Alcohol impairs recognition and uptake of Mycobacterium tuberculosis by suppressing toll‐like receptor 2 expression

Abstract

Background Alcohol impairs pulmonary innate immune function and is associated with an increased risk of tuberculosis (TB). Toll‐like receptor 2 (TLR2) is a pattern recognition receptor on alveolar macrophages that recognizes Mycobacterium tuberculosis (Mtb). The expression of TLR2 depends, in part, on granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) signaling. Given our prior work demonstrating the suppression of GM‐CSF signaling following chronic alcohol ingestion, we hypothesized that alcohol impairs TLR2 expression via the suppression of GM‐CSF and thereby reduces the ability of the macrophage to recognize and phagocytose Mtb. Methods Primary alveolar macrophages were isolated from control‐fed and alcohol‐fed rats. Prior to cell isolation, some alcohol‐fed rats were treated with intranasal GM‐CSF and then endotracheally inoculated with an attenuated strain of Mtb. Primary macrophages were then isolated and immunofluorescence was used to determine phagocytic efficiency and TLR2 expression in the presence and absence of GM‐CSF treatment and phagocytic efficiency in the presence and absence of TLR2 neutralization. Results TLR2 expression and phagocytosis of Mtb were significantly lower in the alveolar macrophages of alcohol‐fed rats than control‐fed rats. In parallel, blocking TLR2 signaling recapitulated this decreased phagocytosis of Mtb. In contrast, intranasal GM‐CSF treatment restored TLR2 expression and Mtb phagocytosis in the alveolar macrophages of alcohol‐fed rats to levels comparable to those of control‐fed rats. Conclusions Chronic alcohol ingestion reduces TLR2 protein expression and phagocytosis of Mtb, likely due to impaired GM‐CSF signaling. GM‐CSF restores membrane‐bound TLR2 expression and phagocytic function.

Pioglitazone reverses alcohol‐induced alterations in alveolar macrophage mitochondrial phenotype

“…Many mechanisms of decreased AM phagocytosis have been proposed previously (Antony et al., 1993; Libon et al., 1993; Morris et al., 2021, 2022; Sadikot et al., 2019; Wigger et al., 2022; Yeligar et al., 2014). Alcohol negatively impacts MT function and impairs AM phagocytosis, but how MT function is impaired is inconsistent between different model species and alcohol use strategies.…”

“…Many mechanisms of decreased AM phagocytosis have been proposed previously (Antony et al, 1993;Libon et al, 1993;Morris et al, 2021Morris et al, , 2022Sadikot et al, 2019;Wigger et al, 2022;Yeligar et al, 2014). together, but not necessarily in sequence, may be in part responsible for AM phagocytic and metabolic dysfunction following chronic alcohol exposure.…”

Paired ATAC- and RNA-seq offer insight into the impact of HIV on alveolar macrophages: a pilot study

“…In addition, macrophages help control inflammation and promote wound healing after infectious or inflammatory insults 40 . Given their myriad important roles in the alveolar space, macrophage dysfunction has been linked to a broad spectrum of pulmonary diseases, including lung infections, emphysema, and pulmonary fibrosis 41 – 43 . In that regard, alveolar macrophages represent a novel and attractive therapeutic target, including for people with HIV who suffer from a disproportionate burden of lung disease 44 .…”

A nomogram for predicting mortality of patients initially diagnosed with primary pulmonary tuberculosis in Hunan province, China: a retrospective study.

“…In demographic characteristics, drinking and HBV infection are also important risk predictors for death in the prognosis of in-hospital patients initially diagnosed with primary PTB because chronic alcohol and HBV reduce the expression of immune proteins in infected patients, further decreasing their immune function (43). HBV infection cycle and the amount or frequency of drinking are positively correlated with TB susceptibility, indicating that both drinking and HBV infection are high-risk factors for the death of TB patients (44)(45)(46)(47).…”