Nge model, suggesting convergent lethal pathways downstream of caspase-1 and caspase-11. Certainly, the COX-1 inhibitor SC-560 rescued poly(I:C) primed mice from LPS lethality (Fig. 4H). Although physiological activation of caspase-11 is advantageous in defense against cytosolic bacterial pathogens (four), its aberrant hyperactivation becomes detrimental throughout endotoxic shock. Our data suggest that when LPS reaches important concentrations for the duration of sepsis, aberrant LPS localization occurs, activating cytosolic surveillance pathways. Clinical sepsis is often a far more complicated pathophysiologic state, where several cytokines, eicosanoids, and other inflammatory mediators are likely to be hyperactivated. Eicosanoid mediators as well as other consequences of pyroptotic cellular lysis (21) needs to be thought of in future therapeutic choices made to treat Gram-negative septic shock. This underscores the concept that Gram-negative and Gram-positive sepsis may cause shock by way of divergent signaling pathways (22), and that therapy choices should really contemplate these as discreet clinical entities.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptSupplementary MaterialRefer to Net version on PubMed Central for supplementary material.AcknowledgmentsThe authors thank V. Dixit for sharing essential mouse strains (Casp11-/- and Nlrc4-/- Asc-/- mice had been supplied beneath an MTA agreement with Genentech). We also thank R. Flavell, M. Heise, and J. Brickey for sharing mice. We thank D. Mao, L. Zhou, and D. Trinh for managing mouse colonies.Imidazo[1,2-a]pyridine-8-carbaldehyde Purity The data presented in this manuscript are tabulated within the major paper and within the supplementary components. This operate was supported by NIH grants AI007273 (JAH), AI097518 (EAM), AI057141 (EAM), and AI101685 (RKE).References and Notes1. Von Moltke J, Ayres JS, Kofoed EM, Chavarr -Smith J, Vance RE. Recognition of bacteria by inflammasomes. Annu. Rev. Immunol. 2013; 31:73?06. [PubMed: 23215645] 2. Masters SL, et al. NLRP1 Inflammasome Activation Induces Pyroptosis of Hematopoietic Progenitor Cells. Immunity. 2012; 37:1009?023. [PubMed: 23219391] three. Kayagaki N, et al. Non-canonical inflammasome activation targets caspase-11. Nature. 2011; 479:117?21. [PubMed: 22002608] 4. Aachoui Y, et al. Caspase-11 Protects Against Bacteria That Escape the Vacuole. Science. 2013; 339:975?78. [PubMed: 23348507] five. Broz P, et al. Caspase-11 increases susceptibility to Salmonella infection within the absence of caspase-1. Nature. 2012; 490:288?91. [PubMed: 22895188] 6. Gurung P, et al. Toll or interleukin-1 receptor (TIR) domain-containing adaptor inducing interferon (TRIF)-mediated caspase-11 protease production integrates Toll-like receptor 4 (TLR4) proteinand Nlrp3 inflammasome-mediated host defense against enteropathogens.Buytert-Butyl 7-bromoheptanoate Journal of Biological Chemistry.PMID:23398362 2012; 287:34474?4483. [PubMed: 22898816]Science. Author manuscript; readily available in PMC 2014 September 13.Hagar et al.Page7. Rathinam VAK, et al. TRIF Licenses Caspase-11-Dependent NLRP3 Inflammasome Activation by Gram-Negative Bacteria. Cell. 2012; 150:606?19. [PubMed: 22819539] 8. Silipo A, Lanzetta R, Amoresano A, Parrilli M, Molinaro A. Ammonium hydroxide hydrolysis: a valuable help inside the MALDI-TOF mass spectrometry analysis of Lipid A fatty acid distribution. J. Lipid Res. 2002; 43:2188?195. [PubMed: 12454282] 9. Broz P, Von Moltke J, Jones JW, Vance RE, Monack DM. Differential requirement for Caspase-1 autoproteolysis in pathogen-induced cell death and cytokine processing. Cell Host Microbe. 2010.