PMID- 25548278 OWN - NLM STAT- MEDLINE DCOM- 20150506 LR - 20210316 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 290 IP - 8 DP - 2015 Feb 20 TI - NLRP3 protein deficiency exacerbates hyperoxia-induced lethality through Stat3 protein signaling independent of interleukin-1beta. PG - 5065-5077 LID - S0021-9258(19)46911-1 [pii] LID - 10.1074/jbc.M114.603217 [doi] AB - 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-1beta 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-1beta(-/-) mice, and there was no difference in IL-1beta 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-1beta production and contributes to the pathophysiology of HALI. CI - (c) 2015 by The American Society for Biochemistry and Molecular Biology, Inc. FAU - Mizushina, Yoshiko AU - Mizushina Y AD - 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. FAU - Shirasuna, Koumei AU - Shirasuna K AD - From the Division of Inflammation Research, Center for Molecular Medicine, and. FAU - Usui, Fumitake AU - Usui F AD - From the Division of Inflammation Research, Center for Molecular Medicine, and. FAU - Karasawa, Tadayoshi AU - Karasawa T AD - From the Division of Inflammation Research, Center for Molecular Medicine, and. FAU - Kawashima, Akira AU - Kawashima A AD - From the Division of Inflammation Research, Center for Molecular Medicine, and. FAU - Kimura, Hiroaki AU - Kimura H AD - From the Division of Inflammation Research, Center for Molecular Medicine, and. FAU - Kobayashi, Motoi AU - Kobayashi M AD - From the Division of Inflammation Research, Center for Molecular Medicine, and. FAU - Komada, Takanori AU - Komada T AD - From the Division of Inflammation Research, Center for Molecular Medicine, and. FAU - Inoue, Yoshiyuki AU - Inoue Y AD - From the Division of Inflammation Research, Center for Molecular Medicine, and. FAU - Mato, Naoko AU - Mato N AD - Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan. FAU - Yamasawa, Hideaki AU - Yamasawa H AD - Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan. FAU - Latz, Eicke AU - Latz E AD - 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. FAU - Iwakura, Yoichiro AU - Iwakura Y AD - 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. FAU - Kasahara, Tadashi AU - Kasahara T AD - From the Division of Inflammation Research, Center for Molecular Medicine, and. FAU - Bando, Masashi AU - Bando M AD - Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan. FAU - Sugiyama, Yukihiko AU - Sugiyama Y AD - Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan. FAU - Takahashi, Masafumi AU - Takahashi M AD - From the Division of Inflammation Research, Center for Molecular Medicine, and. Electronic address: masafumi2@jichi.ac.jp. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20141229 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Carrier Proteins) RN - 0 (IL1B protein, mouse) RN - 0 (Interleukin-1beta) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Nlrp3 protein, mouse) RN - 0 (Proto-Oncogene Proteins c-bcl-2) RN - 0 (STAT3 Transcription Factor) RN - 0 (Stat3 protein, mouse) RN - 114100-40-2 (Bcl2 protein, mouse) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) RN - EC 3.4.24.35 (Mmp9 protein, mouse) SB - IM MH - Acute Lung Injury/genetics/*metabolism/pathology MH - Animals MH - Carrier Proteins/*genetics/metabolism MH - Hyperoxia/genetics/*metabolism/pathology MH - Interleukin-1beta/*metabolism MH - Matrix Metalloproteinase 9/metabolism MH - Mice MH - Mice, Knockout MH - NLR Family, Pyrin Domain-Containing 3 Protein MH - Proto-Oncogene Proteins c-bcl-2/metabolism MH - Pulmonary Alveoli/metabolism/pathology MH - Respiratory Mucosa/metabolism/pathology MH - STAT3 Transcription Factor/*metabolism MH - *Signal Transduction PMC - PMC4335242 OTO - NOTNLM OT - Cytokine OT - Inflammasome OT - Inflammation OT - Lung Injury OT - Signal Transduction EDAT- 2014/12/31 06:00 MHDA- 2015/05/07 06:00 PMCR- 2016/02/20 CRDT- 2014/12/31 06:00 PHST- 2014/12/31 06:00 [entrez] PHST- 2014/12/31 06:00 [pubmed] PHST- 2015/05/07 06:00 [medline] PHST- 2016/02/20 00:00 [pmc-release] AID - S0021-9258(19)46911-1 [pii] AID - M114.603217 [pii] AID - 10.1074/jbc.M114.603217 [doi] PST - ppublish SO - J Biol Chem. 2015 Feb 20;290(8):5065-5077. doi: 10.1074/jbc.M114.603217. Epub 2014 Dec 29.