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

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 mRNA levels of NNCS components and proinflammatory cytokines in sputum were detected using RT-qPCR, and the concentrations of acetylcholine (Ach)-related metabolites were examined using LC-MS/MS. Asthma exacerbations were prospectively investigated during the following 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.