An underlying mechanism behind interventional pulmonology techniques for refractory asthma treatment: Neuro-immunity crosstalk.

Apparently, the relationship between the immune and nervous systems mingle to varying degrees. As neurons receive various stimuli, neurotransmitters serve as an intermediary that can directly act on immune cells, regulating the immune responses [ 115 , 146 ]. This regulation benefits the human body; however, excessive immune responses may lead to chronic inflammatory diseases such as asthma. It is clear that the vagus nerve impacts the inflammation and asthmatic symptoms of the respiratory system via sophisticated regulatory interactions. How the neuro-immunity mechanism works and is maintained, and its related specific cellular interactions with afferent and efferent nerves need to be elucidated in future investigations. Therefore, future asthma management should integrate neuro-immune circuits, both local and systemic, through a more precise and comprehensive concept of airway neurogenic inflammation, in order to better create suitable approaches to control the pathology development of asthma. First, neuropeptides, as the communication medium among sensory neurons and immune cells, can serve as the target in the regulation of neuro-immunity circuits by specifically interfering with their signaling. Shreds of evidence already showed that the entire nervous system possesses the ability to communicate with immune cells, due to the latter expressing receptors for many classes of neurotransmitters, including ACh, catecholamines, and other neuropeptides [ 147 ]. In future studies, we should identify the sources of the neuropeptides. For instance, vagal neurons, enteric neurons [ 148 ], pulmonary neuroendocrine cells [ 136 ], ILC2, and other immune cells can release CGRP during inflammation [ 140 ]. Defining the distinct contribution of individual sources of neuropeptide during type 2 inflammation and asthma progression may provide a very rewarding direction for asthma treatment. Meanwhile, we should also explore other potential neurotransmitters beyond traditional neuronal mediators that participate in this neuro-immunity process. For example, other transmitters, such as neuropeptide Y and corticotropin-releasing hormone also influence the immune response [ 149 , 150 ]. Second, a direct block of the vagus nerve may also be useful in this overactive response situation. The appreciable therapeutic effects of bronchial thermoplasty and its finding of decreased nerve tissue reinforces the confidence in implementing blockade of the vagus nerve with abnormally high excitability using minimally invasive interventional approaches in the treatment of chronic airway diseases such as asthma and COPD. In addition to efferent nerves and ACh secretion, TRPA1, as a target of asthma stimuli, likely promotes exposure-associated asthma exacerbations. Blocking this “signal tower” may be helpful in certain subpopulations of asthmatics through intervening in neuro-immunity processes. Third, in addition to the above major pathways, we speculate that other pathways of the asthma neuro-immunity crosstalk are also worth consideration. Tracy et al. found in 2002 that the “cholinergic anti-inflammatory reflex” is one mechanism that modulates immune responses [ 151 , 152 ]. This reflex depends on ACh acting on macrophages expressing the α7 nicotinic acetylcholine receptor (α7AChR), with an inflammation suppressing effect occurring when either the vagus or splenic nerves were stimulated [ 153 ]. Further studies demonstrated that vagus nerve stimulation or an α7nicotinic agonist apparently limited tumor necrosis factor-α and high mobility group protein-1 release by macrophages, reducing an inflammatory effect. Another essential element during the process of IP treatment is the modification of interfacing tissue close to the heat or cold energy source, especially epithelial and neuroendocrine cells. In the bronchial thermoplasty study, one team demonstrated the decrease of these two cell types after surgery, while the epithelial gene changes in the process was confirmed by another research team. Thus, whether there is a connection between the two studies, and if they are potentially related to the bronchial thermoplasty therapeutic effect needs further validation. Neuroendocrine cells in epithelial tissue are recognized as another underlying control center intimately connected to sensory nerves that express TRPA1 [ 154 ]. Meanwhile, some researchers point out that pro-asthmatic neuropeptides are also released from these pulmonary neuroendocrine cells [ 136 ]. Therefore, the character of neuroendocrine cells in asthma neuro-immunity also deserves further investigation. Moreover, communication between the intestines and lungs occurs constantly through the lymphatic and blood circulation. The gut microbiota plays a significant role in closely interacting with the mucosal immune system, employing both pro-inflammatory and regulatory signals [ 155 ]. While the thoracic duct, as the largest lymphatic vessel, facilitates the rapid encounter of the lung with mesenteric lymph, performing a crucial role in regulating the close relationship between the intestines and lungs and their associated immune responses [ 156 , 157 ]. Numerous studies have provided strong evidence supporting the involvement of gut dysbiosis in the development of pulmonary complications through the concept of the gut-lung axis [ [157] , [158] , [159] ]. A Cross-Sectional Study [ 160 ] revealed variations in the composition of gut microbiota among different asthma patients. While study conducted on children diagnosed with asthma at preschool age also identified evidence of gut bacterial dysbiosis, further bolstering the close association between the gut-lung axis and asthma [ [161] , [162] , [163] ]. Furthermore, in animal models, the administration of probiotics like Lactococcus lactis NZ9000 or Bifidobacterium breve M-16V has demonstrated a decrease in eosinophil infiltration, as well as a reduction in the levels of IL-4, IL-5, IL-13, and IgE, indicating effective control of lung inflammation [ 164 , 165 ]. Additionally, the use of Bacteroides fragilis appears to balance the host's systemic Th1/Th2 ratio, thereby providing protection against allergen-induced airway disorders [ 166 ]. Meanwhile, many bacteria utilize the adrenaline/noradrenaline system to regulate and propagate virulence [ 167 ], potentially influencing both the nervous and immune systems. Whether the gut-lung axis, mediated by the microbiota and probiotics, is interconnected with the lung-brain axis and may influence neuro-immunity crosstalk, also requires thoughtful consideration.

This work was supported by 10.13039/501100001809 National Natural Science Foundation of China (grant number:82270116, 82100089), Science and Technology Innovation Action Plan of Shanghai (grant number: 22Y11901100), Clinical Research Project of Shanghai East Hospital (grant number: DFLC2022002), and The Top-level Clinical Discipline Project of Shanghai Pudong (grant number: PWYgf2021-05).

XL, SG, and FX conceived the content, drafted the manuscript, and approved the final version to be submitted. YW, XW, WG drafted the manuscript and approved the final version to be submitted. MW and JS helped in writing the manuscript and approved the final version to be submitted. KW and DL helped in writing the manuscript, revised it critically for important intellectual content, and approved the final version to be submitted. WX, and QL conceived the content, revised it critically for important intellectual content, and approved the final version to be submitted.

In conclusion, to our knowledge, this is the first review to summarize in detail the potential mechanism of interventional pulmonology techniques in refractory asthma treatment. According to the available evidence, we observed that neuro-immunity changes before and after intervention is a new area that we previously overlooked. Among long-term asthma patients, we further speculated that the main pathway of chronic inflammation and other pathophysiologic processes is the sensory nerve-related neurotransmitter release that forms “neuro-immunity crosstalk” and amplifies airway neurogenic inflammation. Meanwhile, other pathways, including the anti-inflammatory reflex, epithelial changes, and neuroendocrine cell responses to the intervention, also deserve attention. Future investigations on blocking abnormally excited cholinergic parasympathetic nerves and specific neuro-immunity mechanisms will greatly increase our understanding of neuroimmune interactions, and therefore finally lead us towards the elimination of asthma.

Asthma, a common disease that seriously threatens health at all ages, is clinically characterized by recurrent wheezing, chest tightness, and dyspnea accompanied by widely variable reversible airflow limitation, which may resolve spontaneously or in response to medication in most patients. Currently, asthma affects 1–18 % of the population in different countries, as described in the Global Initiative for Asthma (GINA) 2022. According to data from the Global Burden of Disease Study 2017 published in the Lancet [ 1 ] in 2017, nearly 550 million people had a chronic respiratory disease, and asthma was the second leading cause worldwide. Regularly inhaled glucocorticoids and bronchodilators are recommended as treatment options, in addition to macrolide antibiotics and biologically targeted agents such as anti-IgE monoclonal antibodies. With the improvement of the living environment and the increased awareness of personal health, most patients can receive standardized drug therapy and management, and obtain appreciable symptom control. However, there still exists a considerable proportion of patients whose symptoms remain ineffectively controlled after receiving the standard inhaled therapy (GINA steps 4–5), which is referred to as refractory asthma. Some studies [ 2 , 3 ] pointed out that the prevalence of current asthma over age 20 years is 4.2 %, whereas refractory asthma forms account for 15.5 % of the asthma population, manifesting as reduced quality of life and requiring high-dose medication maintenance with a high burden of disease. Faced with this reality, there has been a continuous effort to develop and create new drugs or new approaches to asthma treatment intending to reverse the quandary faced by asthma management. In this review, we will summarize the potential mechanism of interventional pulmonology techniques in refractory asthma treatment. We will also deduce the relationship between these different methods, therefore better understanding the secret of the underlying mechanism behind the interventional pulmonology techniques for refractory asthma treatment.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.