Rmia (Fig. 4F), seizures, peritoneal fluid accumulation, and sometimes intestinal hemorrhage. In contrast, poly(I:C) primed Casp11-/- mice were extra resistant to secondary LPS challenge (Fig. 4G), demonstrating the consequences of aberrant caspase-11 activation. Collectively, our data indicate that activation of caspase-11 by LPS in vivo can lead to fast onset of endotoxic shock independent of TLR4. Mice challenged with the canonical NLRC4 agonist flagellin coupled to the cytosolic translocation domain of anthrax lethal toxin also expertise a fast onset of shock (20). Within this model, NLRC4-dependent caspase-1 activation triggers lethal eicosanoid production by means of COX-1 with similar kinetics to our prime-challenge model, suggesting convergent lethal pathways downstream of caspase-1 and caspase-11. Indeed, the COX-1 inhibitor SC-560 rescued poly(I:C) primed mice from LPS lethality (Fig. 4H). Even though physiological activation of caspase-11 is useful in defense against cytosolic bacterial pathogens (4), its aberrant hyperactivation becomes detrimental GHSR medchemexpress through endotoxic shock. Our data recommend that when LPS reaches critical concentrations throughout sepsis, aberrant LPS localization happens, activating cytosolic surveillance pathways. Clinical sepsis is often a far more complex pathophysiologic state, where multiple cytokines, eicosanoids, and other inflammatory mediators are likely to become hyperactivated. Eicosanoid mediators and other consequences of pyroptotic cellular lysis (21) should be deemed in future therapeutic solutions made to treat Gram-negative septic shock. This underscores the concept that Gram-negative and Gram-positive sepsis may cause shock by means of divergent signaling pathways (22), and that therapy options need to take into account these as discreet clinical entities.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptSupplementary MaterialRefer to Web version on ALDH2 drug PubMed Central for supplementary material.AcknowledgmentsThe authors thank V. Dixit for sharing essential mouse strains (Casp11-/- and Nlrc4-/- Asc-/- mice had been provided under 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. The data presented in this manuscript are tabulated in the main paper and inside the supplementary components. This function 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; 31:7306. [PubMed: 23215645] two. Masters SL, et al. NLRP1 Inflammasome Activation Induces Pyroptosis of Hematopoietic Progenitor Cells. Immunity. 2012; 37:1009023. [PubMed: 23219391] three. Kayagaki N, et al. Non-canonical inflammasome activation targets caspase-11. Nature. 2011; 479:11721. [PubMed: 22002608] 4. Aachoui Y, et al. Caspase-11 Protects Against Bacteria That Escape the Vacuole. Science. 2013; 339:97578. [PubMed: 23348507] five. Broz P, et al. Caspase-11 increases susceptibility to Salmonella infection within the absence of caspase-1. Nature. 2012; 490:28891. [PubMed: 22895188] six. 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. Journal of Biological Chem.