Summary: Researchers have discovered that neurons in the gut play a direct role in guiding immune healing after inflammation by producing a molecule called adrenomedullin 2 (ADM2). This molecule stimulates group 2 innate lymphoid cells (ILC2s) to release amphiregulin, a tissue-repairing factor, offering protection in models of inflammatory bowel disease.
Loss of ADM2 signaling reduced these protective cells and worsened disease, while administering ADM2 expanded them and promoted recovery. The findings reveal a neuro-immune communication pathway present in both mice and humans, highlighting the enteric nervous system as a promising target for new IBD therapies.
Key Facts:
- Neuro-Immune Link: Gut neurons release ADM2, which boosts protective immune cell function.
- Healing Boost: ADM2 expands ILC2 populations, enhancing tissue repair after gut inflammation.
- Therapeutic Potential: ADM2-based strategies could treat IBD by enhancing natural healing.
Source: Weill Cornell University
Neurons in the gut produce a molecule that plays a pivotal role in shaping the gut’s immune response during and after inflammation, according to a new study by Weill Cornell Medicine investigators.
The findings suggest that targeting these neurons and the molecules they produce could open the door to new treatments for inflammatory bowel disease and other disorders driven by gut inflammation.
Hundreds of millions of neurons make up the enteric nervous system, the “second brain” of the body, where they orchestrate essential functions of the gut such as moving food through the intestines, nutrient absorption and blood flow.
While this system is known for regulating these fundamental processes, its role in controlling intestinal inflammatory responses has remained far less clear.
In their study, reported August 15 in Nature Immunology, the investigators focused on group 2 innate lymphoid cells (ILC2s), immune cells that reside within the linings of the gut.
Their previous work revealed that ILC2s are a major source of a tissue-healing growth factor called amphiregulin and have the capacity to receive neuronal signals that modulate their function and can impact disease progression and recovery.
In the new study, they demonstrated that the tissue-protective function of ILC2s depends on production of a molecule called adrenomedullin 2 (ADM2) from the enteric nervous system; administering the molecule expanded this group of ILC2s and provided therapeutic benefit in a preclinical model of inflammatory bowel disease, whereas loss of ADM2 signaling exacerbated disease due to the lack of these protective cells.
“The enteric nervous system has long been neglected when thinking of how we can resolve detrimental intestinal inflammation,” said lead author Dr. Jazib Uddin, an NIH Ruth L. Kirschstein postdoctoral fellow at Weill Cornell Medicine.
“Our work suggests there may be a previously unknown neuro-immune mechanism driving intestinal healing responses.”
Additionally, the investigators performed translational patient-based studies by analyzing human tissue and blood samples from Weill Cornell Medicine’s Jill Roberts Institute for Research in Inflammatory Bowel Disease Live Cell Bank.
This analysis revealed that patients with inflammatory bowel disease had elevated expression of ADM2 compared with control individuals and found that human ILC2s stimulated with ADM2 directly promoted production of tissue-protective amphiregulin.
These findings indicate that the immune-nervous system communication identified in mice is also present in humans, highlighting the enteric nervous system as a promising therapeutic target for inflammatory bowel disease.
“The findings of this current study allow new insights into how the immune and nervous systems ‘speak’ to each other and coordinate complex processes, including tissue inflammation and repair, and offer the potential for new therapies targeting these neuro-immune interactions,” said senior author Dr. David Artis, director of the Jill Roberts Institute for Research in Inflammatory Bowel Disease and the Michael Kors Professor in Immunology at Weill Cornell Medicine and co-director of the Allen Discovery Center for Neuro-immune Interaction.
About this neuroscience and inflammation research news
Author: Barbara Prempeh
Source: Weill Cornell University
Contact: Barbara Prempeh – Weill Cornell University
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“CGRP-related neuropeptide adrenomedullin 2 promotes tissue-protective ILC2 responses and limits intestinal inflammation” by Jazib Uddin et al. Nature Immunology
Abstract
CGRP-related neuropeptide adrenomedullin 2 promotes tissue-protective ILC2 responses and limits intestinal inflammation
Neuro–immune circuits regulate innate and adaptive immunity at barrier surfaces. However, the differential impact of these circuits on proinflammatory versus tissue-protective responses remains poorly defined.
We demonstrate that enteric neurons produce calcitonin gene-related peptide-related adrenomedullin 2 (ADM2) and identify a previously unrecognized role for the ADM2 pathway in promoting intestinal tissue-protective functions of group 2 innate lymphoid cells (ILC2s).
Genomic or ILC2-intrinsic deletion of ADM2 receptor subunits resulted in a significant reduction in tissue-protective ILC2 responses, defective amphiregulin (AREG) production and increased susceptibility to intestinal damage and inflammation.
Conversely, therapeutic delivery of recombinant ADM2 elicited tissue-protective AREG+ ILC2s and limited intestinal inflammation.
Expression of genes encoding human ADM2 receptor (CALCRL and RAMP3) was altered in participants with inflammatory bowel diseases and associated with reduced expression of AREG in ILC2s.
Collectively, these findings identify that the ADM2–ADM2 receptor pathway can promote tissue-protective functions of ILC2s in the context of intestinal damage and inflammation.