Immunity | A New Mechanism of Neural-Immune System Interaction: IL6 from Enteric Nerve Cells Regulates Regulatory T Cell Levels

Written by my best friend, the old Red Riding Hood editor | The digestive tract of mammals is under dual regulation by the immune system and nervous system.
These two systems coordinate and interact with each other to identify beneficial nutrients and harmful chemical molecules, symbiotic bacteria, and The role of pathogenic microorganisms.

The enteric nervous system (ENS) is the largest nerve organ besides the brain.
It has complete sensory neurons, interneurons and motor neurons in composition; it can be divided into two groups of nerve plexus in structure.
One is the submucosal nerve plexus that extends into the intestinal mucosa, and the other is the myenteric nerve plexus that is distributed in the muscular layer of the intestine.

The enteric nervous system can independently respond to external stimuli, thereby regulating functions such as cytokine secretion and intestinal peristalsis [1-4].

There are a large number of ancient immune cells and acquired immune cells in the intestine, which express various cytokine receptors, which can also be defined as large immune organs.

Therefore, it is quite natural to predict that there is a large number of interactions between the enteric nervous system and the immune system [5-8].

Intestinal nerve cells can affect the maturation and function of macrophages by secreting b2 adrenaline and colony stimulating factor 1 (colony stimulating factor 1), thereby regulating intestinal homeostasis.

The maturation and activation of type II intestinal lamina propria lymphocytes can also be regulated by secreting neuropeptides neuromedin U (NMU) and calcitonin gene-related peptide (CGRP), or by secreting Glial cell derived neurotrophic factor (glial cell derived neurotrophic factor) affects type III lamina propria lymphocytes.

Of course, the above-mentioned interaction mechanisms are basically concentrated between the enteric nervous system and the innate immune system.

On March 9, 2021, the research group of Diane Mathis and Christophe Benoist from Harvard University published an article titled Interleukin-6 produced by enteric neurons regulates the number and phenotype of microbe-responsive regulatory T cells in the gut in Immunity.
, Found that enteric nerve cells can regulate the level of regulatory T cells by secreting the cytokine IL6.

Regulatory T cells (regulatory T cells, Treg for short) are a subgroup of CD4+ T cells in the adaptive immune system, and are characterized by the expression of the transcription factor Foxp3.

Moreover, the nuclear hormone receptor RORγ can be divided into two categories by whether it expresses the nuclear hormone receptor RORγ.
One is mainly found in the large intestine, RORγ+Treg related to intestinal commensal bacteria, and the other is mainly found in the small intestine and related to tissue pressure.
Treg.

The author found through immunofluorescence labeling and laser confocal microscopy that regulatory T cells can co-localize with enteric nerve cell fibers, and through fluorescence in situ hybridization technology, enteric nerve fibers can interact with RORγ+Treg and RORγ-Treg.
These two types of regulatory T cells are in contact with each other.

These results indicate that enteric nerve cells are likely to interact with regulatory T cells.

In order to confirm this hypothesis, the authors used in vitro experiments to induce regulatory T cells and found that after co-culture with enteric nerve cells, the level of regulatory T cells decreased with the increase in the number of nerve cells, that is, enteric nerve cells can inhibit regulation.
Growth and differentiation of sex T cells.

Next, the author studies the specific mechanism of this phenomenon.

First, the author studies whether enteric nerve cells function through cell-cell contact or secretion of cytokines.

The author used a semi-permeable membrane culture plate to separate enteric nerve cells and T cells.
The two can only communicate through cell culture medium.
In this case, the level of regulatory T cells will still be suppressed.
This shows that the intestine Tract nerve cells work by secreting certain types of cytokines.

Next, the author determines what kind of cytokine is.

Through RNA sequencing technology, the author found that enteric nerve cells can affect cytokine signaling pathways including IL9, IL2, type II interferon, and IL6; at the same time, they found that enteric nerve cells can highly express LIF, CCL2, IL6 and other cytokines.
T cells also express receptors for these cytokines.

Finally, by adding neutralizing antibodies to cytokines, the author finally determined that IL6 secreted by enteric nerve cells plays a role in suppressing the level of regulatory T cells.

In addition, the author also found that IL6 can also affect the levels of RORγ+Treg and RORγ-Treg to a certain extent.

Regulatory T cells in the intestine can be induced by some symbiotic bacteria, such as C.
ramosum.

Next, the authors investigate whether these symbiotic bacteria affect the level of regulatory T cells by affecting the enteric nervous system.

The authors found through intestinal whole tissue staining and laser confocal microscopy that, compared with normal sterile mice, the regulatory T cell inducer C.
ramosum can reduce the density of intestinal nerve cells and nerve fibers in mice.

By RNA sequencing of the same number of enteric nerve cells, it was found that C.
ramosum can reduce the level of IL6 in a single nerve cell.

These results indicate that the regulatory T cell-inducing bacterium C.
ramosum is likely to induce regulatory T cells by reducing the density of intestinal nerves and the expression level of IL6 in nerve cells.

Immune cells, osteoblasts, smooth muscle cells, etc.
can all be used as sources of IL6.

Finally, the authors determined the role of IL6 derived from enteric nerve cells.

The authors crossed nestin cre and syn1 cre with IL6 flox mice to obtain two types of mice that specifically lack IL6 in nerve cells, and found that the levels of regulatory T cells in the intestines of these two types of mice increased.

Moreover, in vitro co-culture with enteric nerve cells from these two types of mice showed little change in the level of regulatory T cells.

These results all indicate that IL6 secreted by enteric nerve cells plays a role in regulating the level of regulatory T cells.

In summary, the authors determined that enteric nerve fibers can co-localize with regulatory T cells.

In addition, in vitro, enteric nerve cells can inhibit the level of regulatory T cells by secreting IL6; in vivo, the level of regulatory T cells rises in the intestinal tract where nerve cells specifically lack IL6.

Finally, the authors also found that regulatory cell inducers are likely to induce regulatory T cells through the dual effects of reducing the density of the enteric nervous system and the level of IL6 in nerve cells.

The author demonstrated the control circuit of microbial signal-changes in the enteric nervous system-changes in regulatory T cell levels.

This work not only discovered a new mechanism of the enteric nervous system-acquired immune system interaction, but also provided new ideas for understanding and disturbing intestinal homeostasis.

Original link: https://doi.
org/10.
1016/j.
immuni.
2021.
02.
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Instructions for reprinting [original article] BioArt original article, personal sharing is welcome, Reprinting is permitted, and the copyrights of all published works are owned by BioArt.
and Mazmanian, SK (2017).
The Enteric Network: Interactions be- tween the Immune and Nervous Systems of the Gut.
Immunity 46, 910–926.
8.
Huh, JR, and Veiga-Fernandes, H.
(2020).
Neuroimmune circuits in Inter-or- gan communication.
Nat.
Rev.
Immunol.
20, 217–228.
Reprinting instructions [Original Articles] BioArt original articles, personal sharing is welcome, reprinting is prohibited without permission, the copyright of all published works is BioArt Owned.
and Mazmanian, SK (2017).
The Enteric Network: Interactions be- tween the Immune and Nervous Systems of the Gut.
Immunity 46, 910–926.
8.
Huh, JR, and Veiga-Fernandes, H.
(2020).
Neuroimmune circuits in Inter-or- gan communication.
Nat.
Rev.
Immunol.
20, 217–228.
Reprinting instructions [Original Articles] BioArt original articles, personal sharing is welcome, reprinting is prohibited without permission, the copyright of all published works is BioArt Owned. BioArt reserves all statutory rights and offenders must be investigated.