NLRP3 inflammasome deficiency protects against microbial sepsis via increased lipoxin B4 synthesis

Seonmin Lee, Kiichi Nakahira, Jesmond Dalli, Ilias I. Siempos, Paul C. Norris, Romain A. Colas, Jong Seok Moon, Masakazu Shinohara, Shu Hisata, Judie Ann Howrylak, Gee Young Suh, Stefan W. Ryter, Charles N. Serhan, Augustine M.K. Choi

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Rationale: 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. Objectives: 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. Methods: 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. Measurements and Main Results: 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 LXB4 production in vivo and in vitro. Exogenous application of LXB4 reduced inflammation, pyroptosis, and mortality of mice after CLP. Conclusions: Genetic deficiency of NLRP3 promoted resolution of inflammation in polymicrobial sepsis by relieving caspase-7–dependent repression of LXB4 biosynthesis, and increased survival potentially via LXB4 production and inhibition of proinflammatory cytokines.

Original languageEnglish (US)
Pages (from-to)713-726
Number of pages14
JournalAmerican journal of respiratory and critical care medicine
Volume196
Issue number6
DOIs
StatePublished - Sep 15 2017

Fingerprint

Inflammasomes
Sepsis
Inflammation
Punctures
Ligation
Lipids
Peritoneal Lavage
Caspase 7
Mortality
Ascitic Fluid
Bronchoalveolar Lavage Fluid
Caspases
Infection
Leucine
lipoxin B4
Homeostasis
Nucleotides
Public Health
Adenosine Triphosphate
Macrophages

All Science Journal Classification (ASJC) codes

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Lee, Seonmin ; Nakahira, Kiichi ; Dalli, Jesmond ; Siempos, Ilias I. ; Norris, Paul C. ; Colas, Romain A. ; Moon, Jong Seok ; Shinohara, Masakazu ; Hisata, Shu ; Howrylak, Judie Ann ; Suh, Gee Young ; Ryter, Stefan W. ; Serhan, Charles N. ; Choi, Augustine M.K. / NLRP3 inflammasome deficiency protects against microbial sepsis via increased lipoxin B4 synthesis. In: American journal of respiratory and critical care medicine. 2017 ; Vol. 196, No. 6. pp. 713-726.
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abstract = "Rationale: 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. Objectives: 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. Methods: 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. Measurements and Main Results: 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 LXB4 production in vivo and in vitro. Exogenous application of LXB4 reduced inflammation, pyroptosis, and mortality of mice after CLP. Conclusions: Genetic deficiency of NLRP3 promoted resolution of inflammation in polymicrobial sepsis by relieving caspase-7–dependent repression of LXB4 biosynthesis, and increased survival potentially via LXB4 production and inhibition of proinflammatory cytokines.",
author = "Seonmin Lee and Kiichi Nakahira and Jesmond Dalli and Siempos, {Ilias I.} and Norris, {Paul C.} and Colas, {Romain A.} and Moon, {Jong Seok} and Masakazu Shinohara and Shu Hisata and Howrylak, {Judie Ann} and Suh, {Gee Young} and Ryter, {Stefan W.} and Serhan, {Charles N.} and Choi, {Augustine M.K.}",
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Lee, S, Nakahira, K, Dalli, J, Siempos, II, Norris, PC, Colas, RA, Moon, JS, Shinohara, M, Hisata, S, Howrylak, JA, Suh, GY, Ryter, SW, Serhan, CN & Choi, AMK 2017, 'NLRP3 inflammasome deficiency protects against microbial sepsis via increased lipoxin B4 synthesis', American journal of respiratory and critical care medicine, vol. 196, no. 6, pp. 713-726. https://doi.org/10.1164/rccm.201604-0892OC

NLRP3 inflammasome deficiency protects against microbial sepsis via increased lipoxin B4 synthesis. / Lee, Seonmin; Nakahira, Kiichi; Dalli, Jesmond; Siempos, Ilias I.; Norris, Paul C.; Colas, Romain A.; Moon, Jong Seok; Shinohara, Masakazu; Hisata, Shu; Howrylak, Judie Ann; Suh, Gee Young; Ryter, Stefan W.; Serhan, Charles N.; Choi, Augustine M.K.

In: American journal of respiratory and critical care medicine, Vol. 196, No. 6, 15.09.2017, p. 713-726.

Research output: Contribution to journalArticle

TY - JOUR

T1 - NLRP3 inflammasome deficiency protects against microbial sepsis via increased lipoxin B4 synthesis

AU - Lee, Seonmin

AU - Nakahira, Kiichi

AU - Dalli, Jesmond

AU - Siempos, Ilias I.

AU - Norris, Paul C.

AU - Colas, Romain A.

AU - Moon, Jong Seok

AU - Shinohara, Masakazu

AU - Hisata, Shu

AU - Howrylak, Judie Ann

AU - Suh, Gee Young

AU - Ryter, Stefan W.

AU - Serhan, Charles N.

AU - Choi, Augustine M.K.

PY - 2017/9/15

Y1 - 2017/9/15

N2 - Rationale: 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. Objectives: 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. Methods: 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. Measurements and Main Results: 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 LXB4 production in vivo and in vitro. Exogenous application of LXB4 reduced inflammation, pyroptosis, and mortality of mice after CLP. Conclusions: Genetic deficiency of NLRP3 promoted resolution of inflammation in polymicrobial sepsis by relieving caspase-7–dependent repression of LXB4 biosynthesis, and increased survival potentially via LXB4 production and inhibition of proinflammatory cytokines.

AB - Rationale: 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. Objectives: 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. Methods: 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. Measurements and Main Results: 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 LXB4 production in vivo and in vitro. Exogenous application of LXB4 reduced inflammation, pyroptosis, and mortality of mice after CLP. Conclusions: Genetic deficiency of NLRP3 promoted resolution of inflammation in polymicrobial sepsis by relieving caspase-7–dependent repression of LXB4 biosynthesis, and increased survival potentially via LXB4 production and inhibition of proinflammatory cytokines.

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