title: NLRP3 protein deficiency exacerbates hyperoxia-induced lethality through Stat3 protein signaling independent of interleukin-1β.
abstract: Supplemental oxygen inhalation is frequently used to treat severe respiratory failure; however, prolonged exposure to hyperoxia causes hyperoxic acute lung injury (HALI), which induces acute respiratory distress syndrome and leads to high mortality rates. Recent investigations suggest the possible role of NLRP3 inflammasomes, which regulate IL-1β production and lead to inflammatory responses, in the pathophysiology of HALI; however, their role is not fully understood. In this study, we investigated the role of NLRP3 inflammasomes in mice with HALI. Under hyperoxic conditions, NLRP3(-/-) mice died at a higher rate compared with wild-type and IL-1β(-/-) mice, and there was no difference in IL-1β production in their lungs. Under hyperoxic conditions, the lungs of NLRP3(-/-) mice exhibited reduced inflammatory responses, such as inflammatory cell infiltration and cytokine expression, as well as increased and decreased expression of MMP-9 and Bcl-2, respectively. NLRP3(-/-) mice exhibited diminished expression and activation of Stat3, which regulates MMP-9 and Bcl-2, in addition to increased numbers of apoptotic alveolar epithelial cells. In vitro experiments revealed that alveolar macrophages and neutrophils promoted Stat3 activation in alveolar epithelial cells. Furthermore, NLRP3 deficiency impaired the migration of neutrophils and chemokine expression by macrophages. These findings demonstrate that NLRP3 regulates Stat3 signaling in alveolar epithelial cells by affecting macrophage and neutrophil function independent of IL-1β production and contributes to the pathophysiology of HALI.
authors.affiliation: From the Division of Inflammation Research, Center for Molecular Medicine, and; Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Mizushina
authors.affiliation: From the Division of Inflammation Research, Center for Molecular Medicine, and.
authors.forename: Koumei
authors.initials: K
authors.lastname: Shirasuna
authors.affiliation: From the Division of Inflammation Research, Center for Molecular Medicine, and.
authors.forename: Fumitake
authors.initials: F
authors.lastname: Usui
authors.affiliation: From the Division of Inflammation Research, Center for Molecular Medicine, and.
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Karasawa
authors.affiliation: From the Division of Inflammation Research, Center for Molecular Medicine, and.
authors.forename: Akira
authors.initials: A
authors.lastname: Kawashima
authors.affiliation: From the Division of Inflammation Research, Center for Molecular Medicine, and.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kimura
authors.affiliation: From the Division of Inflammation Research, Center for Molecular Medicine, and.
authors.forename: Motoi
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: From the Division of Inflammation Research, Center for Molecular Medicine, and.
authors.forename: Takanori
authors.initials: T
authors.lastname: Komada
authors.affiliation: From the Division of Inflammation Research, Center for Molecular Medicine, and.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Mato
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Yamasawa
authors.affiliation: the Institute of Innate Immunity, University Hospitals, University of Bonn, 53113 Bonn, Germany,; the Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01655.
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.affiliation: the Research Institute for Biomedical Science, Tokyo University of Science, Chiba 278-0022, Japan, and; the Medical Mycology Center, Chiba University, Chiba 260-8673, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.affiliation: From the Division of Inflammation Research, Center for Molecular Medicine, and.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kasahara
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Bando
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Sugiyama
authors.affiliation: From the Division of Inflammation Research, Center for Molecular Medicine, and. Electronic address: masafumi2@jichi.ac.jp.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takahashi
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D018496:Hyperoxia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C052617:Bcl2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: Cytokine; Inflammasome; Inflammation; Lung Injury; Signal Transduction