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Cell Yang Daping reveals a new mechanism by which pain-receptor nerves regulate goblet cell mucus secretion to protect the intestinal mucosa

 Last Update: 2022-10-20
 Source: Internet
 Author: User

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Our gut can quickly recognize and adapt to external environmental changes, ensuring nutrient absorption while ensuring resistance to threats such as foreign microbial invasion, all of which depend on the interaction
between neurons and epithelial cells.
In addition, as an important part of the brain-gut axis, neuron-epithelial cell interaction can also transmit damage in the intestine to the brain with signals such as pain [1].

The intestinal mucosal barrier is mainly composed of epithelial cells and the mucus layer that covers it, which is crucial for the maintenance of intestinal mucosal homeostasis and the resistance to foreign pathogenic microorganisms [2], but we still know very little
about how the body regulates the intestinal mucosal barrier.

Nociceptors originate from the Dorsal Root Ganglion (DRG) and vagus ganglia (Vagal Ganglion), which is widely distributed in intestinal tissues [3].

The pain-sensing nerve is the main pain receptor for inflammatory diseases such as diarrhea and infection in the intestine, and it can also regulate the inflammatory response to promote body protection, but it is not clear
whether it can regulate the mucosal barrier under homeostatic conditions.

On October 14, 2022, Yang Daping from Harvard Medical School published a publication in Cell magazine titled Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and Article by
Gut Barrier Protection.
This article found that the pain-sensing nerves are tightly distributed around the intestinal goblet cells and can promote goblet cell mucus secretion to protect the intestinal mucosa
.
The intestinal mucus layer of mice with pain-receptive nerve loss was significantly thinned and accompanied by intestinal microbiosis, and activation of algesic receptors by chemogenetics and other methods can cause the mucus layer to thicken
rapidly.
The pain-receptor nerve can secrete the neuropeptide CGRP, and its receptor Ramp1 is specifically highly expressed
in intestinal goblet cells in both mice and humans.
Correspondingly, mice with agesic-receptive nerve deletion and mice with Ramp1-specific deletion of epithelial cells showed a susceptibility to enteritis, and either CGRP treatment or activation of the mice's pain-receptor nerves could help them resist enteritis
.

In this study, we first constructed mice with pain-receptor specific deletion of Nav1.
8^DTA, and found that the thickness of the mucus layer in the colon was significantly reduced
by MUC2 immunofluorescence staining and colonic explant culture.
Next, the authors constructed designer receptor exclusively activated by designer drugs mice, whose pain receptors can be activated by the synthetic agonist CNO, which was confirmed in calcium imaging experiments isolated and cultured in vitro of pain receptor nerve cells
。 At the same time, the thickness of the intestinal mucus layer of DREADD mice after treatment in vivo increased
rapidly.
These results suggest that the pain-receptive nerve is likely to influence the thickness
of the mucus layer by regulating goblet cells.

In order to explore the mechanism of pain-receptor nerve regulation of goblet cells, single-cell sequencing of intestinal epithelial cells was performed in this study and the expression
of a series of neuropeptide receptors in various epithelial cell types, including goblet cells and intestinal endocrine cells, was analyzed.
The results of the analysis found that the receptor Ramp1 of the neuropeptide CGRP was specifically highly expressed in goblet cells, which indicated that the pain-sensing nerve was likely to regulate the thickness
of the mucus layer by secreting CGRP on goblet cells.
Indeed, further experiments showed that mice with either CGRP deletion or its receptor Ramp1 deletion showed a decrease
in the intestinal mucus layer.
The next study found that both gut microbes and capsaicin can promote the activation of pain-sensing neurons and the secretion of CGRP, as well as the increase
in the thickness of the intestinal mucus layer.
Through PAS/Alcian blue staining, the authors found that activated pain-sensing neurons promote the secretion of mucous vesicles in goblet cells and that this process relies on CGRP and its receptor, Ramp1
.

16S rDNA sequencing analysis found that Nav1.
8 DTA mice showed obvious intestinal microbial disorders, and single-cell sequencing analysis found that Nav1.
8^DTA mice showed high endoplasmic reticulum stress response in their intestinal epithelial cells.
This is likely due to the decrease in mucus layer thickness due to obstruction of mucus vesicle secretion inside goblet cells, and suggests that the mouse is likely to be more susceptible to intestinal mucosal damage
.
Indeed, using DSS-induced models of mouse enteritis, the authors found that both the loss of pain-sensing neurons and the absence of CGRP receptor Ramp1 in epithelial cells can lead to susceptibility
to enteritis in mice.
Finally, the authors found that both artificially activating the pain-receptor nerve and infusing CGRP back helped mice resist enteritis
.

This study revealed the function and molecular mechanism of the pain-receptive nerve in regulating mucus secretion in goblet cell cells, and demonstrated its key role
in maintaining intestinal mucosal homeostasis and resisting inflammation.
In addition, considering that antagonistic CGRP is a common treatment for migraine in clinical practice, the study suggests possible side effects
of long-term use of CGRP antagonists in the gut.
At the same time, this study also provides clinical treatment ideas
for the treatment of intestinal inflammation by targeting nerves, neuropeptides and their receptors.

The first authors of this paper are Dr.
Daping Yang and Dr.
Amanda Jacobson of Harvard Medical School, and the corresponding author is Professor
Isaac M.
Chiu.

It is worth mentioning that on October 14, 2022, the team of David Artis Laboratory at Weill Cornell Medical College at Cornell University in the United States published a report entitled Gut-innervating nociceptors regulate the intestinal microbiota to in the journal Cell The article promoting tissue protection, which reveals the key protective role played by the pain-receptor neuron TRPV1⁺ in regulating the gut microbiota in intestinal injury and intestinal inflammation, is similar to the above work (see BioArt today's separate push for details).

Original link: 01196-5 https://doi.
org/10.
1016/j.
cell.
2022.
09.
008

Pattern maker: Eleven

References

1 Veiga-Fernandes, H.
& Mucida, D.
Neuro-Immune Interactions at Barrier Surfaces.
Cell 165, 801-811, doi:10.
1016/j.
cell.
2016.
04.
041 (2016).
2 Knoop, K.
A.
& Newberry, R.
D.
Goblet cells: multifaceted players in immunity at mucosal surfaces.
Mucosal immunology 11, 1551-1557, doi:10.
1038/s41385-018-0039-y (2018).
3 Jacobson, A.
, Yang, D.
, Vella, M.
& Chiu, I.
M.
The intestinal neuro-immune axis: crosstalk between neurons, immune cells, and microbes.
Mucosal immunology, doi:10.
1038/s41385-020-00368-1 (2021).

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