Cholinergic sensing of allergen exposure by airway epithelium promotes type 2 immunity in the lungs - 08/03/24

Doi : 10.1016/j.jaci.2023.10.031

Ryusuke Hayashi, MD, PhD ^a,^b,^{^{∗
These authors contributed equally to this work.}}, Yotesawee Srisomboon, PhD ^c,^d,^{^{∗
These authors contributed equally to this work.}}, Koji Iijima, PhD ^a,^b, Peter J. Maniak, MS ^c,^d, Rinna Tei, MD, PhD ^a,^b, Takao Kobayashi, PhD ^a,^b, Mayumi Matsunaga, MD ^a,^b, Huijun Luo, PhD ^a,^b, Mia Y. Masuda, BS ^e,^f, Scott M. O’Grady, PhD ^c,^d,^{^{∗
These authors contributed equally to this work.}}, Hirohito Kita, MD ^a,^b,^g,^h,^⁎^{^{∗
These authors contributed equally to this work.}}
^a Division of Allergy, Asthma and Clinical Immunology, Mayo Clinic, Scottsdale, Ariz
^b Department of Medicine, Mayo Clinic, Scottsdale, Ariz
^c Department of Animal Science, University of Minnesota, St Paul, Minn
^d Department of Integrative Biology and Physiology, University of Minnesota, St Paul, Minn
^e Mayo Clinic Graduate School of Biomedical Sciences, Rochester, Minn
^f Mayo Clinic Graduate School of Biomedical Sciences, Scottsdale, Ariz
^g Department of Immunology, Mayo Clinic Rochester, Rochester, Minn
^h Department of Immunology, Mayo Clinic Arizona, Scottsdale, Ariz

^∗Corresponding author: Hirohito Kita, MD, Division of Allergy, Asthma and Clinical Immunology, Mayo Clinic Arizona, 13400 E Shea Blvd, Scottsdale, AZ 85259.Division of AllergyAsthma and Clinical ImmunologyMayo Clinic Arizona13400 E Shea BlvdScottsdaleAZ85259

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Abstract

Background

Nonneuronal cells, including epithelial cells, can produce acetylcholine (ACh). Muscarinic ACh receptor antagonists are used clinically to treat asthma and other medical conditions; however, knowledge regarding the roles of ACh in type 2 immunity is limited.

Objective

Our aim was to investigate the roles of epithelial ACh in allergic immune responses.

Methods

Human bronchial epithelial (HBE) cells were cultured with allergen extracts, and their ACh production and IL-33 secretion were studied in vitro. To investigate immune responses in vivo, naive BALB/c mice were treated intranasally with different muscarinic ACh receptor antagonists and then exposed intranasally to allergens.

Results

At steady state, HBE cells expressed cellular components necessary for ACh production, including choline acetyltransferase and organic cation transporters. Exposure to allergens caused HBE cells to rapidly release ACh into the extracellular medium. Pharmacologic or small-interfering RNA–based blocking of ACh production or autocrine action through the M3 muscarinic ACh receptors in HBE cells suppressed allergen-induced ATP release, calcium mobilization, and extracellular secretion of IL-33. When naive mice were exposed to allergens, ACh was quickly released into the airway lumen. A series of clinical M3 muscarinic ACh receptor antagonists inhibited allergen-induced IL-33 secretion and innate type 2 immune response in the mouse airways. In a preclinical murine model of asthma, an ACh receptor antagonist suppressed allergen-induced airway inflammation and airway hyperreactivity.

Conclusions

ACh is released quickly by airway epithelial cells on allergen exposure, and it plays an important role in type 2 immunity. The epithelial ACh system can be considered a therapeutic target in allergic airway diseases.

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Key words : ACh, choline acetyltransferase, IL-33, muscarinic receptor antagonists, group 2 innate lymphoid cells, allergens, IL-5, IL-13

Abbreviations used : α7nAChR, ACh, BAL, [Ca²⁺]_i, ChAT, 4-DAMP, EC₅₀, eGFP, FACS, HBE, HDM, H&E, ILC2, i.n., Lin, M1R/M3R, mAChR, OCT-1, PAS, ROI, siRNA, TSLP

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Vol 153 - N° 3

P. 793 - mars 2024 Retour au numéro

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Cholinergic sensing of allergen exposure by airway epithelium promotes type 2 immunity in the lungs - 08/03/24

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Abstract

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