title: IL-36 receptor deletion attenuates lung injury and decreases mortality in murine influenza pneumonia.
abstract: Influenza virus causes a respiratory disease in humans that can progress to lung injury with fatal outcome. The interleukin (IL)-36 cytokines are newly described IL-1 family cytokines that promote inflammatory responses via binding to the IL-36 receptor (IL-36R). The mechanism of expression and the role of IL-36 cytokines are poorly understood. Here, we investigated the role of IL-36 cytokines in modulating the innate inflammatory response during influenza virus-induced pneumonia in mice. The intranasal administration of influenza virus upregulated IL-36α mRNA and protein production in the lungs. In vitro, influenza virus-mediated IL-36α but not IL-36γ is induced and secreted from alveolar epithelial cells (AECs) through both a caspase-1 and caspase-3/7 dependent pathway. IL-36α was detected in microparticles shed from AECs and promoted the production of pro-inflammatory cytokines and chemokines in respiratory cells. IL-36R-deficient mice were protected from influenza virus-induced lung injury and mortality. Decreased mortality was associated with significantly reduced early accumulation of neutrophils and monocytes/macrophages, activation of lymphocytes, production of pro-inflammatory cytokines and chemokines, and permeability of the alveolar-epithelial barrier in despite impaired viral clearance. Taken together, these data indicate that IL-36 ligands exacerbate lung injury during influenza virus infection.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.|Department of Infection Control and Laboratory Diagnostics, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Aoyagi
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Newstead
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Kunkel
authors.affiliation: Department of Infection Control and Laboratory Diagnostics, Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kaku
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Standiford
mesh_terms: D056809:Alveolar Epithelial Cells / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D000818:Animals; D055252:Cell-Derived Microparticles / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D053118:Influenza A Virus, H1N1 Subtype / Q000502:physiology*; D007251:Influenza, Human / Q000276:immunology; D007375:Interleukin-1 / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D055370:Lung Injury / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D019562:Viral Load
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; C543716:interleukin 1F6, mouse; C569500:Il1rl2 protein, mouse