title: Cigarette smoke primes the pulmonary environment to IL-1α/CXCR-2-dependent nontypeable Haemophilus influenzae-exacerbated neutrophilia in mice.
abstract: Cigarette smoke has a broad impact on the mucosal environment with the ability to alter host defense mechanisms. Within the context of a bacterial infection, this altered host response is often accompanied by exacerbated cellular inflammation, characterized by increased neutrophilia. The current study investigated the mechanisms of neutrophil recruitment in a murine model of cigarette smoke exposure and, subsequently, a model of both cigarette smoke exposure and bacterial infection. We investigated the role of IL-1 signaling in neutrophil recruitment and found that cigarette smoke-induced neutrophilia was dependent on IL-1α produced by alveolar macrophages. In addition to being the crucial source of IL-1α, alveolar macrophages isolated from smoke-exposed mice were primed for excessive IL-1α production in response to bacterial ligands. To test the relevance of exaggerated IL-1α production in neutrophil recruitment, a model of cigarette smoke exposure and nontypeable Haemophilus influenzae infection was developed. Mice exposed to cigarette smoke elaborated an exacerbated CXCR2-dependent neutrophilia in response to nontypeable Haemophilus influenzae. Exacerbated neutrophilia was dependent on IL-1α priming of the pulmonary environment by cigarette smoke as exaggerated neutrophilia was dependent on IL-1 signaling. These data characterize a novel mechanism of cigarette smoke priming the lung mucosa toward greater IL-1-driven neutrophilic responses to bacteria, with a central role for the alveolar macrophage in this process.
authors.affiliation: Medical Sciences Graduate Program, McMaster University, Hamilton, Ontario L8S 4K1, Canada;
authors.forename: Jake K
authors.initials: JK
authors.lastname: Nikota
authors.affiliation: Medical Sciences Graduate Program, McMaster University, Hamilton, Ontario L8S 4K1, Canada;
authors.forename: Pamela
authors.initials: P
authors.lastname: Shen
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario L8S 4K1, Canada;
authors.forename: Mathieu C
authors.initials: MC
authors.lastname: Morissette
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario L8S 4K1, Canada;
authors.forename: Kimberly
authors.initials: K
authors.lastname: Fernandes
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario L8S 4K1, Canada;
authors.forename: Abraham
authors.initials: A
authors.lastname: Roos
authors.affiliation: Medical Sciences Graduate Program, McMaster University, Hamilton, Ontario L8S 4K1, Canada;
authors.forename: Derek K
authors.initials: DK
authors.lastname: Chu
authors.affiliation: Medical Sciences Graduate Program, McMaster University, Hamilton, Ontario L8S 4K1, Canada;
authors.forename: Nicole G
authors.initials: NG
authors.lastname: Barra
authors.affiliation: Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo 113-8654, Japan;
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.affiliation: MedImmune LLC, Gaithersburg, MD 20878; and.
authors.forename: Roland
authors.initials: R
authors.lastname: Kolbeck
authors.affiliation: MedImmune LLC, Gaithersburg, MD 20878; and.
authors.forename: Alison A
authors.initials: AA
authors.lastname: Humbles
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario L8S 4K1, Canada; Department of Medicine, Firestone Institute for Respiratory Health at St. Joseph's Healthcare, McMaster University, Hamilton, Ontario L8N 4A6, Canada.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Stampfli
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000096:biosynthesis; D054365:Chemokine CXCL5 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D005260:Female; D006192:Haemophilus Infections / Q000276:immunology / Q000382:microbiology; D006193:Haemophilus influenzae / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D053582:Interleukin-1alpha / Q000276:immunology*; D007958:Leukocyte Count; D008168:Lung / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D023063:Receptors, Interleukin-8B / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D020545:Respiratory Mucosa / Q000276:immunology / Q000382:microbiology; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana / Q000009:adverse effects
chemical_list: D054360:Chemokine CXCL1; D054365:Chemokine CXCL5; C475895:Cxcl1 protein, mouse; C094739:Cxcl5 protein, mouse; D053582:Interleukin-1alpha; D012333:RNA, Messenger; D023063:Receptors, Interleukin-8B; D012906:Smoke