Macrophages: Butlers of Homeostasis

October 26, 2016

In a blog entitled “Fighting Back Infections! Innate immunity in Bacterial Infections” I have alluded to the fact that in the case of infectious disease, it is often difficult to discern the underlying driver of pathology between the damage caused by the immune reaction and the harm resulting from virulence mechanisms of the invading microorganism. It is in fact the case that both factors interplay and are decisive in the outcome of an infection, with one often taking precedence over the other in a context-dependent manner, i.e. different strains of a particular pathogen, site of infection, genetic variations between hosts, etc. In recent years, immunologists have begun paying an increasing amount of attention to the mechanisms, which modulate immune responses, and the ways in which pathogens disrupt these mechanisms to cause disease. In order to get rid of the conceptually misleading dichotomy of “pathogen vs. host,” which tends to oversimplify our understanding of the immune system, we nowadays often talk about immune homeostasis and disruption thereof.

Homeostasis is the property of a system in which variables are regulated so that internal conditions remain stable. I recently had to opportunity to attend a talk by the very prominent contemporary immunologist Ruslan Medzhitov, who provided a very elegant analogy to help understand the concept of homeostasis in the physiological context. To describe the principle of a homeostatic system, he gave the example of a room, in which a thermostat is set to maintain a particular temperature. In this context, the thermostat constantly measures the temperature and sends electric signals to the air conditioner or heating system to compensate for any deviations from the constant temperature, which has been entered. In this system there is a set point value, lets say 22°C. To maintain this value, the controller, i.e. the thermostat, sends signals to instruct the effectors, i.e. the heating and air conditioning systems, to maintain the regulated variable, i.e. the temperature, constant at 22°C. There are many similar homeostatic systems in operation within our body, which maintain an innumerable number of variables within ranges required for health. Two such examples are body temperature and blood glucose. In the first case, our hypothalamus senses and maintains our body temperature constant by sending signals to a number of effectors such as our blood vessels to dilate or constrict, our skin to sweat, or our muscles to induce shivering, all in an effort to increase or decrease our body temperature to the set point of 37°C. Blood glucose levels must also be maintained within a narrow physiologically healthy range. Here, our pancreas senses blood glucose concentrations and secretes hormones, namely insulin or glucagon, in order to instruct our muscle, liver and fat cells to either take up, store and metabolize glucose, or to release it back into the circulation.

Of all the homeostatic systems within our physiology, homeostatic controls of, and by, the immune system are perhaps the most poorly understood due to their multiple layers of complexity. In fact, while immune mechanisms are under homeostatic control, certain components of the immune system themselves act as homeostatic controllers. One generally associates immune cells with responses in the extreme situation of an acute infection. However, under the steady-state condition of health, these cells are increasingly recognized to play perhaps even more important roles in maintaining tissue homeostasis.

This is particularly the case of an innate immune cell type, the macrophage. Macrophages reside in virtually all tissues in our body and have evolutionarily diversified into different subsets, each adapted to carry out specific functions depending on the organ system to which they home. One overlapping feature of all subsets of macrophages is their ability to phagocytose, that is, to engulf particles and degrade them in intracellular vesicles called phagosomes. For example, alveolar macrophages in the lung, an organ typically exposed to large amounts of dust, microorganisms and allergens, play an important role in cleaning up these potentially harmful assaults on our respiratory track by gobbling them up and degrading them. Similarly, macrophages residing in the spleen, the organ that filters our blood, play a role in phagocytosing dying red blood cells and other unwanted blood contaminants. Osteoclasts and osteoblasts are peculiar types of macrophages homing in our bones, which resorb and stimulate growth of bone tissue, respectively, processes that are important for bone remodeling. Macrophages also play an important role in growth and development by for instance resorbing appendages from different stages of embryogenesis or by secreting growth factors to stimulate the development of certain cell types.

In this context, Medzhitov is advocating the idea that macrophages, which historically have received more attention for their function in host defense in response to infection, should instead be viewed as controllers of tissue homeostasis. However, rather than merely acting like the thermostat in a room, which simply switches the heating or the air conditioning on or off depending on the input, the function of macrophages is more analogous to that of butlers. As such, under the homeostatic conditions of health, they carry out mundane tasks required for tissue maintenance. In addition, they are also constantly sensing their environment. When a threat arises that they cannot themselves handle, macrophages will recruit specialized cell types such as neutrophils, which are better equipped to deal with the crisis of an infection, much like a butler would call a plumber or fire fighters in the case of a pipe break or a fire. But more importantly, once the crisis is resolved, macrophages are crucial in restoring homeostasis. In deed, just as a good butler would send the plumber home and clean up the mess once the leak is fixed, macrophages suppress survival signals to neutrophils and coordinate tissue healing once an infection is cleared. Hence, in our quest to decipher the mechanisms through which pathogens disrupt the immune homeostasis to cause disease, Medzhitov stresses the importance of considering the rich and diverse functional repertoire of macrophages beyond their classical role as anti-microbial phagocytes.

Read more about Rusland Medzhitov’s perpective:

Okabe, Y. and R. Medzhitov, Tissue biology perspective on macrophages. Nat Immunol, 2016. 17(1): p. 9-17.