title: Cigarette smoke attenuates the RIG-I-initiated innate antiviral response to influenza infection in two murine models.
abstract: Cigarette smoke (CS) exposure increases the frequency and severity of respiratory tract infections. Despite this association, the mechanisms underlying the increased susceptibility to respiratory virus infection are poorly understood. Retinoic acid-inducible gene I (RIG-I) is an important regulator of influenza virus-induced expression of antiviral cytokines, mainly interferons (IFNs), which are necessary to clear viral infections. In this study, we compared the innate cytokine responses of two mouse CS exposure models following a challenge with influenza A virus (IAV): 1) exposure of the mice to cigarette smoke extract (CSE) intratracheally and 2) exposure of the mice to CS in a whole body exposure chamber. Both intratracheal CSE treatment and whole body CS exposure caused antiviral immunosuppression in these mice, and both CS exposure methods inhibited RIG-I induction. CS attenuated influenza-induced antiviral IFNs and IP-10 expression in vivo. However, we did not find that CS inhibited induction of the proinflammatory cytokines IL-6 and TNF-α, whose expression was induced by IAV. Interestingly, IAV infection also increased Toll-like receptor 3 (TLR3) expression in mouse lung, but CS exposure did not impact TLR3 induction in these mice. Together, the results support our previous finding in a human lung organ culture model that the suppression of RIG-I induction and antiviral cytokine responses by CS are likely important in the enhanced susceptibility of smokers to influenza infection in the lung.
authors.affiliation: Pulmonary and Critical Care Division, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Wenxin
authors.initials: W
authors.lastname: Wu
authors.affiliation: Pulmonary and Critical Care Division, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: The Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, Oklahoma;
authors.forename: Sunil
authors.initials: S
authors.lastname: More
authors.affiliation: Pulmonary and Critical Care Division, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: J Leland
authors.initials: JL
authors.lastname: Booth
authors.affiliation: Pulmonary and Critical Care Division, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Duggan
authors.affiliation: The Lundberg-Kienlen Lung Biology and Toxicology Laboratory, Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, Oklahoma;
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Yan D
authors.initials: YD
authors.lastname: Zhao
authors.affiliation: Pulmonary and Critical Care Division, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; and Veterans Affairs Medical Center, Oklahoma City, Oklahoma jordan-metcalf@ouhsc.edu.
authors.forename: Jordan P
authors.initials: JP
authors.lastname: Metcalf
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D054357:Chemokine CXCL10 / Q000096:biosynthesis; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000096:biosynthesis*; D005260:Female; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D007113:Immunity, Innate / Q000187:drug effects* / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D016899:Interferon-beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008168:Lung / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000517:prevention & control; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects; D014026:Nicotiana / Q000009:adverse effects*; D051196:Toll-Like Receptor 3 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D015850:Interleukin-6; D012906:Smoke; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases
keywords: Toll-like receptor 3; cytokine; lung; mouse; retinoic acid-inducible gene I