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Published on: May 21, 2018
NLRP3 Inflammasome Deficiency Protects against Microbial Sepsis via Increased Lipoxin B4 Synthesis
Seonmin Lee1,2, Kiichi Nakahira1,3, Jesmond Dalli4
11 Division of Pulmonary and Critical Care Medicine and.
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.
Insights
NLRP3 inflammasome deficiency enhances survival in sepsis by promoting the resolution of inflammation and increasing lipoxin B4 (LXB4) production. This suggests targeting NLRP3 could be a therapeutic strategy for sepsis.
Area of Science:
- Immunology
- Inflammation research
- Sepsis pathophysiology
Background:
- Sepsis is a life-threatening condition characterized by organ dysfunction due to a dysregulated host response to infection.
- Excessive inflammation during sepsis can lead to tissue damage and organ failure, despite its role in host defense.
- Resolution of inflammation, mediated by lipid mediators (LMs), is crucial for restoring homeostasis.
Purpose of the Study:
- To investigate the role of the nucleotide-binding domain, leucine-rich repeat-containing receptor, pyrin domain-containing-3 (NLRP3) inflammasome in polymicrobial sepsis.
- To determine how NLRP3 inflammasome activation affects the biosynthesis of lipid mediators (LMs).
- To explore the therapeutic potential of modulating NLRP3 inflammasome activity and LM production in sepsis.
Main Methods:
- Cecal ligation and puncture (CLP) model in mice lacking NLRP3 inflammasome-associated molecules to assess mortality and inflammation.
- Analysis of inflammatory markers in plasma and lavage fluids.
- Mass spectrometry-based metabololipidomics to quantify local LMs in peritoneal lavage fluid.
Main Results:
- Genetic deficiency of NLRP3 inflammasome components significantly improved survival in CLP-induced sepsis.
- NLRP3 deficiency reduced proinflammatory LMs and increased proresolving lipoxin B4 (LXB4) levels.
- NLRP3 activation led to pyroptosis via caspase-7; caspase-7 deficiency mimicked NLRP3 deficiency effects, and exogenous LXB4 reduced sepsis mortality.
Conclusions:
- NLRP3 inflammasome deficiency promotes inflammation resolution in polymicrobial sepsis by enhancing LXB4 biosynthesis through a caspase-7-dependent pathway.
- Increased LXB4 production and reduced proinflammatory cytokines contribute to the enhanced survival observed in NLRP3-deficient septic mice.
- Targeting the NLRP3 inflammasome and modulating LXB4 biosynthesis represent promising therapeutic strategies for sepsis management.
