A body–brain circuit that regulates body inflammatory responses 2024 Jin et al

[Andy]

Abstract

The body-brain axis is emerging as a principal conductor of organismal physiology. It senses and controls organ function1,2, metabolism3 and nutritional state4-6. Here, we show that a peripheral immune insult powerfully activates the body-brain axis to regulate immune responses. We demonstrate that pro- and anti-inflammatory cytokines communicate with distinct populations of vagal neurons to inform the brain of an emerging inflammatory response. In turn, the brain tightly modulates the course of the peripheral immune response. Genetic silencing of this body-to-brain circuit produced unregulated and out-of-control inflammatory responses. By contrast, activating, rather than silencing, this circuit affords exceptional neural control of immune responses. We used single-cell RNA sequencing, combined with functional imaging, to identify the circuit components of this neuro-immune axis, and showed that its selective manipulation can effectively suppress the pro-inflammatory response while enhancing an anti-inflammatory state. The brain-evoked transformation of the course of an immune response offers new possibilities in the modulation of a wide range of immune disorders, from autoimmune diseases to cytokine storm and shock.

Paywall, https://www.nature.com/articles/s41586-024-07469-y

 

[Andy]

Found: the dial in the brain that controls the immune system

"Scientists have long known that the brain plays a part in the immune system — but how it does so has been a mystery. Now, scientists have identified cells in the brainstem that sense immune cues from the periphery of the body and act as master regulators of the body’s inflammatory response.

The results, published on 1 May in Nature1, suggest that the brain maintains a delicate balance between the molecular signals that promote inflammation and those that dampen it — a finding that could lead to treatments for autoimmune diseases and other conditions caused by an excessive immune response.

The discovery is akin to a black-swan event — unexpected but making perfect sense once revealed, says Ruslan Medzhitov, an immunologist at Yale University in New Haven, Connecticut. Scientists have known that the brainstem has many functions, such as controlling basic processes such as breathing. However, he adds, the study “shows that there is whole layer of biology that we haven’t even anticipated”."

https://www.nature.com/articles/d41586-024-01259-2

 

[Jonathan Edwards]

However, he adds, the study “shows that there is whole layer of biology that we haven’t even anticipated”."

Presumably this guy has been asleep for two hundred years.

 

[Creekside]

Presumably this guy has been asleep for two hundred years.

... or he's basing that on medical school knowledge, which also seem to be a bit tardy.

 

[ME/CFS Science Blog]

Sounds interesting. Let's hope it is relevant to ME/CFS and post-infectious illnesses.

 

[rvallee]

Presumably this guy has been asleep for two hundred years.

I was under the impression that, maybe not with such high precision, this was already known. I guess what's significant is finding where and how? Or something like that. Or maybe the significance of vagus neurons in this process.

Although I'm annoyed by the odd body-brain framing, last I checked the brain is definitely part of the body, this could be highly significant, as in major breakthrough. Or not at all. I guess it all depends on what excites academic funding institutions more than anything, who don't seem all that interested in basic science anymore.

I remember a comment VanElzakker made some years ago about how neurologists aren't interested in the old brain anymore, all the cool kids only look at the neocortex and higher/newer brain regions. It'll be good if neurology gains some interest back in the basics, there's definitely a whole lot more to work out here, away from all the nonsense about agency, dysfunctional networks and effort preferences.

 

[Jonathan Edwards]

I was under the impression that, maybe not with such high precision, this was already known.

My point exactly.

I guess what's significant is finding where and how?

Every tiny bit of data, whether good or bad is now a major breakthrough.

Although I'm annoyed by the odd body-brain framing, last I checked the brain is definitely part of the body,

When you get to my age it is even hard to move the head on its own - the neck gets a bit like a rusty shower head fitting.

The hypothalamus does have major influences on the immune system but to be honest, when disease strikes it mostly carries on the way it wants and ignores the head bit.

ME/CFS might be different, but the more I think about it the more I doubt there is actually anything wrong above the Adam's apple. Other than the misery that comes from down below.

 

[Creekside]

last I checked the brain is definitely part of the body,

Hasn't it been fashionable at various times to consider parts of the body as distinctly separate? I seem to recall the word "privileged" applied to the brain, meaning completely separated from the rest of the body's immune systems. I think it's easier to publish new findings than to delete old misconceptions.

Medical school teachers learned those old misconceptions, and pass them on to their students. How many generations does it take to remove those misconceptions from the education system?

 

[rvallee]

Hasn't it been fashionable at various times to consider parts of the body as distinctly separate? I seem to recall the word "privileged" applied to the brain, meaning completely separated from the rest of the body's immune systems. I think it's easier to publish new findings than to delete old misconceptions.

Medical school teachers learned those old misconceptions, and pass them on to their students. How many generations does it take to remove those misconceptions from the education system?

Yeah I guess it's just been taken a little to excess, the blood-brain barrier is definitely significant but it seems to have been taken as license to consider it basically the equivalent of "air-gapped" with physical system security.

 

[SNT Gatchaman]

Open access at Nature and also PubMed.

 

[Hutan]

The area postrema is known to be activated by body malaise17

I thought that was an interesting statement.
Ref #17 is Zhang, C. et al. Area postrema cell types that mediate nausea-associated behaviors. Neuron 109, 461–472.e5 (2021).
I wonder how certain that finding is, and whether that area of the brain stem would be identified as activated during a scan of someone in PEM. I haven't looked at the reference, and 'nausea-associated behaviours' isn't such a good fit for PEM as 'body malaise'.

But, it made me wonder if there has been brain scanning of people with ME/CFS with and without PEM. It is something I'd like to see. You might have to have people resident in a hospital in order to achieve that though.

 

[Hutan]

The cNST, on the other hand, is the primary target of the vagus nerve2,31 and functions as the major conduit in the body–brain axis.

That's the caudal nucleus of the solitary tract (cNST) in the brain stem, and it was activated when the mice were injected with LPS (a proxy of a bacterial infection).

Importantly, injection of LPS in animals with a homozygous knockout for Myd88 (an essential component of the LPS receptor in immune cells32) did not activate cNST neurons (Extended Data Fig. 2), show-ing that LPS stimulates cNST labelling via its action on immune cells. Robust cNST labelling was also observed in response to various other immune insults (Extended Data Fig. 1c,d).

If peripheral inflammation is sensed and transmitted by the vagus nerve to the cNST, then blocking the transfer of vagal signals should abolish LPS-evoked neural activity in the cNST. Indeed, bilateral sub-diaphragmatic transection of the vagus nerve5,34 eliminated cNST responses to LPS (Fig. 1c). These results substantiate the vagal–cNST immune axis and demonstrate that the LPS-evoked activity is not the result of LPS directly accessing cNST neurons.

 

[Hutan]

cNST silencing transforms body immunity

We anticipated that if the LPS-activated neurons in the cNST function as an essential circuit modulating peripheral immune responses, then blocking their activation should significantly affect the inflammatory response.

Chemogenetic inhibition of the cNST neurons resulted in a dramatic increase in the pro-inflammatory response and a concomitant decrease of the anti-inflammatory response (Fig. 2b, bottom panels); in essence, a run-away, out-of-control inflammatory response.
Indeed, the levels of pro-inflammatory cytokines rise to over 300% compared with the levels observed in LPS-treated but not silenced animals (for exam-ple, IL-1β goes from 200 pg ml−1 to 800 pg ml−1; Fig. 2b), whereas the anti-inflammatory component exhibited a profound reduction (IL-10 levels were reduced from 750 pg ml−1 to approximately 250 pg ml−1;Fig. 2b). These results suggest that the cNST functions as a homeostatic neural control of peripheral immune responses.

That suggests that if this particular part of the brainstem was damaged or not functioning or not getting the signal, there would be an uncontrolled inflammatory response to an infection in the periphery.

 

[Hutan]

cNST activation suppresses inflammation

Given that silencing LPS-activated neurons in the cNST leads to greatly intensified inflammation, we hypothesized that artificial activation of this circuit should produce the opposite effect, and thus suppress inflammation.

As predicted, chemogenetic activation of the LPS-TRAPed neurons inhibited the pro-inflammatory response while substantially increasing the anti-inflammatory response. As shown in Fig. 2c, the levels of pro-inflammatory cytokines were reduced by nearly 70% from the levels observed in the control LPS-evoked responses, whereas anti-inflammatory levels were up nearly tenfold.

Activating this circuit in the absence of an immune challenge has no effect on cytokine levels, validating its role in monitoring and regulating an immune response rather than initiating it (for example, no LPS control in Fig. 2c and Extended Data Fig. 3a,b).

zeroing in on which particular neurons in the cNST suppress inflammation

showed that the LPS-TRAPed neurons are primarily found in three related glutamatergic clusters (clusters 7, 10 and 12, with a small number in cluster 2) (Fig. 3b) and one GABAergic cluster (cluster 15) (Extended Data Fig. 3c,d).

We next tested whether chemogenetic activation of the excita-tory (glutamatergic) or inhibitory (GABAergic) neurons could alter LPS-induced responses.

Our results showed that activation of excitatory, but not inhibitory, neurons effectively suppressed LPS-induced inflammation and largely mirrored the results obtained following activation of the LPS-TRAPed neurons (Extended Data Fig. 4a); no effect was observed when activat-ing GABAergic neurons (Extended Data Fig. 4b).

Next, we screened clusters 7, 10 and 12 for common, selectively expressed genes and iden-tified the dopamine β-hydroxylase (Dbh)37 gene as a candidate marker (Fig. 3c). In contrast to previous reports15, DBH-expressing neurons in the brainstem are almost exclusively located in the cNST (see Extended Data Fig. 5 for details) and are strongly activated in response to LPS

So, glutamatergic neurons in the cNST are the ones controlling inflammation and they express the dopamine β-hydroxylase (Dbh)37 gene.

 

[Hutan]

The role of the vagal neurons

How do cNST neurons monitor peripheral immune activity to instruct appropriate immune modulation? Given that information is being transferred via the vagal body–brain axis (Fig. 1c), we reasoned that specific vagal neurons may respond to cytokines released during LPS-induced inflammation and inform the brain of the emerging immune response.

We targeted the calcium indicator GCaMP6s33 to all vagal sensory neurons using a Vglut2-cre driver, and used a one-photon functional imaging setup to record real-time vagal neuron responses6 to cytokine stimuli delivered intraperitoneally. As control, we also imaged responses to LPS and to intestinal delivery of sugar, a stimulus known to activate the nutrient-sensing, gut–brain axis, via a specific population of vagal neurons5,6. Our results showed that anti-inflammatory and pro-inflammatory cytokines activate two discrete non-overlapping populations of vagal sensory neurons, each accounting for a small fraction of all nodose ganglion neurons (Fig. 4a; see the legend).

As anticipated, these do not overlap with the sugar-sensing vagal neurons8 (Fig. 4a, bottom panel). Importantly, LPS does not directly activate vagal neurons (Fig. 4b).

Cytokines stimulate a small percentage of the vagal neurons to send a message to the brain about an infection threat.

Our results showed that activating the transient receptor potential ankyrin 1 (TRPA1)-expressing vagal neurons5 dramatically enhanced the anti-inflammatory response, and severely suppressed the levels of pro-inflammatory cytokines (Fig. 5a,b).

Our experiments showed that IL-10, but not pro-inflammatory cytokines, activated the TRPA1-expressing vagal neurons (Fig. 5c and see also Extended Data Fig. 8e). Given these results, we hypothesized that removing the TRPA1-expressing vagal neurons from this circuit should prevent the transfer of anti-inflammatory sig-nals to the brain. We genetically ablated TRPA1-expressing vagal neu-rons by targeting the diphteria toxin receptor44, and then challenged the animals with IL-10 or LPS. Indeed, our results demonstrated that the cNST was very poorly activated in response to injection of IL-10 (Extended Data Fig. 11a) and, more importantly, the anti-inflammatory response was severely truncated;

IL-10 is acting on a subset of vagal neurons, those expressing TRPA-1, to relay anti-inflammatory signals to the brain.

Next, we explored the vagal neurons responding to pro-inflammatory signals. Our experiments showed that calcitonin-related polypeptide-α (CALCA)-expressing neurons45 in the vagal ganglia responded selec-tively to pro-inflammatory stimuli (Fig. 5f) and their chemogenetic acti-vation significantly altered the levels of circulating pro-inflammatory cytokines (Fig. 5d,e).

IL6 and IL1b acted on a subset of vagal neurons, those expressing CALCA, to relay inflammatory signals to the brain.

 

[Hutan]

Together, these results uncovered two lines of signalling from the vagal ganglia to the brain. One line (TRPA1) carries anti-inflammatory signals and acts on cNST neurons to enhance the anti-inflammatory response (for example, by positive feedback onto immune cells releasing anti-inflammatory cytokines) and helps to suppress the pro-inflammatory state. The other (CALCA neurons) responds to pro-inflammatory signals and helps to tune down the pro-inflammatory response (for example, by negative feedback onto immune cells releas-ing pro-inflammatory cytokines).

So, the authors are saying that both the TRPA1 and CALCA vagal neurons send signals to reduce inflammatory responses, but the TRPA1 neurons are activated by the anti-inflammatory IL-10 (positive feedback to immune cells), while the CALCA neurons are activated by the inflammatory cytokines (negative feedback to immune cells).

They did an experiment giving mice with what would normally be a lethal dose of LPS, and found that they could stop the harmful inflammatory response, resulting in 90% of the mice surviving.

They did another experiment with a mouse model of ulcerative colitis. They make big claims of success in modulating inflammation to prevent harm.

Next, we used a mouse model of ulcerative colitis (dextran sodium sulfate (DSS)-induced intestinal inflammation)49 to examine whether activation of this immunomodulatory circuit can prevent the dramatic loss of colon integrity, increase of pro-inflammatory cytokine levels and high levels of faecal blood observed in this model of colon injury and inflammation. We exposed control mice and animals in which the TRPA1 vagal neurons had been chemogenetically activated by targeted expres-sion of excitatory DREADD to DSS for 7 days (see Methods for details);this time is sufficient for the development of the severe pathologies triggered by DSS treatment50. DSS-treated control animals exhibited dramatic damage to the distal colon, showed significant occult stool blood and had a major increase in the levels of pro-inflammatory cytokines (Fig. 6c–f). By contrast, chemogenetic activation of the TRPA1 vagal neurons protected animals from all three pathological conditions (Fig. 6c–f, hM3Dq animals)

In the last experiment, they found that artificially activating the immune regulatory circuit that dampens down the inflammatory response in the face of an actual infection (Salmonella) actually was harmful -it resulted in bigger bacterial loads. So, it's clear that there is a lot of modulation going on when an infection is successfully dealt with.

It's an impressive paper, assuming all this is new, which I guess it is, and with major implications for dealing with inflammatory conditions. I'm not sure if it has any relevance to ME/CFS, but it's still hope-inducing to see what can be worked out with the various technologies that were employed here.

 

[Jonathan Edwards]

It's an impressive paper, assuming all this is new, which I guess it is,

I think some of the pathway detail may be new, although the influence of an LPS stimulus on these brain areas has been known for yonks. The bit that sounds new is the claim that the brain suppresses uncontrolled inflammation and that if you knock out certain brain functions everything goes berzerk. Human clinical experience with people with brainstem damage probably doesn't support that and I am fairly sceptical. The problem with mouse models is that you produce an artifactual interference with pathways which may have all sorts of unforeseen byproduct effects.

It would be of great importance to ME/CFS if suppression of peripheral immune events by brain was necessary for normal health and we had reason to think there might be changes in brain function in ME/CFS with symptoms due to uncontrolled immune events. But the pathways studied here relate to the inflammatory response to LPS and there isn't an inflammatory response of that sort in ME/CFS. CRP is normal, not 100. Nothing gets red or swollen.

 

[Creekside]

The problem with mouse models is that you produce an artifactual interference with pathways which may have all sorts of unforeseen byproduct effects.

Such as rodents evolving one "bad food" response since they don't regurgitate, while mammals that did evolve a response involving regurgitation might have dramatically different pathways? Then throw in multiple side-mechanisms that evolved along with them.

 

[DMissa]

Relevant to discussions raised in DecodeME thread https://www.s4me.info/threads/initi...2025-decodeme-collaboration.45490/post-646493

 

[Trish]

An off topic discussion of CCI neck surgery and ME/CFS has been moved to this thread:
The science of craniocervical instability and other spinal issues and their possible connection with ME/CFS - discussion thread