Editors' ChoiceImmunology

Inflammasomes and Eicosanoids

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Sci. Signal.  09 Oct 2012:
Vol. 5, Issue 245, pp. ec262
DOI: 10.1126/scisignal.2003674

Various microbial products in the cytosol of infected cells trigger the assembly and activation of inflammasomes, multiprotein complexes containing caspase-1, which is required for the processing and secretion of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. To identify other potential functions of caspase-1, von Moltke et al. engineered Legionella pneumophila flagellin fused to the Bacillus anthracis lethal factor (FlaTox), which could be delivered to the cytosol to activate an inflammasome containing the components NAIP5 and NLRC4. Administration of FlaTox to mice resulted in rapid death that was associated with hypothermia and fluid accumulation in the intestine and peritoneal cavity. Measurement of the percentage volume of blood containing red blood cells (the hematocrit) showed an increase in the concentration of red blood cells in response to FlaTox, indicating that the intestinal fluid resulted from vascular leakage of plasma. Lower doses of FlaTox induced increased hematocrit and triggered hypothermia, termed the early hematopoietic response (EHR), without killing the mice. Mice deficient in NAIP5, NLRC4, or caspase-1 were protected from the EHR in response to FlaTox; however, mice deficient in IL-1β or IL-18 were as sensitive as wild-type mice to FlaTox. Depletion of resident peritoneal macrophages, but not other immune cell types, protected mice from EHR. Analysis of supernatants of FlaTox-treated peritoneal macrophages showed that they secreted multiple eicosanoids, including prostaglandins and leukotrienes, and their secretion depended on the NAIP5/NLRC4 inflammasome and caspase-1. Treatment of macrophages with FlaTox resulted in Ca2+ influx and phosphorylation and activation of cytosolic phospholipase A2, which is required for eicosanoid biosynthesis. Mice deficient in cyclooxygenase 1 (COX1), another enzyme in the eicosanoid biosynthetic pathway, had an attenuated EHR in response to FlaTox compared with that in control mice. Together, these data expand the known signaling components induced by inflammasome activation. Future work should focus on the role of eicosanoids during systemic infections in vivo.

J. von Moltke, N. J. Trinidad, M. Moayeri, A. F. Kintzer, S. B. Wang, N. van Rooijen, C. R. Brown, B. A. Krantz, S. H. Leppla, K. Gronert, R. E. Vance, Rapid induction of inflammatory lipid mediators by the inflammasome in vivo. Nature 490, 107–111 (2012). [PubMed]