title: Cigarette smoke silences innate lymphoid cell function and facilitates an exacerbated type I interleukin-33-dependent response to infection.
abstract: Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease and is presumed to be central to the altered responsiveness to recurrent infection in these patients. We examined the effects of smoke priming underlying the exacerbated response to viral infection in mice. Lack of interleukin-33 (IL-33) signaling conferred complete protection during exacerbation and prevented enhanced inflammation and exaggerated weight loss. Mechanistically, smoke was required to upregulate epithelial-derived IL-33 and simultaneously alter the distribution of the IL-33 receptor ST2. Specifically, smoke decreased ST2 expression on group 2 innate lymphoid cells (ILC2s) while elevating ST2 expression on macrophages and natural killer (NK) cells, thus altering IL-33 responsiveness within the lung. Consequently, upon infection and release, increased local IL-33 significantly amplified type I proinflammatory responses via synergistic modulation of macrophage and NK cell function. Therefore, in COPD, smoke alters the lung microenvironment to facilitate an alternative IL-33-dependent exaggerated proinflammatory response to infection, exacerbating disease.
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kearley
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Silver
authors.affiliation: Department of Experimental Medical Science, Lund University, Lund 22184, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Sanden
authors.affiliation: Department of Translational Sciences, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Aaron A
authors.initials: AA
authors.lastname: Berlin
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: White
authors.affiliation: Department of Experimental Medical Science, Lund University, Lund 22184, Sweden.
authors.forename: Michiko
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Translational Sciences, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Tuyet-Hang
authors.initials: TH
authors.lastname: Pham
authors.affiliation: Department of Translational Sciences, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Christine K
authors.initials: CK
authors.lastname: Ward
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Criner
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Marchetti
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Mustelin
authors.affiliation: Department of Experimental Medical Science, Lund University, Lund 22184, Sweden.
authors.forename: Jonas S
authors.initials: JS
authors.lastname: Erjefalt
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors.forename: Roland
authors.initials: R
authors.lastname: Kolbeck
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, MD 20878, USA. Electronic address: humblesa@medimmune.com.
authors.forename: Alison A
authors.initials: AA
authors.lastname: Humbles
mesh_terms: D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D009980:Influenza A virus / Q000276:immunology; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008822:Mice, Transgenic; D009976:Orthomyxoviridae Infections / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018123:Receptors, Interleukin / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana / Q000737:chemistry; D015431:Weight Loss
chemical_list: C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D018123:Receptors, Interleukin; D012906:Smoke