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β2-Adrenergic Receptor Activation Promotes M2 Polarization of Gut Macrophages: How the Brain–Gut Axis Maintains Tissue Homeostasis

β2-adrenergic M2 Polarization
β2-adrenergic activation – M2 polarization

A new study published in the journal Cell indicates that tissue macrophages located in different regions of the gut, exhibit a high degree of specialization and form a cellular network with enteric neurons. The resulting neuro-immune connections can mediate the intra-tissue adaptation in response to distal bacterial infection keeping a balance between protective immune responses and the tissue tolerance.

A distinct population of macrophages populate intestinal tissues [Denning et al., 2007; Zigmond et al., 2014]. In the intestinal tract, macrophages are found both in the mucosa and deeper layers such as the submucosa and muscularis mucosae. Resident macrophages in the lamina propria (LpMs), are in close proximity to the gut lumen [Mazzini et al., 2014; Zigmond et al., 2014] where they sample luminal bacteria and initiate adaptive immune responses to clear pathogenic bacteria [Niess et al., 2005].

On the other hand, muscularis macrophages (MMs), located beneath the submucosal region between circular and longitudinal muscle layers, regulate the activity of enteric neurons and the gastrointestinal activity [Muller et al., 2014].

These immune cells are essential for local homeostasis but they also play an important role in inflammation and protective immunity when they change from ‘peaceful regulators’ to ‘powerful aggressors’ [Bain and Mowat, 2011]. The presence of abundant innate and adaptive lymphocytes and a rich mix of products such as TGF-β and IL-10 have been implicated as signals that control macrophage responses, and the phenotype of gut macrophages [Bain and Mowat, 2011].

In the present study, using a 3D imaging technique, Ilana Gabanyi et al., under the lead of Daniel Mucida, head of the Laboratory of Mucosal Immunology at the NY Rockefeller University, confirmed the presence of a dense network of macrophages primarily LpMs and MMs throughout the intestinal tissue layers, and showed how these two populations differ in morphology and cellular dynamics.

Moreover, by using transcriptional profiling tools of these two macrophage populations, the authors showed that LpMs preferentially expressed pro-inflammatory, or M1 genes, but MMs resembled alternatively activated, or M2 macrophages, and displayed a tissue-protective and wound healing phenotype.

In addition to variations in how the cells look and move, the authors noticed that enteric neurons were surrounded by macrophages. These neurons released norepinephrine, an autonomic/sympathetic nervous system neurotransmitter involved in the stress response, to ‘instruct’ macrophages to activate an anti-inflammatory response.

The authors showed that gut macrophages differentially expressed the β2-adrenergic receptors (ARs) on their surface that allow them to respond to norepinephrine. Of note, MMs expressed high levels of β2-ARs, while LpMs expressed lower levels. The authors also demonstrated by an in vitro co-culture system that β2-AR mediated alternative activation of macrophages with an anti-inflammatory and tissue-protective profile.

This finding suggests a mechanism by which sympathetic neurons signal the immune cells to restrict inflammation, even though they are not in direct contact with the pathogen. The scientific data and their experimental approach were unique in demonstrating the presence of a macrophage network with enteric neurons, thus unveiling a plethora of complexities in possible neural-immune interactions.

Future studies may have to be conducted to elucidate what effects the β2AR-macrophage activation causes in the gut tissue, and to ascertain whether a severe infection could disrupt this pathway. In several gastrointestinal diseases tissue damage and permanent gastrointestinal changes have been observed and may be explained by way of this disrupted pathway.

Conclusion: These findings could help in the development of innovative strategies for the treatment of irritable bowel syndrome based on immunomodulating compounds such as dopaminergic and adrenergic agents that are already in clinical use for several non-immune indications and with a usually favorable tolerability profile.


on the study by Ilana Gabanyi et al, Cell, 2016 164, 378-391
Neuro-Immune Interactions Drive Tissue Programming in Intestinal Macrophages

Author Affiliation:

Brigitta Buttari – Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy; Email:

Cover Image Credit

Bidirectional communication channels between the gut microbiome, the gut, and the brain. Endocrine-, neurocrine-, and inflammation-related signals generated by the gut microbiota and specialized cells within the gut can, in principal, affect the brain. In turn, the brain can influence microbial composition and function via endocrine and neural mechanisms. From: Gut Microbes and the Brain: Paradigm Shift in Neuroscience, Symposium Gut Microbes and the Brain: Paradigm Shift in Neuroscience, Emeran A. Mayer, Rob Knight, Sarkis K. Mazmanian, John F. Cryan, and Kirsten Tillisc; The Journal of Neuroscience, November 12, 2014, 34(46):15490 –15496

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