title: Nicotine Impairs Macrophage Control of Mycobacterium tuberculosis.
abstract: Pure nicotine impairs macrophage killing of Mycobacterium tuberculosis (MTB), but it is not known whether the nicotine component in cigarette smoke (CS) plays a role. Moreover, the mechanisms by which nicotine impairs macrophage immunity against MTB have not been explored. To neutralize the effects of nicotine in CS extract, we used a competitive inhibitor to the nicotinic acetylcholine receptor (nAChR)-mecamylamine-as well as macrophages derived from mice with genetic disruption of specific subunits of nAChR. We also determined whether nicotine impaired macrophage autophagy and whether nicotine-exposed T regulatory cells (Tregs) could subvert macrophage anti-MTB immunity. Mecamylamine reduced the CS extract increase in MTB burden by 43%. CS extract increase in MTB was also significantly attenuated in macrophages from mice with genetic disruption of either the α7, β2, or β4 subunit of nAChR. Nicotine inhibited autophagosome formation in MTB-infected THP-1 cells and primary murine alveolar macrophages, as well as increased the intracellular MTB burden. Nicotine increased migration of THP-1 cells, consistent with the increased number of macrophages found in the lungs of smokers. Nicotine induced Tregs to produce transforming growth factor-β. Naive mouse macrophages co-cultured with nicotine-exposed Tregs had significantly greater numbers of viable MTB recovered with increased IL-10 production and urea production, but no difference in secreted nitric oxide as compared with macrophages cocultured with unexposed Tregs. We conclude that nicotine in CS plays an important role in subverting macrophage control of MTB infection.
authors.affiliation: 1 Department of Medicine, Denver Veterans Affairs Medical Center, Denver, Colorado.|Departments of 2 Medicine.|3 Academic Affairs, and.|4 Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, Colorado; and.
authors.forename: Xiyuan
authors.initials: X
authors.lastname: Bai
authors.affiliation: 5 Department of Integrative Physiology, Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, Colorado.
authors.forename: Jerry A
authors.initials: JA
authors.lastname: Stitzel
authors.affiliation: 1 Department of Medicine, Denver Veterans Affairs Medical Center, Denver, Colorado.|Departments of 2 Medicine.|3 Academic Affairs, and.
authors.forename: An
authors.initials: A
authors.lastname: Bai
authors.affiliation: 5 Department of Integrative Physiology, Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, Colorado.
authors.forename: Cristian A
authors.initials: CA
authors.lastname: Zambrano
authors.affiliation: 6 Immunology, and.
authors.forename: Matthew
authors.initials: M
authors.lastname: Phillips
authors.affiliation: 6 Immunology, and.|7 Howard Hughes Medical Institute, National Jewish Health, Denver, Colorado.
authors.forename: Philippa
authors.initials: P
authors.lastname: Marrack
authors.affiliation: 1 Department of Medicine, Denver Veterans Affairs Medical Center, Denver, Colorado.|Departments of 2 Medicine.|3 Academic Affairs, and.|4 Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Aurora, Colorado; and.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Chan
mesh_terms: D000071182:Autophagosomes / Q000187:drug effects / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D006801:Humans; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000382:microbiology*; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D021122:Protein Subunits / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D012907:Smoking; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology
chemical_list: D016328:NF-kappa B; D018733:Nicotinic Antagonists; D021122:Protein Subunits; D011978:Receptors, Nicotinic; D009538:Nicotine
keywords: cigarette smoke; host immunity; macrophage; nicotine; tuberculosis