title: NLRP3 Inflammasome Deficiency Protects against Microbial Sepsis via Increased Lipoxin B4Synthesis.
abstract: Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, is a major public health concern with high mortality and morbidity. Although inflammatory responses triggered by infection are crucial for host defense against invading microbes, the excessive inflammation often causes tissue damage leading to organ dysfunction. Resolution of inflammation, an active immune process mediated by endogenous lipid mediators (LMs), is important to maintain host homeostasis.
  
  
  
  We sought to determine the role of the nucleotide-binding domain, leucine-rich repeat-containing receptor, pyrin domain-containing-3 (NLRP3) inflammasome in polymicrobial sepsis and regulation of LM biosynthesis.
  
  
  
  We performed cecal ligation and puncture (CLP) using mice lacking NLRP3 inflammasome-associated molecules to assess mortality. Inflammation was evaluated by using biologic fluids including plasma, bronchoalveolar, and peritoneal lavage fluid. Local acting LMs in peritoneal lavage fluid from polymicrobacterial septic mice were assessed by mass spectrometry-based metabololipidomics.
  
  
  
  Genetic deficiency of NLRP3 inhibited inflammatory responses and enhanced survival of CLP-induced septic mice. NLRP3 deficiency reduced proinflammatory LMs and increased proresolving LM, lipoxin B4(LXB4) in septic mice, and in macrophages stimulated with LPS and ATP. Activation of the NLRP3 inflammasome induced caspase-7 cleavage and pyroptosis. Caspase-7 deficiency similarly reduced inflammation and mortality in CLP-induced sepsis, and increased LXB4production in vivo and in vitro. Exogenous application of LXB4reduced inflammation, pyroptosis, and mortality of mice after CLP.
  
  
  
  Genetic deficiency of NLRP3 promoted resolution of inflammation in polymicrobial sepsis by relieving caspase-7-dependent repression of LXB4biosynthesis, and increased survival potentially via LXB4production and inhibition of proinflammatory cytokines.
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.|2 Department of Critical Care Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Seonmin
authors.initials: S
authors.lastname: Lee
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.|3 Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Kiichi
authors.initials: K
authors.lastname: Nakahira
authors.affiliation: 4 Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Harvard Institutes of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jesmond
authors.initials: J
authors.lastname: Dalli
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.|3 Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, New York.|5 First Department of Critical Care Medicine and Pulmonary Services, Evangelismos Hospital, University of Athens Medical School, Athens, Greece.
authors.forename: Ilias I
authors.initials: II
authors.lastname: Siempos
authors.affiliation: 4 Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Harvard Institutes of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Norris
authors.affiliation: 4 Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Harvard Institutes of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Romain A
authors.initials: RA
authors.lastname: Colas
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.|3 Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Jong-Seok
authors.initials: JS
authors.lastname: Moon
authors.affiliation: 4 Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Harvard Institutes of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Shinohara
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.|3 Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Shu
authors.initials: S
authors.lastname: Hisata
authors.affiliation: 6 Division of Pulmonary and Critical Care Medicine, Penn State College of Medicine, Hershey, Pennsylvania; and.
authors.forename: Judie Ann
authors.initials: JA
authors.lastname: Howrylak
authors.affiliation: 2 Department of Critical Care Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Gee-Young
authors.initials: GY
authors.lastname: Suh
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.|3 Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.affiliation: 4 Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Harvard Institutes of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.|3 Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, New York.|7 New York Presbyterian Hospital, Weill Cornell Medical Center, New York, New York.
authors.forename: Augustine M K
authors.initials: AMK
authors.lastname: Choi
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D058847:Inflammasomes / Q000235:genetics* / Q000378:metabolism*; D044045:Lipoxins / Q000378:metabolism*; D051379:Mice; D020011:Protective Agents; D018805:Sepsis / Q000276:immunology* / Q000382:microbiology*; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D044045:Lipoxins; D020011:Protective Agents
keywords: NLRP3 inflammasome; lipid mediators; sepsis