Session 2: The Inflammatory Response: Activation of the Innate Immune System
Transcript of Part 1: Introduction to Inflammation
00:00:15;00 Hello. 00:00:16;00 My name is Ruslan Medzhitov. 00:00:17;00 I'm a professor at Yale University School of Medicine, and an Investigator from 00:00:21;17 Howard Hughes Medical Institute. 00:00:23;10 In this lecture, I will discuss inflammation, and I'll give a brief overview of the 00:00:28;21 field of inflammation and its role in both host defense and homeostasis, as well as in pathologies. 00:00:37;19 So, inflammation is an enormously huge field with a lot of details known about some aspects 00:00:44;00 of inflammation. 00:00:45;00 And to be able to summarize it in this short overview, I will use a couple of perspectives 00:00:51;28 that summarize some key features of inflammation, and specifically I will start by putting inflammation 00:01:00;09 in the context of the better-understood and better-defined phenomenon of homeostasis, 00:01:06;15 and I'll show the similarities, parallels, and how the two types of processes 00:01:13;13 interact with each other, causing both beneficial and detrimental outcomes. 00:01:18;07 So, just to remind you, homeostasis maintains stability of biological systems 00:01:25;13 in the face of perturbations. 00:01:27;00 And perturbations could be either external or internal to the system. 00:01:31;15 And inflammation is induced when these perturbations exceed homeostatic capacity of the system. 00:01:37;09 So schematically, this could be summarized as follows. 00:01:40;15 If we imagine the position of this ball as the state of the system, here, in the center 00:01:46;26 -- you can see, in the normal state -- the homeostasis is maintained by keeping 00:01:54;13 the state of the system in the desired position. 00:01:57;22 And when it deviates from that position, homeostatic mechanisms will bring it back. 00:02:02;20 But if perturbation is large enough and the system goes outside of its normal control zone, 00:02:10;06 outside of its normal homeostatic range, then homeostatic capacity is no longer sufficient 00:02:17;08 to keep the system in a desired state, and that's when inflammation is induced, 00:02:22;14 to force the system back into the homeostatic state. 00:02:25;17 That's one way to think about connections between homeostasis and inflammation. 00:02:30;21 So, inflammation is something that forces the system to go back into the homeostatic state, 00:02:36;00 when perturbations are large enough and when they overwhelm homeostatic capacity. 00:02:43;04 In modern terms, we can describe homeostasis using the idea of a control circuit. 00:02:49;22 And this is a very simple but very fundamental concept. 00:02:54;04 So here, what is summarized on this slide is key components of a homeostatic circuit. 00:03:00;26 And whenever we speak about homeostasis, that means that we talk about maintenance of 00:03:08;02 some variable of the system. 00:03:09;09 It could be blood sugar; it could be temperature; it could be sodium; it could be any of the 00:03:15;03 variables of the system that the system cares about and wants to maintain. 00:03:19;11 So, that's what's denoted here as X. 00:03:21;24 And when we refer to homeostasis of this variable, that means we want to keep it close to 00:03:27;26 some desired value. 00:03:29;14 And that's what's called the setpoint value, X' here. 00:03:33;02 So, that is... it is the value of that variable, or the difference of that variable value from 00:03:39;20 the setpoint value, that is monitored by the sensor. 00:03:43;00 The sensor is the component of a homeostatic circuit that monitors the value of the variable 00:03:47;28 the system cares about. 00:03:51;01 And the second essential part of the system is the effector part, and that's the part 00:03:56;24 that can change that value. 00:03:58;26 So, the sensor monitors the value; the effector can change the value. 00:04:02;06 And they need to communicate with each other through a signal that's denoted as C, here. 00:04:07;16 So for example, in the case of systemic homeostasis of blood glucose, X would be the actual concentration 00:04:15;23 of glucose in the blood, X' would be the setpoint value, which is in humans about 5 millimolar, 00:04:22;23 and the sensors would be pancreatic alpha and beta cells that monitor how much glucose 00:04:27;04 we have in the blood. 00:04:28;08 Are you eat, glucose level goes up. 00:04:30;26 Beta cells in the pancreas will detect that and will start producing insulin, which is 00:04:35;06 the example of the signal, shown here, which will go on to act on its effectors, 00:04:41;06 which include skeletal muscle, fat, and liver. 00:04:44;04 And the effect of insulin on these target tissues will be to lower blood glucose level, 00:04:49;04 for example by inducing uptake into those tissues or conversion into glycogen or lipids. 00:04:54;24 If the glucose level is lower than the setpoint value, then alpha cells of the pancreas 00:05:01;08 will detect that, a low lev... a low level, and start producing a different hormone, 00:05:06;05 which is glucagon, which will act exactly, again, on effector cells... effector tissues and organs, 00:05:11;25 for example liver, and cause them to start producing glucose to raise it... 00:05:17;07 to raise the level to the desired value. 00:05:20;06 So, that's how a homeostatic circuit works at... at an organismal level, a tissue level, 00:05:27;10 and a cellular level. 00:05:30;12 Now, the origin of the concept of inflammation goes back to... it can be credited to many people, 00:05:38;14 but the two that I want to highlight here are Rudolf Virchow Elle Metchnikoff, 00:05:44;01 who were contemporaries and colleagues. 00:05:49;01 And so, Virchow, of course, is credited with the development of the modern science of pathology, 00:05:53;25 of cellular pathology. 00:05:56;15 And he was an extremely influential scientist in Europe at the time. 00:06:01;01 And Elle Metchnikoff, of course, is known for his discovery of phagocytes and its... 00:06:07;10 their role in innate immunity. 00:06:09;12 But in the context of inflammation, these two individuals provided very important 00:06:15;15 conceptual contributions. 00:06:16;15 But there was one important difference between them, in that Virchow primarily viewed inflammation 00:06:21;15 as a pathological process, whereas Metchnikoff recognized early on that, in addition to these 00:06:27;17 pathological outcomes of inflammation, that the... the primary reason for an 00:06:34;03 inflammatory response is to provide protection from infections. 00:06:38;24 And he visualized and conceptualized the inflammatory response as being part of a spectrum, 00:06:47;28 where at the base of the spectrum would be what he called "harmony/disharmony balance", 00:06:53;28 and this is what we currently would call homeostasis, but the term homeostasis wasn't coined yet, 00:06:59;22 until 1929. 00:07:00;27 Then, the next level would be physiological inflammation, when inflammation plays 00:07:07;11 beneficial roles in host defense. 00:07:09;20 And then pathological inflammation, and finally immunity. 00:07:13;08 And that... that concept of physiological inflammation and the spectrum of 00:07:18;28 inflammatory response from homeostasis to immunity is actually a very profound insight which was 00:07:25;10 largely forgotten until very recently. 00:07:27;11 And only now we are starting to rediscover and realize these fundamental connections 00:07:32;27 between physiological processes and inflammation. 00:07:38;18 So, taking that, Metchnikoff's idea, and putting it in... looking from different dimensions, 00:07:46;13 we can summarize it as follows, as the spectrum of degrees of deviation from homeostatic states. 00:07:53;06 So here, on the... on the left side, you see the range of conditions of a system that 00:08:00;02 would be within a homeostatic state. 00:08:02;23 If it deviates far enough from that, that's what... what we would call a stress response, 00:08:07;11 or we could also call it a physiological inflammatory response. 00:08:11;07 And if it deviates much further than that, that's what we would call inflammation proper. 00:08:16;23 And so this... any deviation from a normal state, therefore, can be... can lead to 00:08:22;07 the induction of the inflammatory response. 00:08:24;18 So, the causes of inflammation from that perspective can be summarized as follows. 00:08:32;09 In the center here, in the middle, you can see that loss of homeostasis per se is sufficient 00:08:36;27 to lead to inflammation as... as I just mentioned. 00:08:41;02 But in addition, there could be exogenous perturbations that can lead to loss of homeostasis. 00:08:48;11 And the two major types of such perturbations will be pathogens (during infection) 00:08:53;25 as well as toxins and allergens and virulence factors produced by pathogens. 00:08:59;02 So, both pathogens and... and toxins can cause loss of inflammation... loss of homeostasis 00:09:06;14 that... and that can lead to inflammation. 00:09:09;10 But in addition, the immune system developed two pre-emptive mechanisms to trigger a protective 00:09:15;04 inflammatory response, even before pathogens or allergens can cause damage to the system. 00:09:22;07 And there are two fundamental ways that the immune system detects these inducers of inflammation. 00:09:27;10 At the top here, what I call structural feature recognition is the property of the 00:09:32;17 innate immune system to detect invariant structures associated with microbial cells. 00:09:40;03 This is sometimes called the pattern recognition system, where receptors of the immune system 00:09:46;10 detect conserved structures that have found in most microbes, for example we lipopolysaccharides 00:09:53;10 of the cell wall or peptidoglycans, lipoteichoic acids, and so on. 00:09:58;07 And detection of these structures is sufficient to trigger inflammation. 00:10:02;23 On the other hand, allergens and toxins and virulence factors, they're extremely diverse. 00:10:07;00 There... there are many different types and there is no way to detect them all based on 00:10:11;08 structural features, because they don't share any structural features. 00:10:15;09 And the strategy of recognition here is what I would call a functional feature recognition, 00:10:20;16 because what is detected is not specific structures but rather specific biochemical activities, 00:10:27;02 such as protease activities, lipase activities, lipid binding, membrane perturbations, 00:10:33;25 pore formation, and so on. 00:10:35;16 Those functional features are detected by that system, and that also can lead to inflammation. 00:10:40;13 And that type of strategy is particularly important in allergic inflammation. 00:10:46;07 So, based on these ideas, we now can summarize how the immune system operates based on 00:10:53;20 the simple logic of the control circuits. 00:10:57;05 So, we know that the immune system... one of the major functions of the immune system 00:11:01;18 is to detect pathogens and to provide a protective response against them by, for example, 00:11:09;01 destroying them or expelling them from the organism. 00:11:14;00 To do so, the immune system has to have two essential components. 00:11:17;04 It has to have a pathogen-sensing component, or pathogen-sensing cells, and it has to have 00:11:25;10 antimicrobial effector cells, and sensor and effector cells have to communicate with 00:11:31;06 each other through a signal, and once the effector receives the signal from the sensor, it elicits 00:11:36;22 a response that leads to defense from the pathogen. 00:11:40;02 So, that's a very simplified view of the immune system. 00:11:45;13 And the signals that are involved in communication between sensors and effectors are what contributes 00:11:51;02 to this enormous complexity of inflammation and understanding of the immunity. 00:11:57;10 There are many different types of signals in the context of inflammation. 00:12:01;28 The signals are usually called inflammatory mediators. 00:12:06;13 And two major types of inflammatory mediators are signals called chemokines and cytokines. 00:12:14;14 Chemokines are short polypeptides that are produced upon infection by sensor cells 00:12:24;05 that detect pathogens or tissue damage. 00:12:27;08 And what chemokines do is they recruit effector cells to the site of infection. 00:12:33;15 For example, macrophages that function as sensor cells, when they detect bacterial pathogens, 00:12:40;04 will produce chemokines that will recruit neutrophils to the site of infection, 00:12:43;24 and then neutrophils will take care of the pathogens. 00:12:47;11 The second type of inflammatory mediators are cytokines. 00:12:50;26 And this is a... again, a very diverse group of signals that belong to different structural families, 00:12:56;14 but basically what cytokines do... they... they, again, are produced by sensor cells 00:13:01;14 when they detect infection, and they activate effector cells to elicit various 00:13:09;16 antimicrobial functions. 00:13:11;25 So, with this in mind, we now can summarize much of the inflammation and diversity of inflammation 00:13:22;02 into these simple and universal components of the inflammatory pathway. 00:13:28;00 Any type of inflammation includes these four universal components. 00:13:31;12 There is always some type of an inducer of inflammation, for example, pathogen, toxin, 00:13:36;22 tissue damage, or loss of homeostasis. 00:13:39;13 There are sensors that detect the inducers. 00:13:42;19 These include various types of cells of the innate immune system, such as macrophages 00:13:48;04 and mast cells, but also various types of sensory neurons. 00:13:54;27 And the sensor cells produce inflammatory mediators, which include cytokines, chemokines, 00:14:01;15 as well as bioactive amines like histamine, peptides, like bradykinin, as well as 00:14:07;28 lipid mediators called eicosanoids, which include, for example, prostaglandins. 00:14:13;07 And these mediators then act on various target tissues. 00:14:16;25 And almost any tissue in the body can be a target for different types of inflammatory mediators. 00:14:23;01 So here, I'm showing liver, vasculature, epithelial cells, and neutrophils. 00:14:30;21 When mediators act on these effector cells, they cause appropriate changes in their 00:14:36;16 state and their function, or in their positioning. 00:14:39;02 Again, chemokines can recruit neutrophils to the site of infection. 00:14:44;11 Cytokines acting on hepatocytes sites or vascular endothelium will cause their activation, 00:14:52;21 changing protein secretion or permeability of the epithelium. 00:14:56;02 And in the case of mucosal epithelium, they can change the production of antimicrobial 00:15:02;21 peptides or mucus. 00:15:04;21 So, this is this inflammatory pathway. 00:15:08;00 And as you... as you may notice, there is... this is very much related to... it's the 00:15:17;21 same kind of a control circuit we just discussed for homeostasis, where we have a sensor, 00:15:23;26 a signal that connects sensor to the effector, and the effector. 00:15:28;06 The only difference is that in this case what is monitored is not a homeostatic variable, 00:15:33;15 but rather some inducer of inflammation, such as a pathogen or toxin. 00:15:38;22 So, there are these clear parallels between homeostatic and inflammatory control circuits. 00:15:45;04 The reason for that has to do with the fundamental importance of these type of control circuits. 00:15:50;02 They're everywhere, from engineering systems to biological systems. 00:15:55;04 And again, the differences between them are related to the types of inducers that are... 00:16:03;18 that are detected by sensors, or homeostatic variables detected by homeostatic sensors. 00:16:10;07 But we should also keep in mind that sometimes the differences between homeostatic and inflammatory 00:16:16;10 control circuits can be arbitrary, because inflammatory mediators used by homeostatic... 00:16:21;16 by inflammatory circuits can also have some homeostatic functions, and homeostatic signals 00:16:29;11 used by homeostatic circuits can participate in regulation of the inflammatory response. 00:16:37;10 There are actually two different designs... versions of the control circuits. 00:16:45;24 Here on the top is the control circuit I just mentioned. 00:16:48;19 That's the simplest one, where you just have sensor and an effector, and the signal 00:16:52;24 that connects them. 00:16:54;21 There is another type of a circuit which has an additional component in between. 00:17:00;12 And that's what's called a controller or integrating unit. 00:17:04;04 So, here we have a sensor that monitors an inflammatory inducer or homeostatic variable. 00:17:11;21 It produces a signal that then acts on the controller, and then the controller does 00:17:15;23 some type of a computation, and then sends a second signal to the effector. 00:17:19;28 This type of a design is particularly prevalent in both immune and nervous systems. 00:17:28;02 In the case of the immune system, the control... the role of a controller is typically played 00:17:31;17 by a lymphocyte. 00:17:33;03 And in the case of the nervous system, it's played by various types of interneurons. 00:17:39;04 So, sensor cells, again, after detecting the inducer, produce one signal, and then 00:17:46;24 the controller produces a second signal. 00:17:48;20 And these two types of signals are distinct in the immune system, as we will discuss. 00:17:55;10 So from that perspective, we can summarize the entire operation of the immune system 00:18:02;00 as... as connections between pathogen sensors and effectors. 00:18:09;11 And there are three types of disconnections. 00:18:11;17 The simplest one is shown at the top, where the sensor and the effector is the same entity, 00:18:17;10 the same cell. 00:18:19;16 The sensor would be, for example, a receptor, and the effector would be, for example, 00:18:24;05 an antimicrobial enzyme. 00:18:27;11 The second type is when the sensor produces a signal that acts on the effector, 00:18:32;07 as we just discussed. 00:18:33;16 And the third type when there is a lymphocyte in between. 00:18:36;22 And the first two types belong entirely to the domain of the innate immune system, 00:18:41;22 and the second... the... the third one, it can be either innate or adaptive immune system, 00:18:48;07 depending on the type of lymphocyte involved. 00:18:50;26 So, we will go through the different versions of these circuits to illustrate how they operate 00:18:58;09 in the context of infection. 00:18:59;25 So, the simplest one is when a cell like a macrophage encounters a pathogen, like a bacterium, phagocytoses then kills it. 00:19:08;13 So in this case, the sensor would be receptors that detect the microbe, and the effectors 00:19:13;17 would be phagocytic machinery and lysosomal enzymes that will kill the microbe. 00:19:17;24 So, that's the simplest one. 00:19:19;16 And more... more commonly, when macrophages detect pathogens, they will produce a signal 00:19:25;27 that will connect them to the effector, such as a neutrophil, and it will either recruit... 00:19:31;22 recruit or activate neutrophils. 00:19:33;05 And neutrophils are specialized in killing bacteria fungi, and they will proceed to do so. 00:19:39;16 And then the system operates in this manner to provide protection from infection. 00:19:47;14 And finally, the third system... the third design would be when cells... sensor cells 00:19:52;25 like macrophages again detect pathogens, then they produce cytokines that act on, now... 00:19:58;12 on lymphocytes first. 00:20:00;23 And then lymphocytes -- that could involve T cells or different types of innate versions 00:20:08;02 of T cells that I'll describe in a second -- which then produce the second-order cytokines. 00:20:13;21 In this case, a first-order cytokine would be IL-12 produced by macrophages, which acts 00:20:18;11 on lymphocytes, and causes lymphocytes to produce second-order cytokine 00:20:22;08 such as interferon-gamma, 00:20:24;08 which will then act on effector cells -- that will be macrophages -- and cause them to 00:20:28;23 become activated to kill bacteria. 00:20:30;23 So, this design is actually... it captures most of the operation of the immune system. 00:20:37;28 And most of the complexity comes from the generation of lymphocytes and their 00:20:42;24 functional heterogeneities. 00:20:44;12 So, we will now... we'll go quickly through different components of these systems, 00:20:49;15 starting with sensors. 00:20:51;04 There are several cell types that can function as sensors in the inflammatory and immune 00:20:56;15 pathways. 00:20:57;15 These include macrophages, mast cells, epithelial cells, dendritic cells, and plasmacytoid dendritic cells. 00:21:05;10 So, these are different sensor cells that have different types of specializations. 00:21:11;06 Macrophages, mast cells, and epithelial cells are kind of general-purpose sensors. 00:21:16;13 They detect a large variety of pathogens and other types of inflammatory inducers. 00:21:24;23 Dendritic cells are specialized on activating T cells. 00:21:28;07 And plasmacytoid dendritic cells are specialized on antiviral responses. 00:21:33;21 The lymphocyte part is... that's where a lot of complexity comes in. 00:21:40;11 They can be... there are two versions of circuits, depending on what kind of lymphocyte is used. 00:21:46;20 And broadly speaking, there are innate lymphocytes that participate in the innate immune system, 00:21:52;15 and lymphocytes involved in the adaptive immune system, which are T and B cells. 00:21:57;22 The innate lymphocytes, again, come in two versions. 00:22:00;04 There are so-called innate lymphoid cells, which are... have been relatively 00:22:04;16 recently discovered. 00:22:05;16 They don't have T cell receptor. 00:22:07;26 They reside in tissues and they respond to cytokines produced by sensor cells, 00:22:13;15 and in turn produce cytokines that affect effectors. 00:22:16;07 Then there are inmate-like lymphocytes that have T cell receptor, but it's not a random receptor; 00:22:23;05 it's invariant, so it's designed to detect very specific subsets of antigens. 00:22:29;10 And finally, the adaptive immune system of course has antigen receptors, T cell receptor 00:22:35;00 and immunoglobulin receptor for B cells, and these are the most complicated cells of the 00:22:41;21 immune system because of the way that they develop and because of the way that 00:22:46;02 their receptors are assembled, and all the additional steps that are involved to make the cells functional, 00:22:51;18 because their receptors are generated at random. 00:22:55;15 Again, when lymphocytes detect cytokines, they respond by producing cytokines. 00:23:02;03 And what's summarized here are some of the types of cytokines that... on the left side, 00:23:07;21 that act on lymphocytes and the different types of lymphocytes 00:23:12;24 and the second-order cytokines produced by lymphocytes. 00:23:16;02 And then these things... cytokines produced by lymphocytes and, again, act on the effector cells, 00:23:21;07 which are... examples are shown here: macrophages, neutrophils, basophils, eosinophils, 00:23:27;06 mast cells, and epithelial cells. 00:23:30;06 Depending on the type of cytokine produced, there would be different type of change 00:23:33;18 in these cells, effector cell types. 00:23:37;06 And in addition to these specialized effectors of the innate immune system, practically 00:23:43;06 any cell in the body can be an effector, because most cells express receptors for at least 00:23:48;15 some of the cytokines produced by lymphocytes. 00:23:52;10 So, now we will quickly go over... with these concepts in mind, we will go over some of 00:24:01;00 the key features of the inflammatory response. 00:24:04;08 And we have to start with one of the oldest notions in the field of inflammation, 00:24:11;05 which is the cardinal signs of inflammation. 00:24:13;10 These were first defined by a Roman physician, Cornelius Celsus, in the first century AD. 00:24:22;12 He defined them as redness and swelling with heat and pain. 00:24:27;25 That was his description of how to diagnose inflammation. 00:24:33;10 And much later, Rudolph Virchow added a fifth cardinal sign of inflammation, which is disturbance 00:24:39;14 of function or loss of function of tissues. 00:24:42;22 The four cardinal signs described by Celsus are a consequence of the changes that 00:24:49;09 occur during acute inflammation. 00:24:52;07 And these are local changes due to alterations in the local vasculature, as we will discuss next. 00:25:01;15 So, this is what typically happens during the most common types of inflammatory responses, 00:25:06;27 when you have a mild infection or papercut or some other splinter or some other injury 00:25:15;03 to the epithelial surfaces. 00:25:18;04 So, microbes or damage to the tissue are detected by sensor cells such as macrophages, dendritic cell, 00:25:28;27 and mast cells, as I just mentioned. 00:25:31;24 And once they detect microbes or tissue damage, these cells start producing inflammatory mediators 00:25:37;00 such as cytokines and chemokines. 00:25:40;00 And one of the effects of these inflammatory mediators, locally, within the tissue, 00:25:44;07 is to act on the local microvasculature. 00:25:47;26 And specifically, they... by acting on postcapillary venules, they cause several characteristic 00:25:54;26 changes of the endothelium of the venules. 00:25:59;04 They cause vasodilation, so there is increased blood flow. 00:26:03;13 And increased blood flow causes heat and redness. 00:26:07;20 And it causes increased vascular permeability, so that plasma starts going from the 00:26:15;02 inside of blood vessels into extravascular spaces within tissues. 00:26:19;12 And that causes swelling, or edema. 00:26:23;12 And together the edema, and effects of inflammatory mediators, also can cause pain. 00:26:29;13 So, redness, swelling, heat, and pain are all [results] of these vascular changes 00:26:35;09 that occur locally. 00:26:37;04 Another important change that happens is that endothelium within postcapillary venules becomes 00:26:42;19 activated, in the sense that it now becomes... acquires adhesive properties such that neutrophils 00:26:51;09 and monocytes and other cell types that go through blood vessels... normally, they would 00:26:56;13 pass through. 00:26:57;16 But when... if there is a local inflammation, the local endothelium becomes sticky, so that 00:27:03;02 these cells now adhere or attach to endothelium, and ultimately they crawl through the endothelial wall 00:27:11;06 into the tissue. 00:27:13;00 And that's the process called extravasation. 00:27:16;01 And the point of that process is to deliver the circulating effector cells to 00:27:21;05 the site of infection. 00:27:22;05 And actually, Elle Metchnikoff was the first to recognize that that's the point of vascular 00:27:27;08 changes during inflammation. 00:27:30;00 So, once neutrophils and other effector cells get to the site of the inflammation, 00:27:35;00 where inflammation is induced, they will then seek out pathogens and will destroy them or 00:27:41;21 repair the damaged tissue. 00:27:44;27 Another important point that was realized probably in the last decade or so is that 00:27:55;11 once inflammation accomplished its goal, which is elimination of pathogens, for example, 00:28:02;23 that is not enough to get back to the normal state. 00:28:06;25 If you just eliminated the cause of inflammation, it doesn't mean that the system automatically 00:28:11;08 goes back by default into homeostatic state. 00:28:14;22 There is another phase between inflammation and homeostatic state -- that's called resolution -- 00:28:19;20 that needs to be actively engaged. 00:28:22;24 This is analogous to a situation if you have, for example, a broken pipe and there's flooding 00:28:27;15 in the system. 00:28:28;15 The cause of the mess would be the broken pipe, so let's say you fix the pipe. 00:28:32;13 That doesn't mean that the system is now back into its original state. 00:28:36;11 Now you have all the water on the floor and you need to get rid of it to return actively 00:28:40;20 back to homeostatic state. 00:28:42;04 So, that's what resolution does. 00:28:44;09 After inflammation accomplishes its goal, there's a lot of mess within the tissue -- 00:28:50;11 there are many dead cells, there is destroyed extracellular matrix, and all of that has to be cleaned up 00:28:57;26 and changed back to the original state. 00:29:01;04 And of course this is something that requires a highly orchestrated and regulated process. 00:29:08;06 And that's what resolution does. 00:29:10;06 And resolution of inflammation is a very important but still not fully understood process, 00:29:16;21 but it's... it's well recognized now that it's an active process -- it's not just 00:29:22;00 passive cessation of inflammation -- and that it's needed to restore the homeostatic state. 00:29:27;23 An additional important point to understand about inflammation is that there are 00:29:35;13 not just different types of inflammation based on the causes, but there are also different modalities 00:29:40;04 of inflammation. 00:29:41;04 And they are historically defined as acute and chronic modalities of the inflammatory response. 00:29:49;12 So they, as the names imply, acute and chronic inflammation obviously differ in duration. 00:29:54;16 Acute inflammation can last from hours to days, and chronic inflammation typically 00:30:01;02 can last from weeks to months to years. 00:30:06;22 But more importantly, it's not just the kinetics of the response, but more importantly 00:30:11;21 acute and chronic inflammation are qualitatively distinct. 00:30:17;20 And the common causes of chronic inflammation include failure to eliminate the inflammatory inducer, 00:30:23;05 for example, if there is a persistent infection. 00:30:27;04 It's a failure of resolution of inflammation. 00:30:31;17 And in some cases it could be a positive feedback, such that the consequence of the inflammatory response, 00:30:37;22 for example, collateral tissue damage, may also be a cause for a secondary inflammatory response. 00:30:44;03 And potentially that can sustain the inflammatory state. 00:30:49;07 The qualitative differences between acute and chronic inflammation have to do with 00:30:53;16 the types of cells involved. 00:30:54;27 It's mostly neutrophils and eosinophils in acute inflammation, but mostly lymphocytes 00:31:01;19 in chronic inflammation, as well as macrophages. 00:31:05;13 And there are many other differences related to the type of the mechanism used to... 00:31:12;19 to deal with a persistent inflammatory inducer that's used during chronic inflammation. 00:31:18;01 Like other defenses, inflammation always operates at a cost. 00:31:23;01 And these costs can be divided into distinct categories. 00:31:27;06 The first class of causes of... the first type of costs of inflammation has to do with 00:31:35;14 intentional suppression of physiological functions that are lower priority than the inflammatory response 00:31:43;00 and that are somehow incompatible with the inflammatory response. 00:31:47;24 For example, if you're sitting on the couch and watching TV and there is a fire, 00:31:52;24 then watching TV, as a function, would be incompatible with dealing with the fire. 00:31:57;28 And it also would be obviously lower priority than dealing with the fire. 00:32:02;08 So, you will intentionally stop watching TV, so that would be a cost, but it's a low cost 00:32:07;17 compared to the benefit of putting away the fire. 00:32:12;05 And then the second type of course is unintentional cost. 00:32:16;10 That is, it's not something you want, but it's something you can't avoid. 00:32:21;03 It's unintentional and unavoidable costs, such as collateral tissue damage. 00:32:24;20 So, when you're putting out the fire and putting water on it, you will cause perhaps some 00:32:30;26 collateral damage to the rest of the room. 00:32:33;21 So, these are two different types of costs. 00:32:36;17 And the sum of these two costs has to be lower than the benefit provided by inflammation 00:32:40;15 for... for... for the system to be evolutionarily stable. 00:32:45;20 So, inflammation can be pathological, therefore, for several reasons. 00:32:51;17 And what's important to understand is that even an appropriately controlled inflammatory response 00:32:57;06 operates at the expense of other functions. 00:33:00;04 So, it's often said that inflammation is beneficial but when dysregulated can be pathological. 00:33:05;01 We should appreciate that even perfectly controlled inflammatory responses operate at a cost, 00:33:09;21 and sometimes these costs can manifest as symptoms that we may refer to as a disease. 00:33:17;08 The second reason for pathology of inflammation is when the response is excessive and... 00:33:24;26 either in magnitude or in duration. 00:33:27;01 And the third cost would be when the response is induced when it shouldn't be induced, 00:33:30;26 for example when it's mistargeted against something that is not harmful. 00:33:37;22 And this is summarized in this schematic. 00:33:41;24 When inflammation causes swelling, pain, fever, mucus overproduction, coughing, sneezing, diarrhea, 00:33:47;11 these are all defenses. 00:33:49;26 These are all manifestations of defenses. 00:33:51;25 They are protective from different types of noxious challenges, but obviously all of them 00:33:57;17 are processes that come at a cost. 00:34:01;15 We do feel ill when we experience those reactions, even though they are protective. 00:34:07;06 And what makes it worse is when they're protective but excessive. 00:34:11;08 Then they would be clearly just pathological. 00:34:15;13 And so these are two different outcomes that need to be distinguished: when pathology is 00:34:19;23 due to excessive response versus when pathology is simply the cost we have to pay for a normal response. 00:34:27;03 And then the third type of pathological outcome is more obvious. 00:34:31;06 It's when there is a... just collateral tissue damage or a mistargeted response. 00:34:36;09 So, when we put it this way, it's clear that the three types of pathological outcomes 00:34:42;01 are very different. 00:34:43;05 And... for example, you don't want to interfere with the first one, you want to dial down 00:34:47;16 the second one, and you want to stop the third one. 00:34:50;24 And the challenge is to be able to distinguish which one they belong to so that we know 00:34:55;19 what to do with them. 00:34:57;08 So, the take-home messages in this brief overview is that inflammation is normally 00:35:03;20 a protective response to infection and injury and other... and loss of tissue homeostasis, 00:35:10;06 that it's induced when homeostatic capacity is overwhelmed, and that all of the diversity and complexity 00:35:18;08 of inflam... of inflammation can be summarized in terms of the inflammatory pathway that 00:35:22;22 consists of inducers, sensors that detect them, mediators they produce, and the effectors 00:35:28;10 that eliminate the inducers. 00:35:32;02 And inflammation is normally followed by a resolution phase, which returns the system 00:35:36;12 to homeostasis. 00:35:39;16 And an inflammatory response always operates at a cost to incompatible lower-priority functions. 00:35:48;16 And inflammation can cause pathology when it's excessive, inappropriately induced, 00:35:53;05 or due to collateral damage. 00:35:55;22 And that completes this overview. 00:35:59;02 I will discuss in the next talk some specific examples of inflammation in the context of 00:36:08;08 inflammatory diseases. 00:36:09;27 And thank you for your attention.