The Cholinergic System Contributes to the Immunopathological Progression of Experimental Pulmonary Tuberculosis

Abstract

The cholinergic system is present in both bacteria and mammals and regulates inflammation during bacterial respiratory infections through neuronal and non-neuronal production of acetylcholine (ACh) and its receptors. However, the presence of this system during the immunopathogenesis of pulmonary tuberculosis (TB) in vivo and in its causative agent Mycobacterium tuberculosis (Mtb) has not been studied. Therefore, we used an experimental model of progressive pulmonary TB in BALB/c mice to quantify pulmonary ACh using high-performance liquid chromatography during the course of the disease. In addition, we performed immunohistochemistry in lung tissue to determine the cellular expression of cholinergic system components, and then administered nicotinic receptor (nAChR) antagonists to validate their effect on lung bacterial burden, inflammation, and pro-inflammatory cytokines. Finally, we subjected Mtb cultures to colorimetric analysis to reveal the production of ACh and the effect of ACh and nAChR antagonists on Mtb growth. Our results show high concentrations of ACh and expression of its synthesizing enzyme choline acetyltransferase (ChAT) during early infection in lung epithelial cells and macrophages. During late progressive TB, lung ACh upregulation was even higher and coincided with ChAT and α7 nAChR subunit expression in immune cells. Moreover, the administration of nAChR antagonists increased pro-inflammatory cytokines, reduced bacillary loads and synergized with antibiotic therapy in multidrug resistant TB. Finally, in vitro studies revealed that the bacteria is capable of producing nanomolar concentrations of ACh in liquid culture. In addition, the administration of ACh and nicotinic antagonists to Mtb cultures induced or inhibited bacterial proliferation, respectively. These results suggest that Mtb possesses a cholinergic system and upregulates the lung non-neuronal cholinergic system, particularly during late progressive TB. The upregulation of the cholinergic system during infection could aid both bacterial growth and immunomodulation within the lung to favor disease progression. Furthermore, the therapeutic efficacy of modulating this system suggests that it could be a target for treating the disease.

Depression of long non-coding RNA SOX2 overlapping transcript attenuates lipopolysaccharide-induced injury in bronchial epithelial cells via miR-455-3p/phosphatase and tensin homolog axis and phosphatidylinositol 3-kinase/protein kinase B pathway

“…The inflammatory response of bronchial epithelial cells is a critical pathogenic mechanism of airway homeostasis and pulmonary diseases [ 1 , 3 , 4 ]. Considering the complications of airway inflammation, the emergence of novel targets might improve further understanding and treatment of chronic inflammation in the respiratory tract.…”

“…The bronchial epithelium is the first anatomical barrier for stimulus and pathogens. Once a stimulus activates bronchial epithelial cells, a series of inflammatory cascades are initiated, accompanied by excessive release of inflammatory cytokines, which eventually lead to cell apoptosis [ 3 , 4 ]. To better understand this complex process, it is important to elucidate the regulatory mechanisms and identify more effective targets of inflammatory response in bronchial epithelial cells.…”

The Role of the Acetylcholine System in Common Respiratory Diseases and COVID-19

“…Meanwhile, nicotine has the potential to increase the growth of Mtb mainly in type II pneumocytes, and inhibit the expression of antimicrobial peptides in type II pneumocytes and airway basal epithelial cells partially mediated by the α7nAChR [ 134 ]. During the periods of experimental pulmonary tuberculosis, there are high concentrations of ACh and expression of choline acetyltransferase (ChAT) in lung epithelial cells and macrophages at the early infection stage, besides, the upregulation of lung ACh was even higher and coincided with ChAT and α7nAChR subunit expression in immune cells at late progressive TB [ 135 ]. Surprisingly, in vitro studies revealed that the bacteria have the potential to produce nanomolar concentrations of ACh in liquid culture and the administration of ACh/nicotinic antagonists to Mtb cultures can promote or inhibit bacterial proliferation, respectively.…”

Itaconate, Arginine, and Gamma-Aminobutyric Acid: A Host Metabolite Triad Protective Against Mycobacterial Infection

“…It is unclear how acetylcholine results in the suppression of Mtb clearance. Given the recent findings that acetylcholine and cholinergic system favor the progression of mycobacterial infection (70), targeting the non-neuronal cholinergic system in the lungs may contribute to the development of new therapeutics against TB.…”