Activated non-neuronal cholinergic system correlates with non-type 2 inflammation and exacerbations in severe asthma

Dan Huang; Li Zhang; Ying Liu; Ji Wang; Jie Zhang; Katherine J Baines; Gang Liu; Alan Chen-Yu Hsu; Fang Wang; Zhihong Chen; Brian G Oliver; Min Xie; Ling Qin; Dan Liu; Huajing Wan; Fengming Luo; Weimin Li; Gang Wang; Peter G Gibson

doi:10.1016/j.anai.2024.03.009

Activated non-neuronal cholinergic system correlates with non-type 2 inflammation and exacerbations in severe asthma

Ann Allergy Asthma Immunol. 2024 Mar 16:S1081-1206(24)00150-9. doi: 10.1016/j.anai.2024.03.009. Online ahead of print.

Authors

Dan Huang¹, Li Zhang², Ying Liu³, Ji Wang⁴, Jie Zhang⁵, Katherine J Baines⁶, Gang Liu⁷, Alan Chen-Yu Hsu⁸, Fang Wang⁹, Zhihong Chen¹⁰, Brian G Oliver¹¹, Min Xie¹², Ling Qin¹³, Dan Liu¹⁴, Huajing Wan⁴, Fengming Luo⁴, Weimin Li¹⁴, Gang Wang¹⁵, Peter G Gibson¹⁶

Affiliations

¹ Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, People's Republic of China; The State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, People's Republic of China; Division of Internal Medicine, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China; Laboratory of Pulmonary Immunology and inflammation, Frontiers Science Center for Disease-related Molecular Network, Sichuan University, Chengdu, People's Republic of China.
² Division of Internal Medicine, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China; Laboratory of Pulmonary Immunology and inflammation, Frontiers Science Center for Disease-related Molecular Network, Sichuan University, Chengdu, People's Republic of China.
³ The State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, People's Republic of China; Division of Internal Medicine, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China; Laboratory of Pulmonary Immunology and inflammation, Frontiers Science Center for Disease-related Molecular Network, Sichuan University, Chengdu, People's Republic of China.
⁴ Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, People's Republic of China; The State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, People's Republic of China; Laboratory of Pulmonary Immunology and inflammation, Frontiers Science Center for Disease-related Molecular Network, Sichuan University, Chengdu, People's Republic of China.
⁵ Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Jilin University, Changchun, Jilin, People's Republic of China.
⁶ Priority Research Center for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle, Callaghan, Australia.
⁷ School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW, Australia; Centre for Inflammation, Centenary Institute, Camperdown, NSW, Australia.
⁸ Priority Research Center for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle, Callaghan, Australia; Programme in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore.
⁹ Department of Pathogen Biology, Basic Medical College, Jilin University, Changchun, Jilin, People's Republic of China.
¹⁰ Respiratory Division of Zhongshan Hospital, Shanghai Institute of Respiratory Disease, Fudan University, Shanghai, People's Republic of China.
¹¹ School of Life Sciences, University of Technology Sydney, Ultimo, NSW, Australia; Woolcock Institute of Medical Research, The University of Sydney, NSW, Australia.
¹² Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
¹³ Department of Respiratory and Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, People's Republic of China.
¹⁴ Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, People's Republic of China; The State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, People's Republic of China; Respiratory Microbiome Laboratory, Frontiers Science Center for Disease-related Molecular Network, Sichuan University, Chengdu, People's Republic of China.
¹⁵ Department of Respiratory and Critical Care Medicine, Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, People's Republic of China; The State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, People's Republic of China; Laboratory of Pulmonary Immunology and inflammation, Frontiers Science Center for Disease-related Molecular Network, Sichuan University, Chengdu, People's Republic of China. Electronic address: wcums-respiration@hotmail.com.
¹⁶ Priority Research Center for Healthy Lungs, Hunter Medical Research Institute, The University of Newcastle, Callaghan, Australia; National Health and Medical Research Council Center for Research Excellence in Severe Asthma and Treatable Traits, The University of Newcastle, Newcastle, NSW, Australia; Department of Respiratory and Sleep Medicine, John Hunter Hospital, Hunter Medical Research Institute, Newcastle, NSW, Australia.

PMID: 38499061
DOI: 10.1016/j.anai.2024.03.009

Abstract

Background: Non-neuronal cholinergic system (NNCS) contributes to various inflammatory airway diseases. However, the role of NNCS in severe asthma (SA) remains largely unexplored.

Objective: To explore airway NNCS in SA.

Methods: In this prospective cohort study based on the Australasian Severe Asthma Network in a real-world setting, patients with SA (n = 52) and non-SA (n = 104) underwent clinical assessment and sputum induction. The messenger RNA (mRNA) levels of NNCS components and proinflammatory cytokines in the sputum were detected using real-time quantitative polymerase chain reaction, and the concentrations of acetylcholine (Ach)-related metabolites were evaluated using liquid chromatography coupled with tandem mass spectrometry. Asthma exacerbations were prospectively investigated during the next 12 months. The association between NNCS and future asthma exacerbations was also analyzed.

Results: Patients with SA were less controlled and had worse airway obstruction, a lower bronchodilator response, higher doses of inhaled corticosteroids, and more add-on treatments. The sputum mRNA levels of NNCS components, such as muscarinic receptors M1R-M5R, OCT3, VACHT, and ACHE; proinflammatory cytokines; and Ach concentration in the SA group were significantly higher than those in the non-SA group. Furthermore, most NNCS components positively correlated with non-type (T) 2 inflammatory profiles, such as sputum neutrophils, IL8, and IL1B. In addition, the mRNA levels of sputum M2R, M3R, M4R, M5R, and VACHT were independently associated with an increased risk of moderate-to-severe asthma exacerbations.

Conclusion: This study indicated that the NNCS was significantly activated in SA, leading to elevated Ach and was associated with clinical features, non-T2 inflammation, and future exacerbations of asthma, highlighting the potential role of the NNCS in the pathogenesis of SA.

Clinical trial registration: ChiCTR-OOC-16009529 (http://www.chictr.org.cn).