaker, the sinoatrial (SA) node, which consists of a group of specialized cells located in the upper right atrium. The SA node fires regular electrical impulses 60 to 100 times per minute, causing the atria to contract and force blood down into the ventricles. Next, the electrical signals pause at the atrioventricular (AV) node for a fraction of a second, allowing the ventricles to fill with blood. After this brief delay, the signals finally reach the ventricles and stimulate them to contract and pump blood to the body, resulting in the familiar sensation of a heartbeat.
What We Already Knew about Macrophages and the Heart
Up until recently, we believed that the these finely coordinated events were primarily being orchestrated by the heart muscle cells, also known as cardiomyocytes. However, cardiomyocytes are not the only cells found in the heart.
In vertebrates (animals with spines), macrophages reside within all organs, adopting different functions according to the local environment. Scientists have known for decades that the heart contains numerous tissue-resident macrophages. In particular, previous studies had demonstrated that macrophages increase in number in response to heart attack and heart failure, facilitating cardiac healing after injury. However, nothing was known about the role of macrophages in the heart of healthy individuals with no known underlying cardiac condition. Why would a working, normally beating heart need so many macrophages beyond what’s required for maintenance or defense? Could all this just be a preventative mechanism in case of heart injury, or do these cells also play a role in normal heart physiology? A surprising finding shed some light on this question.
A Serendipitous Discovery
Everything began when a technician, interested in understanding how macrophages affect the heart, performed an MRI scan on a mouse that lacked macrophages and noticed something odd: the animal’s electrical rhythms were abnormal. MRI scans usually get information from the blood, but this mouse’s heart was beating too slowly to get an accurate scan. The scientists also noticed that the rodent’s heart had an AV block, which prevented the electrical signals emitted from the atria from reaching the ventricles and ultimately resulted in a slower heartbeat. Clinically, people with AV abnormalities present with serious complications that can result in abnormal blood flow, fainting, and eventually death if not properly treated with the installment of a pacemaker.
Adding the Missing Pieces to the Puzzle
Why would a loss of macrophages impact the normal beating of the heart? The fact that mice lacking cardiac macrophages have abnormal heartbeats strongly implies that heart macrophages are important, but what role are they fulfilling? To answer these questions, the scientists first sought to visualize the location and appearance of heart macrophages. As such, they imaged the hearts of mice that expressed a green fluorescent protein (GFP) only in their cardiac macrophages, causing these cells alone to glow green. By tracking the location of the green cells, they found that these macrophages were more abundant in the AV node. Surprisingly, they also found that these macrophages resembled heart muscle cells, with long-reaching projections that enable them to interact with neighboring cardiac cells. When analyzing the cellular components of the AV node macrophages, the researchers were surprised to find that the cells had many molecules involved electrical conduction.
One of their major findings was that the macrophages produced a molecule (a protein in this case) known as connexin 43 (Cx43). This result was both surprising and intriguing because the protein connexin is one of the major components of gap junctions, which are bridge-like structures that can connect two adjacent cells in order to facilitate their electrical communication. Previous studies had shown that Cx43 was produced in cardiac muscle cells, where it enabled the heart cells to electrically communicate with each other and lead to heart muscle contraction. As such, it appears that macrophages make a protein known to be instrumental in making the heart beat.
It didn’t take long for the researchers to put the pieces of the puzzle together: since heart-resident macrophages both resemble and share the same connecting structures as cardiomyocytes, could this mean that the two cell types can actually communicate with each other – and potentially even share a role in regulating the heartbeat?
This was exactly what the authors observed. To test their hypothesis, the researchers used genetically modified mice whose macrophages were made responsive to light. When exposed to light, the macrophages would automatically fire an electrical impulse and, if macrophages and cardiomyocytes were working together, this should result in better electrical communication, and ultimately in a faster contraction rhythm. Indeed, when macrophages were artificially stimulated by light, the beating of the heart significantly improved, suggesting that macrophages and cardiac muscle cells were working together to transmit electrical currents and promote heart contraction (Figure 2).
How can we use this knowledge for medical purposes?
Besides describing an exciting new role for macrophages that goes far beyond their well-established roles in host-defense, this study has and will inspire new studies to better our understanding of normal heart function. These findings have opened up a plethora of clinically relevant questions: can defects in macrophage function translate to heart problems? Conversely, can we target macrophages to treat cardiac disease? What are the cardiac risks associated with some of the current immunosuppressive therapies (currently used to treat diseases like cancer) that aim to ablate cells of the immune system? Could this discovery explain why anti-inflammatory drugs, which target immune cells such as neutrophils and macrophages, are linked to higher risk of heart failure? We expect to see many new studies emerge in the near future that will try to tackle some of these questions.
Giulia Notarangelo is a first year graduate student in the Biological and Biomedical Sciences PhD program at Harvard Medical School.
For more information:
The original research article: http://www.cell.com/fulltext/S0092-8674(17)30412-9