How the immune system puts the brakes on allergic inflammation

When the body mistakenly reacts to an environmental stimulus, the allergic response usually includes some type of inflammation. Interactions between the nervous system and the immune system appear to regulate this process, but scientists still don’t fully understand all of the cell types and mechanisms involved in maintaining a normal or inflamed state in different tissues.

To learn more about how the human body triggers and responds to inflammation, scientists must pull apart the cellular circuits and pathways involved in the immune and nervous systems. Two recent studies led by researchers at the Broad Institute of MIT and Harvard, Massachusetts General Hospital, and Brigham and Women’s Hospital have uncovered a new type of molecular crosstalk between these systems, in both the lung and the intestine in mice, in a cellular circuit that suppresses inflammation.

The work adds to the emerging picture of how cells keep inflammation in check when they encounter environmental triggers. Figuring out which cell types and molecules interact to maintain healthy cell states or cause inflammation to spiral out of control could someday help drug developers discover new treatments for allergies. The two papers appeared in the journal Immunity and were funded in part by the Food Allergy Science Initiative (FASI) at the Broad Institute.

“One of our main goals is to eventually help develop therapies for food allergies — so we first need to understand which cell types are contributing to these reactions, what the pathways are, and how they regulate each other,” says Ramnik Xavier, a senior author of one of the papers, and core institute member at Broad and director of the Center for Computational and Integrative Biology at Massachusetts General Hospital. ”Characterizing the interactions between the immune cells and the nervous system may help us find ways to interrupt or otherwise control these circuits.

Xavier and Aviv Regev, core institute member and director of the Klarman Cell Observatory at Broad, professor of biology at MIT, and Howard Hughes Medical Institute Investigator, with first authors Heping Xu, a former postdoc in the Xavier and Regev labs, and Jiarui Ding, a postdoc in the Regev lab, led the study related to intestinal cells.

Senior authors Vijay Kuchroo, institute member at the Broad and director of the Evergrande Center for Immunologic Diseases at Harvard Medical School and Brigham and Women’s Hospital (BWH), and Regev, with first authors Antonia Wallrapp, a graduate student in the Kuchroo lab, Patrick Burkett, a pulmonologist and researcher at BWH, and Samantha Riesenfeld, a postdoc in the Kuchroo and Regev labs, led the study related to lung cells.

An inhibitory feedback loop

The researchers identified a new cellular circuit involving a type of immune cell called “type 2 innate lymphoid cells,” or ILC2s. Typically, when triggered by the nervous system, ILC2s boost certain kinds of immune responses — such as those that fight parasites or cause allergic reactions.

Now, the teams describe a new function for these cells: inhibiting inflammatory processes in response to a neuropeptide called CGRP (calcitonin gene-related peptide). Single-cell data from mouse lung and intestine tissue showed that ILC2s were able to both respond to CGRP and express it themselves. Further physiological and genetic analyses in mice helped elucidate the mechanics of this interaction: When ILC2s sense this molecule from the nervous system, they also, in turn, begin producing their own CGRP to continue signaling and ultimately suppress the inflammatory reaction.

“When the nervous system signals the immune system to react to a stimulus, we think it can get  activated in two different directions depending on the neuropeptide produced — one to increase inflammation, to help deal with the threat, or one to pull back the body’s reaction,” says Wallrapp. “That’s where this CGRP signal likely factors in.”

“You can think of this circuit like a brake on the inflammatory response,” adds Xu. “The single-cell data suggested that these immune cells are sensing CGRP from the nervous system and then responding in an organized, self-sufficient way throughout the tissue, suppressing themselves and the tissue inflammation so it’s not too severe.”

The teams are continuing to follow up on this and other immune cell pathways that emerged from their single-cell analyses to better understand how the immune system triggers and responds to inflammation. This type of research may someday point researchers towards potential drug targets for managing allergies.

“There appears to be crosstalk between the nervous and immune systems that’s involved in many, many different processes, as the immune system integrates and balances diverse cues,” says Kuchroo. “These studies highlight just one area that could inform a therapeutic strategy for allergic diseases, including food allergy.”

Funding for Xu et al. provided in part by the Food Allergy Science Initiative, NIH (DK114784, DK 043351), the Crohn’s & Colitis Foundation, the National Natural Science Foundation of China (31970842), the Westlake Education Foundation of Westlake University, the Klarman Cell Observatory, and HHMI.

Funding for Wallrapp et al. provided in part by the Food Allergy Scientific Initiative, NIH (1K08AI123516, 1K08HL130540, F32AI138458, R01 HL122531, R01 AI130019, R01 AI139536), Boehringer Ingelheim Fonds, the Klarman Cell Observatory, and HHMI.