scholarly journals Nicotine Increases Macrophage Survival through α7nAChR/NF-κB Pathway in Mycobacterium avium paratuberculosis Infection

2021 ◽  
Vol 9 (5) ◽  
pp. 1086
Author(s):  
Dania AlQasrawi ◽  
Ebraheem Naser ◽  
Saleh A. Naser
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Mycobacterium Avium ◽  
Nuclear Translocation ◽  
Mycobacterium Avium Subspecies Paratuberculosis ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Macrophage Response ◽  
Mycobacterium Avium Paratuberculosis ◽  
Cellular Survival

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.

scholarly journals Mycobacterium Avium Paratuberculosisand the Etiology of Crohn’s Disease: A Review of the Controversy from the Clinician’s Perspective

2010 ◽  
Vol 24 (10) ◽  
pp. 619-624 ◽  
Author(s):  
Greg Rosenfeld ◽  
Brian Bressler
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Mycobacterium Avium ◽  
Immunosuppressive Agents ◽  
Infectious Agent ◽  
Causative Role ◽  
Mycobacterium Avium Paratuberculosis ◽  
Considerable Research ◽  
Chronic Inflammatory Condition

Mycobacterium avium paratuberculosis(MAP) is an obligate intracellular organism that has frequently been associated with Crohn’s disease (CD). Because CD is a chronic inflammatory condition, many researchers have speculated that an infectious agent must be the cause of CD. MAP has often been proposed to be one such agent; however, despite considerable research, the evidence remains inconclusive. Higher levels of MAP have been found in the tissues and blood of CD patients than in controls, forming the foundation for much of the research into the role of MAP in CD and the primary argument in support of a causative role for MAP in CD. MAP is a slow-growing and fastidious organism that is difficult to grow in culture and, therefore, challenging to detect in patients. As a result, there has been variability in the results of studies attempting to detect the presence of MAP in CD patients, and considerable controversy over whether this organism has a causative role in the etiology of CD. Two main hypotheses exist with respect to the role of MAP in CD. The first is that MAP is a principal cause of CD, while the second is that MAP is more prevalent because of the immune dysfunction seen in CD but does not play a causative role. Clinicians are often faced with questions regarding the role of this organism and the need to treat it. The present article attempts to provide an overview of the controversy including the nature of the mycobacterium, the difficulty in detecting it, the use of antimycobacterial agents to treat it and the effect of immunosuppressive agents – all from a clinician’s perspective. Although the role of MAP in CD remains controversial and an area of considerable research, it is currently only of academic interest because there is no clinically useful test to identify the presence of the organism, and no evidence to support the use of antibiotics to eradicate it for the treatment of CD.

scholarly journals Molecular identification of Mycobacterium avium subspecies paratuberculosis in oral biopsies of Crohn’s disease patients

Gut Pathogens ◽  
2013 ◽  
Vol 5 (1) ◽  
pp. 18 ◽  
Author(s):  
Paola Molicotti ◽  
Antonio M Scanu ◽  
Aurea Lumbau ◽  
Sara Cannas ◽  
Alessandra Bua ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Molecular Identification ◽  
Mycobacterium Avium ◽  
Mycobacterium Avium Subspecies Paratuberculosis

scholarly journals Notch-1 Signaling Modulates Macrophage Polarization and Immune Defense against Mycobacterium avium paratuberculosis Infection in Inflammatory Diseases

2020 ◽  
Vol 8 (7) ◽  
pp. 1006 ◽  
Author(s):  
Esra’a Keewan ◽  
Saleh A. Naser
Keyword(s):  
Inflammatory Response ◽  
Notch Signaling ◽  
Mycobacterium Avium ◽  
Macrophage Polarization ◽  
Immune Defense ◽  
Notch 1 ◽  
Macrophage Response ◽  
Mycobacterium Avium Paratuberculosis ◽  
Vitro Effect

Despite the extensive research on Notch signaling involvement in inflammation, its specific role in macrophage response in autoimmune disease and defense mechanisms against bacterial infection, such as Mycobacterium avium paratuberculosis (MAP), remains unknown. In this study, we investigated the molecular role of Notch-1 signaling in the macrophage response during MAP infection. In particular, we measured the in vitro effect of MAP on Notch-1 signaling and downstream influence on interleukin (IL)-6 and myeloid cell leukemia sequence-1 (MCL-1) and consequent cellular apoptosis, MAP viability, and macrophage polarization. Overall, the data show significant upregulation in Notch-1, IL-6, and MCL-1 in MAP-infected macrophages, parallel with a decrease in apoptosis and elevated pro-inflammatory response in these infected cells. On the contrary, blocking Notch signaling with γ-secretase inhibitor (DAPT) decreased MAP survival and burden, increased apoptosis, and diminished the pro-inflammatory response. In particular, the treatment of infected macrophages with DAPT shifted macrophage polarization toward M2 anti-inflammatory phenotypic response. The outcome of this study clearly demonstrates the critical role of Notch signaling in macrophage response during infection. We conclude that MAP infection in macrophages activates Notch-1 signaling and downstream influence on IL-6 which hijack MCL-1 dependent inhibition of apoptosis leading to its chronic persistence, and further inflammation. This study supports Notch-1 signaling as a therapeutic target to combat infection in autoimmune diseases such as Crohn’s disease and Rheumatoid Arthritis.

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