von Moltke, J. et al. Rapid induction of inflammatory lipid mediators by the inflammasome in vivo. Nature 490, 107-111

Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California at Berkeley, Berkeley, California 94720, USA.
Nature (Impact Factor: 41.46). 08/2012; 490(7418):107-11. DOI: 10.1038/nature11351
Source: PubMed


Detection of microbial products by host inflammasomes is an important mechanism of innate immune surveillance. Inflammasomes activate the caspase-1 (CASP1) protease, which processes the cytokines interleukin (IL)-1β and IL-18, and initiates a lytic host cell death called pyroptosis. To identify novel CASP1 functions in vivo, we devised a strategy for cytosolic delivery of bacterial flagellin, a specific ligand for the NAIP5 (NLR family, apoptosis inhibitory protein 5)/NLRC4 (NLR family, CARD-domain-containing 4) inflammasome. Here we show that systemic inflammasome activation by flagellin leads to a loss of vascular fluid into the intestine and peritoneal cavity, resulting in rapid (less than 30 min) death in mice. This unexpected response depends on the inflammasome components NAIP5, NLRC4 and CASP1, but is independent of the production of IL-1β or IL-18. Instead, inflammasome activation results, within minutes, in an 'eicosanoid storm'--a pathological release of signalling lipids, including prostaglandins and leukotrienes, that rapidly initiate inflammation and vascular fluid loss. Mice deficient in cyclooxygenase-1, a critical enzyme in prostaglandin biosynthesis, are resistant to these rapid pathological effects of systemic inflammasome activation by either flagellin or anthrax lethal toxin. Inflammasome-dependent biosynthesis of eicosanoids is mediated by the activation of cytosolic phospholipase A(2) in resident peritoneal macrophages, which are specifically primed for the production of eicosanoids by high expression of eicosanoid biosynthetic enzymes. Our results therefore identify eicosanoids as a previously unrecognized cell-type-specific signalling output of the inflammasome with marked physiological consequences in vivo.

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    • "Nevertheless, upstream interference can be achieved by modulation of COX-1/2-dependent pathways, e.g. by aspirin in a murine model of myocardial infarction [20]. This is supported by findings in COX-1 knockout mice, which are protected against pathological effects of high concentrations of PGs that are released in response to inflammasome activation [14]. Pharmacological targeting of lipocalin-type PGD synthase, a powerful marker for coronary artery diseases in humans [21], might represent another indirect approach to impair PGD 2 levels. "

    International Journal of Cardiology 11/2014; 177(1):140–141. DOI:10.1016/j.ijcard.2014.09.111 · 4.04 Impact Factor
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    • "Recent data describe a range of effector functions mediated by NAIP/NLRC4 inflammasomes that operate independently of IL-1β, IL-18 and pyroptosis. The NAIP5/NLRC4 inflammasome has been implicated in the activation of phospholipase A2 (cPLA2) with a consequent production of lipid mediators, such as prostaglandins and leukotrienes (74). Authors demonstrated that systemic cytosolic flagellin stimulation leads to an “eicosanoid storm” that initiates inflammation and the loss of vascular fluids, resulting in a very fast death in mice. "
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    ABSTRACT: Neuronal apoptosis inhibitory protein (NAIP)/NOD-like receptor (NLR) containing a caspase activating and recruitment domain (CARD) 4 (NLRC4) inflammasome complexes are acti-vated in response to proteins from virulent bacteria that reach the cell cytosol. Specific NAIP proteins bind to the agonists and then physically associate with NLRC4 to form an inflammasome complex able to recruit and activate pro-caspase-1. NAIP5 and NAIP6 sense flagellin, component of flagella from motile bacteria, whereas NAIP1 and NAIP2 detect needle and rod components from bacterial type III secretion systems, respectively. Active caspase-1 mediates the maturation and secretion of the pro-inflammatory cytokines, IL-1β and IL-18, and is responsible for the induction of pyroptosis, a pro-inflammatory form of cell death. In addition to these well-known effector mechanisms, novel roles have been described for NAIP/NLRC4 inflammasomes, such as phagosomal maturation, activation of inducible nitric oxide synthase, regulation of autophagy, secretion of inflammatory media-tors, antibody production, activation of T cells, among others. These effector mechanisms mediated by NAIP/NLRC4 inflammasomes have been extensively studied in the context of resistance of infections and the potential of their agonists has been exploited in therapeutic strategies to non-infectious pathologies, such as tumor protection. Thus, this review will discuss current knowledge about the activation of NAIP/NLRC4 inflammasomes and their effector mechanisms.
    Frontiers in Immunology 07/2014; 5. DOI:10.3389/fimmu.2014.00309
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    • "The partial effectiveness of MMCs in their function to control L. monocytogenes and the alterations in their infiltration into the splenic WP after inflammasome activation implies that triggering the inflammasome may induce changes in the microenvironment that supersedes the established role of MMCs in bacterial containment and clearance. Recent reports show that activation of Nlrc4 results in an “eicosanoid storm” from activated macrophages [45]. Eicosanoids, which are crucial for the activation of inflammation, could have a positive effect on host defense by increasing local vascular permeability at the site of infection, allowing for the influx of immune cells, such as MMCs that can kill bacteria [45,46]. "
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    ABSTRACT: Activation of the Nlrc4 inflammasome results in the secretion of IL-1β and IL-18 through caspase-1 and induction of pyroptosis. L. monocytogenes engineered to activate Nlrc4 by expression of Legionella pneumophilia flagellin (L. monocytogenes L.p.FlaA) are less immunogenic for CD8(+) T cell responses than wt L. monocytogenes. It is also known that IL-1β orchestrates recruitment of myelomonocytic cells (MMC), which have been shown to interfere with T cell-dendritic cells (DC) interactions in splenic white pulp (WP), limiting T cell priming and protective immunity. We have further analyzed the role of MMCs in the immunogenicity of L. monocytogenes L.p.FlaA. We confirmed that MMCs infiltrate the WP between 24-48 hours in response to wt L. monocytogenes infection and that depletion of MMCs enhances CD8(+) T cell priming and protective memory. L. monocytogenes L.p.FlaA elicited accelerated recruitment of MMCs into the WP. While MMCs contribute to control of L. monocytogenes L.p.FlaA, MMC depletion did not increase immunogenicity of L.p.FlaA expressing strains. There was a significant decrease in L. monocytogenes L.p.FlaA in CD8α(+) DCs independent of MMCs. These findings suggest that limiting inflammasome activation is important for bacterial accumulation in CD8α(+) DCs, which are known to be critical for T cell response to L. monocytogenes.
    PLoS ONE 12/2013; 8(12):e83191. DOI:10.1371/journal.pone.0083191 · 3.23 Impact Factor
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