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Rapid induction of inflammatory lipid mediators by the inflammasome in vivo

Nature volume 490, pages 107–111 (2012)Cite this article

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Abstract

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 pyroptosis1. 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) inflammasome2,3,4. 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 A2 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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Figure 1: Systemic cytosolic delivery of flagellin in vivo induces NAIP5/NLRC4-dependent but IL-1β and IL-18-independent vascular leakage.
Figure 2: Resident peritoneal macrophages are critical for the early FlaTox response in vivo.
Figure 3: Inflammasome-dependent eicosanoid biosynthesis.
Figure 4: Mechanism and in vivo role of eicosanoid production.

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Acknowledgements

We thank S. Mariathasan and V. Dixit for Nlrc4−/− mice; I. Bergin and S. Griffey for pathology reports; D. Crown for help with survival experiments; L. Lopez for support in our animal facility; D. Bautista and R. Nichols for help with calcium imaging; and M. Fontana and members of the Barton and Vance laboratories for discussions. Work in R.E.V.’s laboratory is supported by Investigator Awards from the Burroughs Wellcome Fund and the Cancer Research Institute and by National Institutes of Health (NIH) grants AI075039, AI080749 and AI063302. K.G.’s laboratory is supported by NIH grants EY016136 and EY022208. J.v.M. is supported by a grant from the Cancer Research Coordinating Committee of the University of California.

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Authors and Affiliations

  1. Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California at Berkeley, Berkeley, 94720, California, USA

    Jakob von Moltke, Norver J. Trinidad & Russell E. Vance

  2. Department of Chemistry, University of California at Berkeley, Berkeley, 94720, California, USA

    Alexander F. Kintzer & Bryan A. Krantz

  3. Vision Science Program, School of Optometry, University of California at Berkeley, Berkeley, 94720, California, USA

    Samantha B. Wang & Karsten Gronert

  4. Laboratory of Parasitic Diseases, Microbial Pathogenesis Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Mahtab Moayeri & Stephen H. Leppla

  5. Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, Amsterdam, 1081 BT, The Netherlands

    Nico van Rooijen

  6. Department of Veterinary Pathobiology, University of Missouri, Columbia, 65211, Missouri, USA

    Charles R. Brown

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  1. Jakob von Moltke
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Contributions

J.v.M. and R.E.V. conceived the study. J.v.M., R.E.V. and K.G. designed the experiments and wrote the paper. J.v.M. performed the experiments with help from N.J.T. M.M. performed experiments shown in Fig. 1a and Supplementary Fig. 1f. J.v.M., N.J.T., M.M., S.B.W., K.G. and R.E.V. analysed the results. A.F.K., B.A.K., C.R.B., S.H.L. and N.v.R. provided mice and/or reagents.

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Correspondence to Karsten Gronert or Russell E. Vance.

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von Moltke, J., Trinidad, N., Moayeri, M. et al. Rapid induction of inflammatory lipid mediators by the inflammasome in vivo. Nature 490, 107–111 (2012). https://doi.org/10.1038/nature11351

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