Hello. My name is Ruslan Medzhitov. I’m a professor at Yale University School of Medicine, and an Investigator from Howard Hughes Medical Institute. In this lecture, I will discuss inflammation, and I’ll give a brief overview of the field of inflammation and its role in both host defense and homeostasis, as well as in pathologies. So, inflammation is an enormously huge field with a lot of details known about some aspects of inflammation. And to be able to summarize it in this short overview, I will use a couple of perspectives that summarize some key features of inflammation, and specifically I will start by putting inflammation in the context of the better-understood and better-defined phenomenon of homeostasis, and I’ll show the similarities, parallels, and how the two types of processes interact with each other, causing both beneficial and detrimental outcomes. So, just to remind you, homeostasis maintains stability of biological systems in the face of perturbations. And perturbations could be either external or internal to the system. And inflammation is induced when these perturbations exceed homeostatic capacity of the system. So schematically, this could be summarized as follows. If we imagine the position of this ball as the state of the system, here, in the center — you can see, in the normal state — the homeostasis is maintained by keeping the state of the system in the desired position. And when it deviates from that position, homeostatic mechanisms will bring it back. But if perturbation is large enough and the system goes outside of its normal control zone, outside of its normal homeostatic range, then homeostatic capacity is no longer sufficient to keep the system in a desired state, and that’s when inflammation is induced, to force the system back into the homeostatic state. That’s one way to think about connections between homeostasis and inflammation. So, inflammation is something that forces the system to go back into the homeostatic state, when perturbations are large enough and when they overwhelm homeostatic capacity. In modern terms, we can describe homeostasis using the idea of a control circuit. And this is a very simple but very fundamental concept. So here, what is summarized on this slide is key components of a homeostatic circuit. And whenever we speak about homeostasis, that means that we talk about maintenance of some variable of the system. It could be blood sugar; it could be temperature; it could be sodium; it could be any of the variables of the system that the system cares about and wants to maintain. So, that’s what’s denoted here as X. And when we refer to homeostasis of this variable, that means we want to keep it close to some desired value. And that’s what’s called the setpoint value, X’ here. So, that is… it is the value of that variable, or the difference of that variable value from the setpoint value, that is monitored by the sensor. The sensor is the component of a homeostatic circuit that monitors the value of the variable the system cares about. And the second essential part of the system is the effector part, and that’s the part that can change that value. So, the sensor monitors the value; the effector can change the value. And they need to communicate with each other through a signal that’s denoted as C, here. So for example, in the case of systemic homeostasis of blood glucose, X would be the actual concentration of glucose in the blood, X’ would be the setpoint value, which is in humans about 5 millimolar, and the sensors would be pancreatic alpha and beta cells that monitor how much glucose we have in the blood. Are you eat, glucose level goes up. Beta cells in the pancreas will detect that and will start producing insulin, which is the example of the signal, shown here, which will go on to act on its effectors, which include skeletal muscle, fat, and liver. And the effect of insulin on these target tissues will be to lower blood glucose level, for example by inducing uptake into those tissues or conversion into glycogen or lipids. If the glucose level is lower than the setpoint value, then alpha cells of the pancreas will detect that, a low lev… a low level, and start producing a different hormone, which is glucagon, which will act exactly, again, on effector cells… effector tissues and organs, for example liver, and cause them to start producing glucose to raise it… to raise the level to the desired value. So, that’s how a homeostatic circuit works at… at an organismal level, a tissue level, and a cellular level. Now, the origin of the concept of inflammation goes back to… it can be credited to many people, but the two that I want to highlight here are Rudolf Virchow Elle Metchnikoff, who were contemporaries and colleagues. And so, Virchow, of course, is credited with the development of the modern science of pathology, of cellular pathology. And he was an extremely influential scientist in Europe at the time. And Elle Metchnikoff, of course, is known for his discovery of phagocytes and its… their role in innate immunity. But in the context of inflammation, these two individuals provided very important conceptual contributions. But there was one important difference between them, in that Virchow primarily viewed inflammation as a pathological process, whereas Metchnikoff recognized early on that, in addition to these pathological outcomes of inflammation, that the… the primary reason for an inflammatory response is to provide protection from infections. And he visualized and conceptualized the inflammatory response as being part of a spectrum, where at the base of the spectrum would be what he called “harmony/disharmony balance”, and this is what we currently would call homeostasis, but the term homeostasis wasn’t coined yet, until 1929. Then, the next level would be physiological inflammation, when inflammation plays beneficial roles in host defense. And then pathological inflammation, and finally immunity. And that… that concept of physiological inflammation and the spectrum of inflammatory response from homeostasis to immunity is actually a very profound insight which was largely forgotten until very recently. And only now we are starting to rediscover and realize these fundamental connections between physiological processes and inflammation. So, taking that, Metchnikoff’s idea, and putting it in… looking from different dimensions, we can summarize it as follows, as the spectrum of degrees of deviation from homeostatic states. So here, on the… on the left side, you see the range of conditions of a system that would be within a homeostatic state. If it deviates far enough from that, that’s what… what we would call a stress response, or we could also call it a physiological inflammatory response. And if it deviates much further than that, that’s what we would call inflammation proper. And so this… any deviation from a normal state, therefore, can be… can lead to the induction of the inflammatory response. So, the causes of inflammation from that perspective can be summarized as follows. In the center here, in the middle, you can see that loss of homeostasis per se is sufficient to lead to inflammation as… as I just mentioned. But in addition, there could be exogenous perturbations that can lead to loss of homeostasis. And the two major types of such perturbations will be pathogens (during infection) as well as toxins and allergens and virulence factors produced by pathogens. So, both pathogens and… and toxins can cause loss of inflammation… loss of homeostasis that… and that can lead to inflammation. But in addition, the immune system developed two pre-emptive mechanisms to trigger a protective inflammatory response, even before pathogens or allergens can cause damage to the system. And there are two fundamental ways that the immune system detects these inducers of inflammation. At the top here, what I call structural feature recognition is the property of the innate immune system to detect invariant structures associated with microbial cells. This is sometimes called the pattern recognition system, where receptors of the immune system detect conserved structures that have found in most microbes, for example we lipopolysaccharides of the cell wall or peptidoglycans, lipoteichoic acids, and so on. And detection of these structures is sufficient to trigger inflammation. On the other hand, allergens and toxins and virulence factors, they’re extremely diverse. There… there are many different types and there is no way to detect them all based on structural features, because they don’t share any structural features. And the strategy of recognition here is what I would call a functional feature recognition, because what is detected is not specific structures but rather specific biochemical activities, such as protease activities, lipase activities, lipid binding, membrane perturbations, pore formation, and so on. Those functional features are detected by that system, and that also can lead to inflammation. And that type of strategy is particularly important in allergic inflammation. So, based on these ideas, we now can summarize how the immune system operates based on the simple logic of the control circuits. So, we know that the immune system… one of the major functions of the immune system is to detect pathogens and to provide a protective response against them by, for example, destroying them or expelling them from the organism. To do so, the immune system has to have two essential components. It has to have a pathogen-sensing component, or pathogen-sensing cells, and it has to have antimicrobial effector cells, and sensor and effector cells have to communicate with each other through a signal, and once the effector receives the signal from the sensor, it elicits a response that leads to defense from the pathogen. So, that’s a very simplified view of the immune system. And the signals that are involved in communication between sensors and effectors are what contributes to this enormous complexity of inflammation and understanding of the immunity. There are many different types of signals in the context of inflammation. The signals are usually called inflammatory mediators. And two major types of inflammatory mediators are signals called chemokines and cytokines. Chemokines are short polypeptides that are produced upon infection by sensor cells that detect pathogens or tissue damage. And what chemokines do is they recruit effector cells to the site of infection. For example, macrophages that function as sensor cells, when they detect bacterial pathogens, will produce chemokines that will recruit neutrophils to the site of infection, and then neutrophils will take care of the pathogens. The second type of inflammatory mediators are cytokines. And this is a… again, a very diverse group of signals that belong to different structural families, but basically what cytokines do… they… they, again, are produced by sensor cells when they detect infection, and they activate effector cells to elicit various antimicrobial functions. So, with this in mind, we now can summarize much of the inflammation and diversity of inflammation into these simple and universal components of the inflammatory pathway. Any type of inflammation includes these four universal components. There is always some type of an inducer of inflammation, for example, pathogen, toxin, tissue damage, or loss of homeostasis. There are sensors that detect the inducers. These include various types of cells of the innate immune system, such as macrophages and mast cells, but also various types of sensory neurons. And the sensor cells produce inflammatory mediators, which include cytokines, chemokines, as well as bioactive amines like histamine, peptides, like bradykinin, as well as lipid mediators called eicosanoids, which include, for example, prostaglandins. And these mediators then act on various target tissues. And almost any tissue in the body can be a target for different types of inflammatory mediators. So here, I’m showing liver, vasculature, epithelial cells, and neutrophils. When mediators act on these effector cells, they cause appropriate changes in their state and their function, or in their positioning. Again, chemokines can recruit neutrophils to the site of infection. Cytokines acting on hepatocytes sites or vascular endothelium will cause their activation, changing protein secretion or permeability of the epithelium. And in the case of mucosal epithelium, they can change the production of antimicrobial peptides or mucus. So, this is this inflammatory pathway. And as you… as you may notice, there is… this is very much related to… it’s the same kind of a control circuit we just discussed for homeostasis, where we have a sensor, a signal that connects sensor to the effector, and the effector. The only difference is that in this case what is monitored is not a homeostatic variable, but rather some inducer of inflammation, such as a pathogen or toxin. So, there are these clear parallels between homeostatic and inflammatory control circuits. The reason for that has to do with the fundamental importance of these type of control circuits. They’re everywhere, from engineering systems to biological systems. And again, the differences between them are related to the types of inducers that are… that are detected by sensors, or homeostatic variables detected by homeostatic sensors. But we should also keep in mind that sometimes the differences between homeostatic and inflammatory control circuits can be arbitrary, because inflammatory mediators used by homeostatic… by inflammatory circuits can also have some homeostatic functions, and homeostatic signals used by homeostatic circuits can participate in regulation of the inflammatory response. There are actually two different designs… versions of the control circuits. Here on the top is the control circuit I just mentioned. That’s the simplest one, where you just have sensor and an effector, and the signal that connects them. There is another type of a circuit which has an additional component in between. And that’s what’s called a controller or integrating unit. So, here we have a sensor that monitors an inflammatory inducer or homeostatic variable. It produces a signal that then acts on the controller, and then the controller does some type of a computation, and then sends a second signal to the effector. This type of a design is particularly prevalent in both immune and nervous systems. In the case of the immune system, the control… the role of a controller is typically played by a lymphocyte. And in the case of the nervous system, it’s played by various types of interneurons. So, sensor cells, again, after detecting the inducer, produce one signal, and then the controller produces a second signal. And these two types of signals are distinct in the immune system, as we will discuss. So from that perspective, we can summarize the entire operation of the immune system as… as connections between pathogen sensors and effectors. And there are three types of disconnections. The simplest one is shown at the top, where the sensor and the effector is the same entity, the same cell. The sensor would be, for example, a receptor, and the effector would be, for example, an antimicrobial enzyme. The second type is when the sensor produces a signal that acts on the effector, as we just discussed. And the third type when there is a lymphocyte in between. And the first two types belong entirely to the domain of the innate immune system, and the second… the… the third one, it can be either innate or adaptive immune system, depending on the type of lymphocyte involved. So, we will go through the different versions of these circuits to illustrate how they operate in the context of infection. So, the simplest one is when a cell like a macrophage encounters a pathogen, like a bacterium, phagocytoses then kills it. So in this case, the sensor would be receptors that detect the microbe, and the effectors would be phagocytic machinery and lysosomal enzymes that will kill the microbe. So, that’s the simplest one. And more… more commonly, when macrophages detect pathogens, they will produce a signal that will connect them to the effector, such as a neutrophil, and it will either recruit… recruit or activate neutrophils. And neutrophils are specialized in killing bacteria fungi, and they will proceed to do so. And then the system operates in this manner to provide protection from infection. And finally, the third system… the third design would be when cells… sensor cells like macrophages again detect pathogens, then they produce cytokines that act on, now… on lymphocytes first. And then lymphocytes — that could involve T cells or different types of innate versions of T cells that I’ll describe in a second — which then produce the second-order cytokines. In this case, a first-order cytokine would be IL-12 produced by macrophages, which acts on lymphocytes, and causes lymphocytes to produce second-order cytokine such as interferon-gamma, which will then act on effector cells — that will be macrophages — and cause them to become activated to kill bacteria. So, this design is actually… it captures most of the operation of the immune system. And most of the complexity comes from the generation of lymphocytes and their functional heterogeneities. So, we will now… we’ll go quickly through different components of these systems, starting with sensors. There are several cell types that can function as sensors in the inflammatory and immune pathways. These include macrophages, mast cells, epithelial cells, dendritic cells, and plasmacytoid dendritic cells. So, these are different sensor cells that have different types of specializations. Macrophages, mast cells, and epithelial cells are kind of general-purpose sensors. They detect a large variety of pathogens and other types of inflammatory inducers. Dendritic cells are specialized on activating T cells. And plasmacytoid dendritic cells are specialized on antiviral responses. The lymphocyte part is… that’s where a lot of complexity comes in. They can be… there are two versions of circuits, depending on what kind of lymphocyte is used. And broadly speaking, there are innate lymphocytes that participate in the innate immune system, and lymphocytes involved in the adaptive immune system, which are T and B cells. The innate lymphocytes, again, come in two versions. There are so-called innate lymphoid cells, which are… have been relatively recently discovered. They don’t have T cell receptor. They reside in tissues and they respond to cytokines produced by sensor cells, and in turn produce cytokines that affect effectors. Then there are inmate-like lymphocytes that have T cell receptor, but it’s not a random receptor; it’s invariant, so it’s designed to detect very specific subsets of antigens. And finally, the adaptive immune system of course has antigen receptors, T cell receptor and immunoglobulin receptor for B cells, and these are the most complicated cells of the immune system because of the way that they develop and because of the way that their receptors are assembled, and all the additional steps that are involved to make the cells functional, because their receptors are generated at random. Again, when lymphocytes detect cytokines, they respond by producing cytokines. And what’s summarized here are some of the types of cytokines that… on the left side, that act on lymphocytes and the different types of lymphocytes and the second-order cytokines produced by lymphocytes. And then these things… cytokines produced by lymphocytes and, again, act on the effector cells, which are… examples are shown here: macrophages, neutrophils, basophils, eosinophils, mast cells, and epithelial cells. Depending on the type of cytokine produced, there would be different type of change in these cells, effector cell types. And in addition to these specialized effectors of the innate immune system, practically any cell in the body can be an effector, because most cells express receptors for at least some of the cytokines produced by lymphocytes. So, now we will quickly go over… with these concepts in mind, we will go over some of the key features of the inflammatory response. And we have to start with one of the oldest notions in the field of inflammation, which is the cardinal signs of inflammation. These were first defined by a Roman physician, Cornelius Celsus, in the first century AD. He defined them as redness and swelling with heat and pain. That was his description of how to diagnose inflammation. And much later, Rudolph Virchow added a fifth cardinal sign of inflammation, which is disturbance of function or loss of function of tissues. The four cardinal signs described by Celsus are a consequence of the changes that occur during acute inflammation. And these are local changes due to alterations in the local vasculature, as we will discuss next. So, this is what typically happens during the most common types of inflammatory responses, when you have a mild infection or papercut or some other splinter or some other injury to the epithelial surfaces. So, microbes or damage to the tissue are detected by sensor cells such as macrophages, dendritic cell, and mast cells, as I just mentioned. And once they detect microbes or tissue damage, these cells start producing inflammatory mediators such as cytokines and chemokines. And one of the effects of these inflammatory mediators, locally, within the tissue, is to act on the local microvasculature. And specifically, they… by acting on postcapillary venules, they cause several characteristic changes of the endothelium of the venules. They cause vasodilation, so there is increased blood flow. And increased blood flow causes heat and redness. And it causes increased vascular permeability, so that plasma starts going from the inside of blood vessels into extravascular spaces within tissues. And that causes swelling, or edema. And together the edema, and effects of inflammatory mediators, also can cause pain. So, redness, swelling, heat, and pain are all [results] of these vascular changes that occur locally. Another important change that happens is that endothelium within postcapillary venules becomes activated, in the sense that it now becomes… acquires adhesive properties such that neutrophils and monocytes and other cell types that go through blood vessels… normally, they would pass through. But when… if there is a local inflammation, the local endothelium becomes sticky, so that these cells now adhere or attach to endothelium, and ultimately they crawl through the endothelial wall into the tissue. And that’s the process called extravasation. And the point of that process is to deliver the circulating effector cells to the site of infection. And actually, Elle Metchnikoff was the first to recognize that that’s the point of vascular changes during inflammation. So, once neutrophils and other effector cells get to the site of the inflammation, where inflammation is induced, they will then seek out pathogens and will destroy them or repair the damaged tissue. Another important point that was realized probably in the last decade or so is that once inflammation accomplished its goal, which is elimination of pathogens, for example, that is not enough to get back to the normal state. If you just eliminated the cause of inflammation, it doesn’t mean that the system automatically goes back by default into homeostatic state. There is another phase between inflammation and homeostatic state — that’s called resolution — that needs to be actively engaged. This is analogous to a situation if you have, for example, a broken pipe and there’s flooding in the system. The cause of the mess would be the broken pipe, so let’s say you fix the pipe. That doesn’t mean that the system is now back into its original state. Now you have all the water on the floor and you need to get rid of it to return actively back to homeostatic state. So, that’s what resolution does. After inflammation accomplishes its goal, there’s a lot of mess within the tissue — there are many dead cells, there is destroyed extracellular matrix, and all of that has to be cleaned up and changed back to the original state. And of course this is something that requires a highly orchestrated and regulated process. And that’s what resolution does. And resolution of inflammation is a very important but still not fully understood process, but it’s… it’s well recognized now that it’s an active process — it’s not just passive cessation of inflammation — and that it’s needed to restore the homeostatic state. An additional important point to understand about inflammation is that there are not just different types of inflammation based on the causes, but there are also different modalities of inflammation. And they are historically defined as acute and chronic modalities of the inflammatory response. So they, as the names imply, acute and chronic inflammation obviously differ in duration. Acute inflammation can last from hours to days, and chronic inflammation typically can last from weeks to months to years. But more importantly, it’s not just the kinetics of the response, but more importantly acute and chronic inflammation are qualitatively distinct. And the common causes of chronic inflammation include failure to eliminate the inflammatory inducer, for example, if there is a persistent infection. It’s a failure of resolution of inflammation. And in some cases it could be a positive feedback, such that the consequence of the inflammatory response, for example, collateral tissue damage, may also be a cause for a secondary inflammatory response. And potentially that can sustain the inflammatory state. The qualitative differences between acute and chronic inflammation have to do with the types of cells involved. It’s mostly neutrophils and eosinophils in acute inflammation, but mostly lymphocytes in chronic inflammation, as well as macrophages. And there are many other differences related to the type of the mechanism used to… to deal with a persistent inflammatory inducer that’s used during chronic inflammation. Like other defenses, inflammation always operates at a cost. And these costs can be divided into distinct categories. The first class of causes of… the first type of costs of inflammation has to do with intentional suppression of physiological functions that are lower priority than the inflammatory response and that are somehow incompatible with the inflammatory response. For example, if you’re sitting on the couch and watching TV and there is a fire, then watching TV, as a function, would be incompatible with dealing with the fire. And it also would be obviously lower priority than dealing with the fire. So, you will intentionally stop watching TV, so that would be a cost, but it’s a low cost compared to the benefit of putting away the fire. And then the second type of course is unintentional cost. That is, it’s not something you want, but it’s something you can’t avoid. It’s unintentional and unavoidable costs, such as collateral tissue damage. So, when you’re putting out the fire and putting water on it, you will cause perhaps some collateral damage to the rest of the room. So, these are two different types of costs. And the sum of these two costs has to be lower than the benefit provided by inflammation for… for… for the system to be evolutionarily stable. So, inflammation can be pathological, therefore, for several reasons. And what’s important to understand is that even an appropriately controlled inflammatory response operates at the expense of other functions. So, it’s often said that inflammation is beneficial but when dysregulated can be pathological. We should appreciate that even perfectly controlled inflammatory responses operate at a cost, and sometimes these costs can manifest as symptoms that we may refer to as a disease. The second reason for pathology of inflammation is when the response is excessive and… either in magnitude or in duration. And the third cost would be when the response is induced when it shouldn’t be induced, for example when it’s mistargeted against something that is not harmful. And this is summarized in this schematic. When inflammation causes swelling, pain, fever, mucus overproduction, coughing, sneezing, diarrhea, these are all defenses. These are all manifestations of defenses. They are protective from different types of noxious challenges, but obviously all of them are processes that come at a cost. We do feel ill when we experience those reactions, even though they are protective. And what makes it worse is when they’re protective but excessive. Then they would be clearly just pathological. And so these are two different outcomes that need to be distinguished: when pathology is due to excessive response versus when pathology is simply the cost we have to pay for a normal response. And then the third type of pathological outcome is more obvious. It’s when there is a… just collateral tissue damage or a mistargeted response. So, when we put it this way, it’s clear that the three types of pathological outcomes are very different. And… for example, you don’t want to interfere with the first one, you want to dial down the second one, and you want to stop the third one. And the challenge is to be able to distinguish which one they belong to so that we know what to do with them. So, the take-home messages in this brief overview is that inflammation is normally a protective response to infection and injury and other… and loss of tissue homeostasis, that it’s induced when homeostatic capacity is overwhelmed, and that all of the diversity and complexity of inflam… of inflammation can be summarized in terms of the inflammatory pathway that consists of inducers, sensors that detect them, mediators they produce, and the effectors that eliminate the inducers. And inflammation is normally followed by a resolution phase, which returns the system to homeostasis. And an inflammatory response always operates at a cost to incompatible lower-priority functions. And inflammation can cause pathology when it’s excessive, inappropriately induced, or due to collateral damage. And that completes this overview. I will discuss in the next talk some specific examples of inflammation in the context of inflammatory diseases. And thank you for your attention.