Brain-Body Immune Axis Controls Inflammatory Response

The title on this one is pretty straightforward: "Brain-body circuit that regulates the immune response." But for its refreshing simplicity and straightforwardness, especially for a Nature paper, the data presented, produced by the Zucker lab in this paper, are nonetheless incredible. These data are so new and exciting, in fact, that as I go through the data in the paper, you're going to notice there's a watermark, "accelerated article preview." I suppose because Nature just couldn't wait to get the data out there, and I couldn't wait to review them to get the final paper. So there's going to be this little watermark. Take it as a mark of enthusiasm to share data. And by the time this video is actually posted, maybe the final paper will be out. Anyway, let's now learn together how the brain controls the immune response. Welcome to my channel, stay curious. I'm not even going to waste time on the background for this one because I think for a lot of listeners it's going to be intuitive. Like, there's a gut-brain axis, so why wouldn't there be an immune system-brain axis? The brain is integrated with everything. So let's get into what they did straight away. What they did was try first to identify what brain regions are activated by an inflammatory insult. In this case, they use lipopolysaccharide, or LPS for short, which is part of the outer membrane of gram-negative bacteria. Just got a little shudder. Gram-negative bacteria— microbiology is like the bane of medical students' existence. So much memorization. Ugh. Anyway, they wanted to use LPS to induce an inflammatory response in the mice whereby a bunch of inflammatory cytokines were released and then see what brain regions were activated. So you see the inflammatory response here. They give the mice the LPS and then over a period of time, really peaking at around 2 hours, you see a release of pro-inflammatory cytokines including interleukin or IL-6, interleukin-1 beta, and TNF-alpha, and then also anti-inflammatory IL-10. So throughout the paper they actually code pro-inflammatory as red and anti-inflammatory as green, which makes it nice and easy. So overall there's a pro-inflammatory response, but there's some anti-inflammatory signal there as well to help balance things off. And then they measured brain brain activity via a proxy for neuronal activity, an immediate early gene, FOS. So when neurons become active, certain genes get expressed very early on. One's called FOS. So you can use it to kind of see what areas of the brain are being activated. And two areas kind of popped out, one called the area postrema, and the other, which is really the focus of this paper, the caudal nucleus of the solitary tract, abbreviated CNST. So CNST, caudal nucleus of the solitary tract. And the thing about the CNST is it gets a lot of input from the vagal nerve, the vagus nerve, or the 10th cranial nerve, which is kind of a, a very major conduit between the body and the brain in a lot of respects. You can think about it as like a telephone line from the body to the brain. So it kind of makes sense, right? The vagus nerve is communicating to this area of the brain, the CNST, that might be receiving signals about pro-inflammatory insults from the periphery. Next, to start to unpack the axis a little bit, they genetically modified mice to generate a reporter, to express a reporter in their brains called GCN. CNP6. And I want to talk a little bit about the methodology just because I think it's super cool. Basically, these neurons will express a fusion protein including a green fluorescent protein that when bound to calcium will fluoresce green. Long story short, they're making mice with neurons, brain cells, that will glow green when they become active. And you can measure this, which I think is pretty cool, right? It's a cool way to measure activity. And they showed that LPS, the inflammatory insult to the body, provoked activity in the CNST, the caudal nucleus of the solitary tract. You can see that here in the blue bar, which is just a quantification of how much activity there is in this brain region when you give the LPS. And then what they did to show the vagus nerve was very important in this communication was they chopped the vagus nerve. That's the vagotomy, that's the orange bar. And you can see when they chopped the vagus nerve, the activity in this brain region went away, showing the vagus nerve is communicating to the nucleus of the solitary tract, the CNST. Now, if you were a researcher, what would you want to do next in order to show that the CNST then communicates and regulates the immune response in a top-down fashion? Think about what you do just at a high level. Pause the video, think about it, come back. So I hope you actually paused the video and thought about it, but here's what I would do and here's what the researchers did at a high level. I'd find a way to activate and inhibit the CNST and see how that modulates the immune response to lipopolysaccharide. Basically, does, let's say the CNST acts as a brake, then inhibiting it should break the brake and you should have an out of control immune response. Or if the CNST is the brake and you activate it, then the immune response should be really downregulated, tamped down, and there should be way less inflammation. And that's exactly what they did. And what they did is use a chemogenetic tool called DREADD. I'm not going to actually describe what DREADD is, I just wanted to say the word DREADD. And there is iDREADD for inhibitory DREADD and then DREADD for activating DREADD. And basically they use the DREADD tool to first inhibit the cNST and then give the LPS. And what do they see? Well, they saw if they inhibited the cNST, which is actually the brakes, let's say, on the immune system, then there was a massive cytokine response with the inflammatory cytokines more than tripling and the anti-inflammatory cytokines like interleukin-10 dropping. By contrast, when they use activating DREADD, activating the CNST, then they're putting the brakes on the immune response. And what they found was there was a massive drop in the pro-inflammatory cytokines and a 10-fold increase in the anti-inflammatory cytokines, just showing that the CNST does indeed regulate the immune response in a top-down fashion. And importantly, this is a modulatory effect, so it isn't like there's going to be a lot less inflammation if you just activate the CNST without any peripheral insult. It's when you give the LPS, if you're activating this brain region, you have less inflammation. And if you're inhibiting it, then there's going to be an out-of-control immune response. Hopefully that makes sense. Now there's quite a bit more in this paper. They do further experiments by which they show a specific subset of neurons in the CNST, dopamine beta-hydroxylase positive neurons, were especially important in the response. They also showed that there were two separate tracks along the vagus nerve, one that carried information about anti-inflammatory cytokines. So the anti-inflammatory cytokines acted on the vagus nerve via this tract to signal to the nucleus of the solitary tract to then reinforce that anti-inflammatory signal in a positive feedback loop whereby the anti-inflammatory cells, they release anti-inflammatory molecules, then signals to the brain to reinforce the anti-inflammatory response. And then the other path was a negative feedback pathway whereby the brain was responding to pro-inflammatory signals to then tamp down the pro-inflammatory response. So together, these two pathways via the vagus nerve to the nucleus of the solitary tract really were acting to protect against runaway inflammation. That's the 50,000-foot view. Now, in a final experiment I want to highlight, they used a mouse model of ulcerative colitis and tried to see, could they activate the vagus nerve pathway activating the CNST to improve the ulcerative colitis in the mouse— in the mice. Mice is plural. And they found indeed there was massive improvements in colonic integrity, inflammation markers, and a decrease in bleeding. So that's just one example of what should be pretty obvious by this point. The incredible immune modulatory power of the nervous system and how we can leverage that for therapeutic ends. Ulcerative colitis, rheumatoid arthritis, maybe things like lupus, all sorts of autoimmune and pro-inflammatory diseases. I think this is super cool and just goes to show the power of the brain-body axis and how our immune system governs almost everything with respect to our body and how we can leverage that for the benefit of our own health. I think this is super cool. Hats off to the Zucker Lab and also a hat tip to Andrew Huberman who made me aware of this paper. Toodles!