Study finds neurons in gut regulate the immune system to control inflammation.


The immune system exercises constant vigilance to protect the body from external threats, including what the person eats and drinks. A careful balancing act plays out as digested food travels through the intestine. Immune cells must remain alert to protect against harmful pathogens such as Salmonella, however, their activity also needs to be tempered since an overreaction can lead to too much inflammation and permanent tissue damage.  Now, a study from researchers at Rockefeller University shows that neurons play a role in protecting intestinal tissue from over-inflammation. The team state that their findings could have treatment implications for gastrointestinal diseases such as irritable bowel syndrome.  The study is published in the journal Cell.  

Previous studies show that intestinal tissue is continuously exposed to numerous microbe-and food-derived antigens. In order to deal with pathogens, resistance to infections needs to be coupled with tolerance to the delicacy of the system.  It is known that different populations of macrophages are among the many types of immune cells present in intestinal tissue. Lamina propria macrophages are found very close to the lining of the intestinal tube, while muscularis macrophages are in the deeper tissue layer, distant from what passes through the intestine.  Although the role of environmental cues in the adaptation of immune cells to these conditions has been increasingly investigated, the nature of these signals and the mechanisms by which they influence immune cells are still unclear.  The current study identifies a mechanism by which neurons work with immune cells to help intestinal tissue respond to perturbations without going too far.

The current study uses an imaging technique which allows the lab to view cellular structures three-dimensionally, as well as the differences between the two populations. In addition to variations in how the cells look and move, the group also observed that intestinal neurons are surrounded by macrophages.  Results show that lamina propria macrophages preferentially express pro-inflammatory genes. Data findings show, in contrast, that the muscularis macrophages preferentially express anti-inflammatory genes, and these are boosted when intestinal infections occur.

Results show that muscularis macrophages carry receptors on their surface that allow them to respond to norepinephrine, a signaling substance produced by neurons.  The team state that the presence of this receptor might indicate a mechanism by which neurons signal to the immune cells to put a stop to inflammation.  They go on to add this suggests that one of the main signals which induces a different response to infection appears to come from neurons, which are encircled by the muscularis macrophages.

The group also observed that the muscularis macrophages are activated within one to two hours following an infection, significantly faster than a response would take if it were completely immunological, and not mediated by neurons. The lab state that because these deeply embedded macrophages receive signals from neurons, they are able to respond rapidly to an infection, even though they are not in direct contact with the pathogen.

The team surmise that the global medical community now have a much better picture of how the communication between neurons and macrophages in the intestine helps to prevent potential damage from inflammation.  They go on to add it’s plausible that a severe infection could disrupt this pathway, leading to the tissue damage and permanent gastrointestinal changes seen in diseases such as irritable bowel syndrome. For the future, the researchers state that these findings could be harnessed to develop treatments for such diseases.

Source: The Rockefeller University

Proper adaptation to environmental perturbations is essential for tissue homeostasis. In the intestine, diverse environmental cues can be sensed by immune cells, which must balance resistance to microorganisms with tolerance, avoiding excess tissue damage. By applying imaging and transcriptional profiling tools, we interrogated how distinct microenvironments in the gut regulate resident macrophages. We discovered that macrophages exhibit a high degree of gene-expression specialization dependent on their proximity to the gut lumen. Lamina propria macrophages (LpMs) preferentially expressed a pro-inflammatory phenotype when compared to muscularis macrophages (MMs), which displayed a tissue-protective phenotype. Upon luminal bacterial infection, MMs further enhanced tissue-protective programs, and this was attributed to swift activation of extrinsic sympathetic neurons innervating the gut muscularis and norepinephrine signaling to β2 adrenergic receptors on MMs. Our results reveal unique intra-tissue macrophage specialization and identify neuro-immune communication between enteric neurons and macrophages that induces rapid tissue-protective responses to distal perturbations.  Neuro-immune Interactions Drive Tissue Programming in Intestinal Macrophages.  Mucida et al 2016.

Proper adaptation to environmental perturbations is essential for tissue homeostasis. In the intestine, diverse environmental cues can be sensed by immune cells, which must balance resistance to microorganisms with tolerance, avoiding excess tissue damage. By applying imaging and transcriptional profiling tools, we interrogated how distinct microenvironments in the gut regulate resident macrophages. We discovered that macrophages exhibit a high degree of gene-expression specialization dependent on their proximity to the gut lumen. Lamina propria macrophages (LpMs) preferentially expressed a pro-inflammatory phenotype when compared to muscularis macrophages (MMs), which displayed a tissue-protective phenotype. Upon luminal bacterial infection, MMs further enhanced tissue-protective programs, and this was attributed to swift activation of extrinsic sympathetic neurons innervating the gut muscularis and norepinephrine signaling to β2 adrenergic receptors on MMs. Our results reveal unique intra-tissue macrophage specialization and identify neuro-immune communication between enteric neurons and macrophages that induces rapid tissue-protective responses to distal perturbations. Neuro-immune Interactions Drive Tissue Programming in Intestinal Macrophages. Mucida et al 2016.

3 comments

  • Copy editing saves criticism. Is there actually a “lab state” or did you mean “the lab states.” Did you mean that “the team surmises,” which would make more sense?

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