Signaling from Nervous System Helped Control Inflammatory Response in IBD, Mouse Study Shows

Signaling from Nervous System Helped Control Inflammatory Response in IBD, Mouse Study Shows

Signaling from the nervous system through the β2-adrenergic receptor can help control the type of inflammation that characterizes inflammatory bowel disease (IBD), a new mouse study shows.

These findings suggest that new therapies targeting the same pathway as the nervous system may help control inflammation in IBD.

The study, “β2-adrenergic receptor–mediated negative regulation of group 2 innate lymphoid cell responses,” was published in the journal Science.

Diseases that are characterized by inflammation, such as IBD, tend to exhibit a type of inflammation known as the type 2 inflammatory response, which happens when an individual is exposed to infectious and environmental triggers — helminth infections, allergens, venoms, and other stimuli.

One of the main characteristics of the type 2 response is the activation of immune cells called the T helper 2 (TH2) cells, and the release of signaling molecules, called type 2 cytokines, which play major roles in activating the inflammatory response.

Recent studies have identified another group of immune cells — called group 2 innate lymphoid cells (ILC2s) — as a potent source of type 2 cytokines and, consequently, contributing to type 2 inflammatory responses.

Although considerable advances have been made to define the cytokines and environmental stimuli that trigger ILC2 responses, the regulatory mechanisms that regulate their response and type 2 inflammation are not fully understood.

So, researchers conducted a study to determine the regulation of ILC2 responses, looking particularly to the regulation of ILC2 by the central nervous system.

ILC2s are activated by a chemical called norepinephrine that is released by nerve cells. Norepinephrine binds to a receptor on the ILC2 surface known as β2 adrenergic receptors (β2AR).

Researchers wanted to determine the role of β2AR in the regulation of ILC2. They used mice that lacked β2AR and infected them with helminths.

Researchers found that deficiency of β2AR resulted in exaggerated ILC2 responses and type 2 inflammation in intestinal and lung tissues, and a quicker clearance of the pathogen.

In contrast, when they used normal mice and treated them with drugs that induce β2AR expression, the immune response by ILC2 cells was decreased and inflammation reduced. As a result, the helminths infection worsened.

Researchers found that this response was because the binding of norepinephrine to β2AR plays a role in controlling growth of the ILC2 cells; lack of β2AR led to much higher levels of ILC2 cells, which explains the exaggerated immune response.

“We demonstrate that the β2AR pathway is a cell-intrinsic negative regulator of ILC2 responses through inhibition of cell proliferation,” they wrote.

Many drugs that are used to control allergy symptoms stimulate β2AR. This study now has an explanation for why stimulation of β2AR helps control the immune response.

“If we understand more mechanistically how this class of drugs works,” David Artis, PhD, said in a press release. Artis is director of the Jill Roberts Institute for Research in Inflammatory Bowel Disease and the Michael Kors Professor of Immunology at Weill Cornell Medicine. “It might give us new avenues to develop additional therapies built around the biology.”

Overall, these findings suggest that therapies that mimic the nervous system regulatory network could help control the inflammation that characterizes IBD.