Why Is Inflammation a Dangerous Necessity?

We have heard a lot about the immune system over the last couple of years, but it fights off more than the coronaviruses. Sometimes the immune system can attack our own bodies, causing harmful and even deadly inflammation, and it is 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 800-313-5780 Steven Strogatz talks with Shruti Naik, an assistant professor of biological sciences at the Langone Medical Center of New York University, to learn why the immune system works so well and how it can backfire.

You can listen to it on one of the following: Apple Podcasts, Spotify, or your favorite podcasting app, or you can stream it from Quanta.

Steve Strogatz is the host of The Joy of Why, which takes you into some of the biggest unanswered questions in math and science.

In the last couple of years, we have heard a lot about the immune system, as scientists and doctors learn how to deal with COVID-19. Our immune system does more than fight COVID. It helps us fight many other diseases. It repairs our skin and other tissues when they are damaged. Sometimes the immune system goes awry, like when it starts attacking our own bodies or when it causes chronic inflammation. Maintaining the right balance of immune activity is important for our health. How does the immune system work?

Shruti Naik is here to discuss all this. She is an assistant professor of biological sciences at NYU. Her lab studies stem cells, microbes, and immunity, which includes looking at inflammation throughout the body, but with a special focus on the skin, and especially how skin cells remember injuries and exposure to irritants. She's interested in how immune cells interact with other cells in the body, like stem cells. She is making discoveries that could have implications for a variety of health problems, including skin conditions like Psoriasis, and even cancer. Shruti Naik, thank you for joining us.

Shruti Naik thanks you for the focus on inflammation, which is a really important part of our health and a really critical driver of disease.

That is exactly why we wanted to have you. After hearing that a lot of the diseases that we used to think of as being about something else might actually be, secretly, problems of inflammation, I have been curious about inflammation for years.

Naik is absolutely right. Alzheimer's and cardiovascular disease were thought to be issues with the brain not functioning as well as it could, or the heart having some issues with metabolism. The root cause of many of these ailments is that your immune system is malfunctioning. If we just take a step back and think about it, we realize that the immune system is inescapable, and every cell in your body touches an immune cell at one time or another. The implications of that are really remarkable. The immune system is the central hub of health. How this works and how it can go wrong.

Can we just do a little of the biology that we learned in school, or should we have learned more about the immune system? I think a way to start is to say it in a way that makes it sound like it's one system, but then you guys, the experts in immunology, tell us to think in terms of two systems. Is there a difference between the innate immune system and the adaptive immune system? What do they do?

They are two different systems, but they work together. They are partner systems, right? The biggest difference between the two systems is that the adaptive immune system, which are your T cells and your B cells, are cells that have a really remarkable ability to see pathogens in a very specific way. The adaptive immune system is more specific than the innate immune system.

The innate immune system can fight and see pathogens, but it doesn't discriminate. It calls into action much faster. The adaptive immune system takes a little longer to kick in than the first line of defense.

I'm speaking in broad strokes now. Some cells act like the innate immune system and some cells act like the adaptive immune system in an in-between between between between the two of these. Those are the extremes of the continuum. Think of them as the pawns of the game, and things that take a little bit longer as the generals of the game.

That is an interesting distinction. Is it correct to think of it as like the innate is quick and dirty, and the adaptive system is a little more sophisticated? Slower, but more refined?

Naik is right. That is exactly what it is. Something is going wrong here and the innate immune system is going to come and say something. The adaptive immune system is going to take its time and learn about the pathogen, and pick its best general, so to speak.

The word "adaptive" suggests that something is adapting, learning, and evolving over time. We think of learning as a higher function of something with consciousness or at least with a mind. You don't mean that kind of learning. How do we see this? Let's start with the adaptive immune system learning. What does that mean? How can things like that learn?

This is a very different kind of learning. Both the adaptive and innate immune system can learn. They are systems that remember their experiences, but the way they learn is very different.

Think of the adaptive immune system as a pool of 10 people, each of whom can only see one color of the rainbow. The person who is going to see purple is going to be the best suited to live in that world. The person who sees the purple starts making more of themselves. The cells that can see one particular pathogen are selected for and given all of the body's resources, so these cells make more of themselves. Picking the best adaptive immune cell is a way to expand it.

Interesting. I like the analogy, but if we could get a little more in the world of what's really happening. I want to think about shapes as a mathematician. One of the most remarkable things is that you can have a disease that your body has never seen before. The immune system can eventually recognize virtually anything. Is it that thing that has the right shape that can bind onto the pathogen? It can start to fight it better if it can stick. Is it about shape recognition?

That is exactly what it is. The shape recognition is based on the bug's genes. So, when we think about COVID, the ones that work really, really well, are the ones that recognize the spike proteins, right? It recognizes the folds of the three-dimensional structure. The adaptive immune cells that have good structural recognition are the ones that the body picks and says, "Okay, let's make more of you." We know that you will be able to take care of business, and that you will be able to see the bad guy. We're going to make more of you, even when the bad guy is gone, and we're not going to let you go away.

That's interesting. The fighters that were well-adapted or had good shape recognition ability were the ones that were going to hold you. Is there a sort of reserve for those fighters? Do we keep the instructions to make the reserves?

Naik says that they keep a reserve of fighters.

Strogatz asks if we actually do.

Naik said yes.

The fighters themselves.

Naik is right. We call it memory. We talk about memory B cells and memory T cells. These are the cells that give rise to the vaccine proprietors. People have been a little bit scared by that information, so antibodies don't stick around forever. When they get a vaccine, they look at their vaccine titers for a while. The memory B cells are the cells that make those antibodies.

Ah, okay, Strogatz.

The measure of how good your immune response is and how well it remembers is how well it secures those cells and allows them to persist.

When you say that the memory cells go into a different state after the battle is over, what does that mean? What happened to the memory B cells? Do they calm down or stop making antibodies? Maybe they send the instructions to another cell to make the antibodies, or maybe they are not the ones making it. You have to admit, it's very confusing. There are a lot of different types of cells in your subject.

There is a lot of different types of cells. Your body keeps the memory cells in different places. It can deposit them at our barriers, like the skin and the gut. They will be at that interface. If the bad guy comes back, you have people that are ready to go, right?

Sometimes it will put memory B cells in our bone marrow. The blood system comes from the bone marrow. If you want a cell to make a lot of antibody, you want it to be in a secure location, in the bone marrow, and you want it to have easy access to the blood. The body distributes memory cells. There is a group of memory cells that circulate around and patrol the body to make sure there is no funny business going on.

If we think of our body as a country, you want to keep a few people that have been proven to be good soldiers, or good generals.

If I'm right, what we're talking about at the moment is what would traditionally be thought of as an adaptive immune system. Our focus in this discussion is going to be on what leads to inflammation and what happens when it goes wrong. We should start talking about that now. Our innate system has a kind of memory. The B cells and the T cells get a lot of attention.

Naik (11:31) is right.

We used to hear a lot about T cells. The players in the innate system have strange names. What are the right words for things like macrophages? What memories do they have?

For a long time, we thought that the adaptive immune system could only do memory, because it has this property of specificity. There was a landmark study 15 years ago that found that memory could be a feature of the innate immune system, but it worked differently than the adaptive immune system.

The innate immune system is made up of short-lived cells. These are cells that are 888-609- 888-609- 888-609- 888-609- 888-609- They eat the dead cells. They make a lot of inflammatory cytokines. They make a lot of things that killbacteria. Caustic agents cause physical damage to the pathogen.

Inflammation is a subset of innate immune cells that can cause a lot of damage to pathogens by producing these types of molecules that can kill them. This is chemical warfare. It was thought that these guys were pawns, and they died off quickly. They just showed up and died.

While the short-lived cells may die off, their predecessors, their progenitors, their stem cells live. They can remember the inflammatory experiences of the body. They don't do it by remembering the bad guy's shape.

You have the flu. This happens in COVID as well. You have evidence. All of the host inflammatory proteins are going around. Stem cells of those innate immune cells are the ones that are sensed by your innate immune system. They change the genes of the cells. You can essentially amplify the expression of a bunch of different fighters. This will help us get rid of the bad guys. The cells never close up the DNA after that. When you have a second hit, they can respond much, much faster. You are training your cells to be better killers, better fighters, and you are doing it to every single cell. They behave differently to a second pathogen regardless of what first pathogen they see.

The image that came to my mind was of fire extinguishers that are kept in a special case with the glass. You might keep the door open the second time. You are speaking in terms of open and closed. The accessibility of the DNA is either less or more accessible.

Naik said that the cells are now able to make more of the factor because the instructions for it are open. In your analogy, if you revved up the fire extinguisher so it could pump out more, you were keeping the door open.

Strogatz: Okay. Yeah, whatever it needs.

Naik said it was a fire-fighting substance. I don't know what comes out of the fire extinguishers.

The analogy isn't great, because whatever is needed to put out a fire is what the problem is. It is something to be helpful.

Naik: Exactly.

So we keep talking about inflammation. Let's switch gears a bit and talk about inflammation. What is inflammation? What are the hallmarks of it?

I think immunologists love giving them names. Maybe this is a science thing. Acute inflammation is what we think of as inflammation. If you have a bug bite, a cut, or some kind of infections on your skin, you can see that there is pain, redness, and swelling. These are signs of inflammation.

Strogatz is also hot.

Naik said it was hot. Exactly. You can feel inflammation right away. Chronic inflammation is a little stealthier and more deceptive. Chronic inflammation is associated with a lot of different diseases. Aging goes up with us now. You don't have overt signs of inflammation like redness, swelling, heat, or pain, but you have a low-grade production of inflammatory mediators, the same things that are helping kill the bugs. They are doing more harm than good. We don't know how to shut this type of information off or how to detect it until it's too late.

It's very frustrating, isn't it? If you can help solve this, I think it's an important thing. I'm frustrated because I think of other chronic things that when people go to doctors, they may say, "We can't find anything wrong with that."

Naik: No, exactly. It may be too late for the doctor to realize that you are too sick if you know that you have chronic inflammation.

I want to take a moment to distinguish between inflammation and inflammatory diseases. You can sense things like IBD, inflammatory bowel disease, and others, which are really overt. Psoriasis, you have flares. Those are chronic inflammatory diseases. You don't realize that you are causing these sorts of damages when you have low grade inflammation, because you don't realize that it could be caused by bad eating habits. You can even convey it if it's not something like chronic fatigue. It may be something that you don't realize is happening.

Wow, Strogatz. It was stealthy.

Naik said it was stealthy.

Strogatz wants to know about diseases that are thought to be related to diseases of inflammation, that don't seem like they are. I think you mentioned cardiovascular disease. Is that about inflammation?

Naik: Let's simplify cardiovascular disease, like clogged arteries, right? A lot of that comes from the cells of your innate immune system. Along with the fats and the lipids, it makes a nasty gamish that causes a blockade. We realize that the inflammatory mediators that get pulled into all of this and build up cause the blockade. The blockade of the vessel is driven by the immune cells.

We used to hear about cholesterol all the time.

Naik (19:29) is correct. Cholesterol is a bad player. We aren't saying it's not. The immune cells that are propagating this disease are now getting a lot more attention to that effect, as you also have this other key element.

What is the cancer connection?

The immune cell can either be a hero or a villain in cancer. It can be a hero when it comes to cancer immunotherapy. The immune system has been harnessed to fight cancer in the same way that it fights diseases, like COVID, and other viruses. Now people have learned to train their immune cells to recognize shapes on cancer cells and kill them, this is where the specificity comes into play. That shape is on a cancer cell, but not on a healthy cell. The immune system will kill the cancer cell. This has changed the way we treat cancer.

The immune system plays a role in cancer. A lot of different kinds of cancers are associated with this low-grade chronic inflammation or with tissue damage and the inflammation that ensues, which is why chronic inflammation has this villainous role to play in cancer. There are many different types of cancer. This is where we don't really understand what is happening and why the inflammation is creating a fertile ground for cancer cells.

So as a person with a lot of moles. When I was a kid, I used to play tennis outside and take my shirt off, but now I have a skin problem. Why am I asking you about this? If you get a lot of bad sunburns as a kid, and you have fair skin, you are more likely to get skin cancer later in life. I don't know if it was the UV that caused my cells to change, or if I created an inflammatory response because I got burned. Is this the kind of thing that you could talk about?

Naik thinks you hit the nail on the head. It's just an amount of mutations, that's what we've classically thought. Changes in your DNA code at certain genes are what cause cell multiplication or limiting cell death. These cells are allowed to grow out of control when the mutations form. It has been thought for a long time that the number of these genes is what determines your susceptibility to cancer. We are not just walking around with tumors all over our skin when we see that many, many cells have these mutations.

The field is trying to understand why that is. What other things are needed for this cell with a genetic abnormality that makes it more likely to form a cancer? The burn and the inflammation that ensues may be creating a sort of environment that sustains that. We are doing these experiments in the lab. This is what we call preliminary data.

If we give a mouse, it will get an inflammatory insult. We give it an irritation. It resolves inflammation. After exposing it to a carcinogen, it forms many more tumors.

Hmm, Strogatz.

Naik says the skin goes back to looking normal. If we compare the mouse that has inflammation with the one that has never before been inflammatory, it will be ten times more tumors.

Strogatz: Hm!

Naik says they are trying to figure out why everything looks normal. There is something going on with the types of cells that are retained after that acute bout of inflammation, or how that acute bout of inflammation may be fundamentally changing the cancer-causing cells, or the cells that become cancer. There are a lot of questions that need to be answered here.

It almost seems like you could measure the number of mutations in the control group versus the group that had the inflammatory insult, but would it be possible in the system you just described? It isn't the genes that make the difference in the susceptibility to cancer. It is something else.

There are two things that could happen. Either there is an equal amount of the same number of the same number of the same number of the same number of the same number of the same number of the same number of the same number of the same number of the same number of the same number of the same number of the same number The same things that are found in immune progenitors are also found in the cells that are able to sense more changes. The way their cells respond to damage may change.

All of our cells have these amazing repair machines that come and fix things and make sure that you don't have any damage to your DNA. The codebook of your body is your genome. You want to keep this code straight. We don't know how inflammation changes the response to DNA damage. If we're really going to understand, what are the signals that allow cancer cells to take off, and can we reverse those signals? Is it possible to reverse those changes and prevent those cells from taking off?

Strogatz (25:31): I'm glad that you made this into some of your own work, because it's very remarkable. I want to make sure we have time to talk about what you and your students are doing. I think we should get out of the way before we get into that. When I read about your work, I have been reading it. What is it? How does it relate to inflammation studies?

That is a new technique. It is so fancy and informative. We can break that down into the words that are being used. One cell, right? Transcriptomics is the study of transcriptomics. The genes are being produced into the code. Genes become proteins, but they are not the only ones. At a single-cell level, we measure the transcripts of the messenger RNAs of every single cell. Cell A is making thousand genes, Cell B is making thousand genes, and Cell C is making thousand genes.

I can figure out what the cells in my tissue are making at any given time by using this method. It is possible to figure out which cell is making what in this heterogeneous tissue. How do I know who is making factor A if I say your skin is 40, 50 different types of cells? What are the signals that drive the expression of that factor? By using single-cell level technologies, we can now home in on the cell that is doing this at a given time, and the other cell that is doing the same thing.

This is fantastic. It means that the ability to see, whether it was through a microscope or a telescope, leads to many advances in science. One of the main things that you study is how tissues sense inflammation and respond to it, if we can start drilling in. Let's talk about mice. You mentioned that they were annoying their skin. You irritate their skin, then what? What is it you are looking for? What did you find?

At the beginning of the conversation, we were talking about how immune cells communicate with each other. We wondered what the consequences of those conversations were. If every cell of the body is talking to an immune cell, and if you have a pathogen encounter, that pathogen is also seen by the cells in your skin. The outermost cells of your skin. It's also visible by your blood vessels, your neurons, fibroblasts, and the cells of your connective tissue. The cells of the tissue work together to eliminate the pathogen and then heal. When your tissue has experiences like that, what happens after the fact? Can cells outside the immune system remember in the same way that cells inside the immune system do?

We gave our mice an irritant that was short-lived. The skin went back to being normal when the irritant was removed. How is that skin different now? How are the long-lived cells of that skin different? The stem cells of the tissue. The reason we wanted to know long-lived cells was because we know that the short-lived cells are going to die off. The cells that are removed from the surface of your skin are going to be gone, so it doesn't matter if they are changed by inflammation or not. The stem cells that live in the lowermost layer of your skin constantly pump out tissue and give rise to all of your other cells. How are those cells different?

We challenged them to make tissue by causing a wound. After this small bout of inflammation, these cells were so much better at healing, they had learned from this inflammatory assault, to now be in a poise state, maintain accessibility at different wound repair sites, and different inflammatory sites in their DNA. Even if the secondary wound came half a year later, they were able to repair it much, much faster.

So first comes the irritation and then the wound?

Naik says you have a first inflammatory bout. It leaves. You assume that your stem cells have returned to their normal state. They have learned from that. They are much better at healing when they have a secondary challenge.

Strogatz thinks this is revolutionary. Maybe you don't want to talk about your own stuff. This is a new kind of learning for healing that is not happening in the immune system. Maybe we should have a better idea of what the immune system is.

Naik thinks both. I think it's cool because it says that your body is constantly learning, and it's learning at the level of its cells. It's putting its experiences in a book. I want to say that every cell in the body is likely to do this.

The long-lived cells remember their encounters. It is a process of education. Your cell is learning from its experiences and getting better and adapting, which is why it is sitting along there. To me, that is a very hopeful way of looking at our body.

Strogatz said it was learning in this way that had to do with DNA accessibility modifications.

Naik is right. The innate immune system learns by the way it learns. If you have a cell that has never seen inflammation before or never seen a wound before, it will open up the genes that make up the wound-response and inflammatory genes. The DNA is still accessible and open after the wound is done. When you have a second assault, it is much better to respond. The idea is that it can come back to it if it remembers and stores parts of the DNA that it needs.

Strogatz thinks we should just say what we're talking about.

Naik says that they always talk about the code for genes. If your genes are closed, you can translate the code. You have open DNA, and then you have the ability to bind it to something, and make something with it. Without open DNA that doesn't happen.

Strogatz was wild. Since you are telling me so many things that are blowing my mind, let me ask about this long-lived idea. I don't know what you mean by long-lived cells, but I'm used to the idea that the cells of my outermost layer of skin do go away.

Naik said it was about 42 days.

Strogatz: That's pretty specific. Forty-two days, what, a month and a half, or something?

Naik: Yeah.

So what does that mean? A cell might expect to live there for 42 days.

Naik says that your skin is a multi-layered organ. You have the outer layer, the skin, and the inner layer, the skin beneath it, right? The epidermis has many layers. The progenitors are where your stem cells live. These cells don't get removed. The tether is on the lower layer. They attach and then produce daughter cells that make the rest of the layers disappear. New cells are produced from the lowermost layer as the layers fall. The lowermost layer is going to be with you for the rest of your life.

Strogatz asked if that was right.

Naik (33:33): Correct.

Strogatz: Really?

Naik said that the mutations accumulate there. That's where.

Strogatz: Oh, whoa.

Naik: Those are your stem cells.

They are going to be with us for the rest of our lives.

Naik said "forever, forever". You can take those out, expand them out, and recreate a whole new skin, like I could do with your skin.

Strogatz wants to go all kinds of different directions with you. Some of the implications of your findings about the memories that other kinds of cells retain, that aren't just immune cells, should be discussed. What are the implications of this kind of research for things like wound repair or aging?

Naik (34:47): Yeah, all of the above, right? We talked about implications for cancer, which is a wound that doesn't heal, but there are implications for aging and autoimmunity. A lot of autoimmune diseases come back and go away. They wax and wane. They happen in the same place.

Despite the fact that our skin is a large organ, it's still a problem. In patients, it will go away and come back in the same location. There is something in that tissue that remembers the disease. It was thought to be immune cells for a long time.

Immune-targeting therapies do not get rid of the disease. There is no cure. This is where our work shined the light on other cells, and if we should be targeting these other cells, to have curative therapies for autoimmune disease. One of the things that we are trying to pursue is how to take away inflammatory memories in disease contexts. How do we promote wound repair with inflammatory memories?

Achieving a balance is an evolutionary tradeoff. Inflammation can make you better at wound healing. You are walking a tight rope. I think where we are now and what we are trying to tackle.

When people look at the genes of cells from older people, they find that inflammatory genes are more accessible. This idea has come up over and over again, which is, maybe that phenomenon of aging is just an accumulation of your inflammatory encounters over your lifetime, to the point where it is sort of a Goldilocks effect. You want to find a good point. It is detrimental beyond that.

This is crazy. I thought that aging had to do with the way we used to talk and think, because I had been like that my whole life. You're making me think that it's also about the accumulation of inflammatory events. It's a little different, right? Quite different.

There is a shortening of the telomeres, but there is also anAccumulation of Mutations. Inflammation has been linked with shortening of the telomeres.

Strogatz suggests that we remind ourselves what telomeres are.

Naik: That's right.

Strogatz: That's okay. Let's do it.

Naik said these are the ends of your chromosomes. They get shorter with age, and every time your cell is duplicated. The shortening of the telomeres is a hallmark of aging. I think that it is more than one thing. I would not say that it is just inflammation, or that it is just inflammatory memory, or that it is just your metabolism going crazy. Understanding how they are interrelated is going to be critical.

There are a lot of ways to get old. You are discovering new ones.

Naik said yes, exactly. Exactly.

The people in your line of work.

Naik wants to find ways to increase health span and reverse some of that. I am hopeful that there will be inroads in the next decade that will allow us to do that.

This is an uplifting ending. I would like to say thank you very much, Shruti, this has been a really interesting conversation.

Naik thanks you for having him. It was fun talking about the immune system.

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