Abstract
Recently, we reported that nicotine plays a role in the failure of the macrophage in the clearance of Mycobacterium avium subspecies paratuberculosis (MAP) during infection in Crohn’s disease smokers. We also demonstrated that nicotine enhances macrophages cellular survival during MAP infection. Blocking α7 nicotinic acetylcholine receptor (α7nAChR) with the pharmacological antagonist—mecamylamine—subverted the anti-inflammatory effect of nicotine in macrophages. Yet, it is still unknown how α7nAChR is involved in the modulation of the macrophage response during MAP infection. Here, we studied the mechanistic role of nicotine-α7nAChR interaction in modulating NF-ĸB survival pathway, autophagy, and effect on cathelicidin production in MAP-infected macrophages using THP-1 cell lines. Our results showed that nicotine upregulated α7nAChR expression by 5-folds during MAP infection compared to controls. Bcl-2 expression was also significantly increased after nicotine exposure. Moreover, Nicotine inhibited autophagosome formation whereas infection with MAP in absence of nicotine has significantly increased LC-3b in macrophages. Nicotine also further upregulated NF-ĸB subunits expression including Rel-B and p100, and increased nuclear translocation of p52 protein. We also discovered that cathelicidin production was significantly suppressed in MAP-infected macrophages, treatment with nicotine showed no effect. Overall, the study provides new insight toward understanding the cellular role of nicotine through α7nAChR/NF-ĸB p100/p52 signaling pathway in inducing anti-apoptosis and macrophage survival during MAP infection in Crohn’s disease smokers.
Highlights
The cigarette smoke (CS) epidemic is a fatal public health problem resulting in over 8 million deaths per year [1]
Bacterial infection caused by Mycobacterium avium subspecies paratuberculosis (MAP), adherent-invasive Escherichia coli (AIEC), and Klebsiella pneumoniae are strongly associated with Crohn’s disease (CD), which is exacerbated by smoking [4,5,6]
Our results indicate that nicotine significantly elevated α7 nicotinic acetylcholine receptor (α7nAChR) expression on uninfected macrophages (10.57 ± 1.61; p < 0.001) while macrophages with no nicotine treatment exhibited the lowest levels of α7nAChR (0.48 ± 0.22); these groups were used as reference controls
Summary
The cigarette smoke (CS) epidemic is a fatal public health problem resulting in over 8 million deaths per year [1]. 7 million of these deaths are due to the direct consumption of tobacco, while the remaining. Epidemiological studies have reported that tobacco consumption increases the risk of developing CD. It has been reported that individuals who smoke more than 20 cigarettes a day have a two to four times increased risk of CD relapse [3]. Other studies have elucidated that smokers are five times more prone to develop active CD than non-smoking individuals [3]. It has been reported that the risk of death is seven times higher for smokers than it is for never-smokers [3].
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