NLRP3 Inflammasome Deficiency Protects against Microbial Sepsis via Increased Lipoxin B 4 Synthesis

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 inflammat...

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Published inAmerican journal of respiratory and critical care medicine Vol. 196; no. 6; pp. 713 - 726
Main Authors 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
Format Journal Article
LanguageEnglish
Published United States 15.09.2017
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Summary: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 B (LXB ) 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 LXB production in vivo and in vitro. Exogenous application of LXB reduced 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 LXB biosynthesis, and increased survival potentially via LXB production and inhibition of proinflammatory cytokines.
ISSN:1073-449X
1535-4970
DOI:10.1164/rccm.201604-0892OC