Regulation of the Inflammatory Response: Group 2 Innate Lymphoid Cells Interact With the Nervous System

Type 2 inflammatory responses involve both innate and adaptive immune systems and are triggered by exposure to infectious pathogens and environmental antigens, as for example helminths, allergens, and venoms. These responses are characterized by activation of T helper 2 cells and subsequent release of type 2 cytokines, such as interleukin-4 (IL-4), IL-5, IL-9, and IL-13, resulting in production of immunoglobulin E (IgE) and activation of different types of effector cells—basophils, mast cells, and eosinophils. Typically, these responses promote increased mucus production and muscle contractions which, together, help to expel the parasite or allergen from the body.

Group 2 innate lymphoid cells (or ILC2s for short) are a potent source of type 2 cytokines and therefore are involved in type 2 inflammatory responses. These cells are present in human lung tissue, peripheral blood, gastrointestinal tract, skin, and sinonasal tissue, and likely contribute to chronic rhinosinusitis, asthma, atopic dermatitis, and gastrointestinal allergic disease.

Results from a study published in the scientific journal Science (2-adrenergic receptor–mediated negative regulation of group 2 innate lymphoid cell responses) show that ILC2s are involved in a crosstalk between the nervous and the immune system, thus playing an important role in regulating acute and chronic inflammation. But what are the mechanisms at the basis of these regulatory processes?

Tapeworm, SEM image. Credit: Mogana Das Murtey and Patchamuthu Ramasamy, CC BY-SA 3.0

Researchers used mice to discover that ILC2s express the β2-adrenergic receptor (β2AR) and are located in the intestine in close proximity to adrenergic neurons. Adrenergic neurons release either the neurotransmitter adrenaline (epinephrine), or noradrenaline, or dopamine, which interact with β2ARs—β2ARs give nerve cells the ability to interact with each other and influence the immune response.

The researchers then infected mice that lack β2ARs with the gastrointestinal helminth Nippostrongylus brasiliensis, which was already known to induce potent ILC2 responses that play an important role in the expulsion of the parasite through production of IL-5 and IL-13. These mice had exaggerated ILC2 responses to the helminth infection in intestinal and lung tissues resulting in faster expulsion of the parasites. By contrast, when they treated normal mice with drugs that stimulate β2AR, the immune response was blunted and the helminth infections worsened. In addition, the researchers found that the β2AR pathway negatively regulates the ILC2 responses through inhibition of cell proliferation and effector functions. Collectively, these data provide the first evidence of a neuronal-derived regulatory circuit that limits ILC2-dependent type 2 inflammation. All together, the study results highlight a previously unrecognized regulatory circuit that operates between the adrenergic nervous system and the innate immune system to control type 2 inflammation at multiple mucosal sites.

The most commonly used drugs to treat asthma also stimulate β2AR, which may explain why they are so effective at controlling allergy symptoms. David Artis, senior author of the study, said in a press release: “We must have given tens of millions of doses of these drugs to shut down the acute symptoms of asthma. Nobody could agree on how these drugs work, but it may be that they are working in part through targeting the innate immune system. If we understand more mechanistically how this class of drugs works, it might give us new avenues to develop additional therapies built around the biology.”

In their published paper, the researchers conclude that the mammalian nervous system appears to have evolved dual mechanisms to rapidly activate or repress group 2 innate lymphoid cells to protect the host against diverse inflammatory stimuli.

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