Vagal‐α7nAChR signaling attenuates allergic asthma responses and facilitates asthma tolerance by regulating inflammatory group 2 innate lymphoid cells

Abstract

Disorders of immune tolerance may lead to allergic asthma. Group 2 innate lymphoid cells (ILC2s) and inflammatory ILC2s (iILC2s) are key players in asthma. The vagus nerve innervating the airways releases acetylcholine or neuropeptides (i.e. calcitonin gene‐related peptide) via pulmonary C‐fibers (PCFs), which could regulate ILC2 activity upon binding the α7 nicotinic acetylcholine receptor (α7nAChR, coded by Chrna7) or neuropeptide receptors. Whether and how α7nAChR and PCFs regulate asthma and the formation of asthma tolerance via ILC2s or iILC2s are poorly understood. We used vagotomized, PCF degeneration and Chrna7 knockout mice to investigate ovalbumin (OVA)‐induced asthma and oral OVA feeding‐induced asthma tolerance. Our results revealed that vagotomy could generally suppress lung ILC2s and iILC2s, which mitigated allergic asthma responses but disrupted asthmatic tolerance. Removal of neuropeptides by PCF degeneration also reduced lung ILC2s and iILC2s, attenuating asthma responses, but did not affect asthma tolerance. In comparison, deletion of Chrna7 increased resident ILC2s and trafficking iILC2s in the lung, worsened allergic inflammation and disrupted oral tolerance. Mechanistically, deletion of Chrna7 in asthma‐tolerant conditions upregulated T helper 2 cytokine‐ (Il4, Il13 and Il25) and sphingosine‐1‐phosphate (S1P)‐related genes (S1pr1 and Sphk1). Blockade of S1P reduced iILC2 recruitment into asthmatic lungs. Our work is the first to demonstrate that vagal‐α7nAChR signaling engaging with iILC2s and S1P not only alleviates asthma but also facilitates asthma tolerance. These findings may provide a novel therapeutic target for attenuating asthma by enhancing asthmatic tolerance.

Perivascular stromal cells: Directors of tissue immune niches

“…ILC2s, which also express the α7‐nicotinic acetylcholine receptor (α7nAChR), are negatively regulated by a specific agonist for α7nAChR. This agonist reduced ILC2 effector function, decreasing the ILC2 transcription factor Gata3 and inflammatory modulator NF‐κB in several experimental mouse models of allergic asthma 86,87 . A subset of IMs that express CX3CR1 hi Lyve1 lo MHCII hi are conserved across tissues and are located adjacent to nerves 46 .…”

Nicotinic Acetylcholine Receptors in the Respiratory Tract

“…Besides eosinophilia, group 2 innate lymphoid cells (ILC2) play an important role in asthma and allergic diseases in generating type 2 immune responses, as recently reviewed by Zheng and coworkers [ 53 ]. A recent study discovered that vagotomy reduced the number of ILC2 in an ovalbumin-induced asthma model of allergic inflammation and that this effect was dependent on α7 nAChR, as ILC2 numbers were increased in α7 nAChR-deficient mice [ 54 ]. Additionally, the application of an α7 nAChR agonist resulted in reduced cytokine expression in ILC2, and attenuated ILC2-induced airway hyperreactivity [ 55 ].…”

Nicotinic Acetylcholine Receptor Involvement in Inflammatory Bowel Disease and Interactions with Gut Microbiota

“…Elevated expression levels of dupα7 in human large and small intestines are associated with inflammatory bowel disease (IBD) [82]. Control of inflammation through the CAP has been demonstrated in animal models of human disease including sepsis, IBD, arthritis, hemorrhagic shock, asthma, and pancreatitis [75,[83][84][85][86][87][88][89]. In humans, the importance of the role α7 nAChRs play in the CAP and the regulation of exacerbated inflammation has been shown in sterile endotoxemia [90,91] and sepsis [92].…”