Monitoring of the cytosolic compartment by the innate immune system for pathogen-encoded products or pathogen activities often enables the activation of a subset of caspases. In most cases, the cytosolic surveillance pathways are coupled to activation of caspase-1 via canonical inflammasome complexes. A related set of caspases, caspase-11 in rodents and caspase-4 and caspase-5 in humans, monitors the cytosol for bacterial lipopolysaccharide (LPS). Direct activation of caspase-11, caspase-4 and caspase-5 by intracellular LPS elicits the lytic cell death called ‘pyroptosis’, which occurs in multiple cell types. The pyroptosis is executed by the pore-forming protein GSDMD, which is activated by cleavage mediated by caspase-11, caspase-4 or caspase-5. In monocytes, formation of GSDMD pores can induce activation of the NLRP3 inflammasome for maturation of the cytokines IL-1β and IL-18. Caspase-11-mediated pyroptosis in response to cytosolic LPS is critical for antibacterial defense and septic shock. Here we review the emerging literature on the sensing of cytosolic LPS and its regulation and pathophysiological functions.
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Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).
Pandey, S., Kawai, T. & Akira, S. Microbial sensing by Toll-like receptors and intracellular nucleic acid sensors. Cold Spring Harb. Perspect. Biol. 7, a016246 (2014).
Man, S. M., Karki, R. & Kanneganti, T. D. Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol. Rev. 277, 61–75 (2017).
Friedlander, A. M. Macrophages are sensitive to anthrax lethal toxin through an acid-dependent process. J. Biol. Chem. 261, 7123–7126 (1986).
Zychlinsky, A., Prevost, M. C. & Sansonetti, P. J. Shigella flexneri induces apoptosis in infected macrophages. Nature 358, 167–169 (1992).
Fink, S. L., Bergsbaken, T. & Cookson, B. T. Anthrax lethal toxin and Salmonella elicit the common cell death pathway of caspase-1-dependent pyroptosis via distinct mechanisms. Proc. Natl Acad. Sci. USA 105, 4312–4317 (2008).
Martinon, F., Burns, K. & Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol. Cell 10, 417–426 (2002).
Zhao, Y. & Shao, F. Diverse mechanisms for inflammasome sensing of cytosolic bacteria and bacterial virulence. Curr. Opin. Microbiol. 29, 37–42 (2016).
Broz, P. & Dixit, V. M. Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16, 407–420 (2016).
Raetz, C. R. & Whitfield, C. Lipopolysaccharide endotoxins. Annu. Rev. Biochem. 71, 635–700 (2002).
Park, B. S. et al. The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature 458, 1191–1195 (2009).
Li, P. et al. Mice deficient in IL-1β-converting enzyme are defective in production of mature IL-1β and resistant to endotoxic shock. Cell 80, 401–411 (1995).
Wang, S. et al. Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. Cell 92, 501–509 (1998).
Kayagaki, N. et al. Non-canonical inflammasome activation targets caspase-11. Nature 479, 117–121 (2011).
Kang, S. J. et al. Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions. J. Cell Biol. 149, 613–622 (2000).
Hagar, J. A., Powell, D. A., Aachoui, Y., Ernst, R. K. & Miao, E. A. Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science 341, 1250–1253 (2013).
Kayagaki, N. et al. Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science 341, 1246–1249 (2013).
Perkins, C., Kim, C. N., Fang, G. & Bhalla, K. N. Overexpression of Apaf-1 promotes apoptosis of untreated and paclitaxel- or etoposide-treated HL-60 cells. Cancer Res. 58, 4561–4566 (1998).
Srinivasula, S. M. et al. The PYRIN-CARD protein ASC is an activating adaptor for caspase-1. J. Biol. Chem. 277, 21119–21122 (2002).
Shi, J. et al. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 514, 187–192 (2014).
Kayagaki, N. et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526, 666–671 (2015).
Shi, J. et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526, 660–665 (2015).
Napier, B. A. et al. Complement pathway amplifies caspase-11-dependent cell death and endotoxin-induced sepsis severity. J. Exp. Med. 213, 2365–2382 (2016).
Akhter, A. et al. Caspase-11 promotes the fusion of phagosomes harboring pathogenic bacteria with lysosomes by modulating actin polymerization. Immunity 37, 35–47 (2012).
Broz, P. et al. Caspase-11 increases susceptibility to Salmonella infection in the absence of caspase-1. Nature 490, 288–291 (2012).
Gurung, P. et al. Toll or interleukin-1 receptor (TIR) domain-containing adaptor inducing interferon-β (TRIF)-mediated caspase-11 protease production integrates Toll-like receptor 4 (TLR4) protein- and Nlrp3 inflammasome-mediated host defense against enteropathogens. J. Biol. Chem. 287, 34474–34483 (2012).
Rathinam, V. A. et al. TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by gram-negative bacteria. Cell 150, 606–619 (2012).
Aachoui, Y. et al. Caspase-11 protects against bacteria that escape the vacuole. Science 339, 975–978 (2013).
Case, C. L. et al. Caspase-11 stimulates rapid flagellin-independent pyroptosis in response to Legionella pneumophila. Proc. Natl Acad. Sci. USA 110, 1851–1856 (2013).
Lagrange, B. et al. Human caspase-4 detects tetra-acylated LPS and cytosolic Francisella and functions differently from murine caspase-11. Nat. Commun. 9, 242 (2018).
Shi, J., Gao, W. & Shao, F. Pyroptosis: gasdermin-mediated programmed necrotic cell death. Trends Biochem. Sci. 42, 245–254 (2017).
Saeki, N. & Sasaki, H. Gasdermin Superfamily: A Novel Gene Family Functioning in Epithelial Cells. in Endothelium and Epithelium: Composition, Functions, And Pathology (eds. Carrasco, J. & Matheus, M.) 193–211 (Nova Science Publishers, Hauppauge, NY, 2011).
Aglietti, R. A. et al. GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes. Proc. Natl Acad. Sci. USA 113, 7858–7863 (2016).
Ding, J. et al. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535, 111–116 (2016).
Liu, X. et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535, 153–158 (2016).
Sborgi, L. et al. GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. EMBO J. 35, 1766–1778 (2016).
Wang, Y. et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 547, 99–103 (2017).
Kuang, S. et al. Structure insight of GSDMD reveals the basis of GSDMD autoinhibition in cell pyroptosis. Proc. Natl Acad. Sci. USA 114, 10642–10647 (2017).
Liu, Z. et al. Structures of the gasdermin D C-terminal domains reveal mechanisms of autoinhibition. Structure 26, 778–784.e3 (2018).
Platnich, J. M. et al. Shiga toxin/lipopolysaccharide activates caspase-4 and gasdermin D to trigger mitochondrial reactive oxygen species upstream of the NLRP3 inflammasome. Cell Rep. 25, 1525–1536.e7 (2018).
Ruan, J., Xia, S., Liu, X., Lieberman, J. & Wu, H. Cryo-EM structure of the gasdermin A3 membrane pore. Nature 557, 62–67 (2018).
Mulvihill, E. et al. Mechanism of membrane pore formation by human gasdermin-D. EMBO J. 37, e98321 (2018).
He, W. T. et al. Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion. Cell Res. 25, 1285–1298 (2015).
Evavold, C. L. et al. The pore-forming protein gasdermin D regulates interleukin-1 secretion from living macrophages. Immunity 48, 35–44.e6 (2018).
Heilig, R. et al. The gasdermin-D pore acts as a conduit for IL-1β secretion in mice. Eur. J. Immunol. 48, 584–592 (2018).
Kanneganti, A. et al. GSDMD is critical for autoinflammatory pathology in a mouse model of familial Mediterranean fever. J. Exp. Med. 215, 1519–1529 (2018).
Xiao, J. et al. Gasdermin D mediates the pathogenesis of neonatal-onset multisystem inflammatory disease in mice. PLoS Biol. 16, e3000047 (2018).
Knodler, L. A. et al. Noncanonical inflammasome activation of caspase-4/caspase-11 mediates epithelial defenses against enteric bacterial pathogens. Cell Host Microbe 16, 249–256 (2014).
Pallett, M. A. et al. Bacterial virulence factor inhibits caspase-4/11 activation in intestinal epithelial cells. Mucosal Immunol. 10, 602–612 (2017).
Wang, J. et al. Caspase-11-dependent pyroptosis of lung epithelial cells protects from melioidosis while caspase-1 mediates macrophage pyroptosis and production of IL-18. PLoS Pathog. 14, e1007105 (2018).
Rühl, S. & Broz, P. Caspase-11 activates a canonical NLRP3 inflammasome by promoting K+ efflux. Eur. J. Immunol. 45, 2927–2936 (2015).
Russo, A. J., Behl, B., Banerjee, I. & Rathinam, V. A. K. Emerging insights into noncanonical inflammasome recognition of microbes. J. Mol. Biol. 430, 207–216 (2018).
Aachoui, Y. et al. Canonical inflammasomes drive IFN-γ to prime caspase-11 in defense against a cytosol-invasive bacterium. Cell Host Microbe 18, 320–332 (2015).
Wang, J. et al. Caspase-11 deficiency impairs neutrophil recruitment and bacterial clearance in the early stage of pulmonary Klebsiella pneumoniae infection. Int. J. Med. Microbiol. 307, 490–496 (2017).
Wang, W. et al. Caspase-11 plays a protective role in pulmonary Acinetobacter baumannii infection. Infect. Immun. 85, e00350–17 (2017).
Jorgensen, I., Zhang, Y., Krantz, B. A. & Miao, E. A. Pyroptosis triggers pore-induced intracellular traps (PITs) that capture bacteria and lead to their clearance by efferocytosis. J. Exp. Med. 213, 2113–2128 (2016).
Chen, K. W. et al. Noncanonical inflammasome signaling elicits gasdermin D-dependent neutrophil extracellular traps. Sci. Immunol. 3, eaar6676 (2018).
Cheng, K. T. et al. Caspase-11-mediated endothelial pyroptosis underlies endotoxemia-induced lung injury. J. Clin. Invest. 127, 4124–4135 (2017).
Mandal, P. et al. Caspase-8 collaborates with caspase-11 to drive tissue damage and execution of endotoxic shock. Immunity 49, 42–55.e6 (2018).
Opal, S. M. et al. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. J. Am. Med. Assoc. 309, 1154–1162 (2013).
Lin, X. Y., Choi, M. S. & Porter, A. G. Expression analysis of the human caspase-1 subfamily reveals specific regulation of the CASP5 gene by lipopolysaccharide and interferon-γ. J. Biol. Chem. 275, 39920–39926 (2000).
Vanaja, S. K. et al. Bacterial outer membrane vesicles mediate cytosolic localization of LPS and caspase-11 activation. Cell 165, 1106–1119 (2016).
Kulp, A. & Kuehn, M. J. Biological functions and biogenesis of secreted bacterial outer membrane vesicles. Annu. Rev. Microbiol. 64, 163–184 (2010).
Kaparakis-Liaskos, M. & Ferrero, R. L. Immune modulation by bacterial outer membrane vesicles. Nat. Rev. Immunol. 15, 375–387 (2015).
Chen, S. et al. Dysregulated hemolysin liberates bacterial outer membrane vesicles for cytosolic lipopolysaccharide sensing. PLoS Pathog. 14, e1007240 (2018).
Wacker, M. A., Teghanemt, A., Weiss, J. P. & Barker, J. H. High-affinity caspase-4 binding to LPS presented as high molecular mass aggregates or in outer membrane vesicles. Innate Immun. 23, 336–344 (2017).
Finethy, R. et al. Inflammasome activation by bacterial outer membrane vesicles requires guanylate binding proteins. MBio 8, e01188–17 (2017).
Santos, J. C. et al. LPS targets host guanylate-binding proteins to the bacterial outer membrane for non-canonical inflammasome activation. EMBO J. 37, e98089 (2018).
Bitto, N. J. et al. Membrane vesicles from Pseudomonas aeruginosa activate the noncanonical inflammasome through caspase-5 in human monocytes. Immunol. Cell Biol. 96, 1120–1130 (2018).
Gu, L. et al. Toll-like receptor 4 signaling licenses the cytosolic transport of lipopolysaccharide from bacterial outer membrane vesicles. Shock 51, 256–265 (2019).
Cecil, J. D. et al. Outer membrane vesicles prime and activate macrophage inflammasomes and cytokine secretion in vitro and in vivo. Front. Immunol. 8, 1017 (2017).
Kim, B. H. et al. Interferon-induced guanylate-binding proteins in inflammasome activation and host defense. Nat. Immunol. 17, 481–489 (2016).
Kim, B. H. et al. A family of IFN-γ-inducible 65-kD GTPases protects against bacterial infection. Science 332, 717–721 (2011).
Yamamoto, M. et al. A cluster of interferon-γ-inducible p65 GTPases plays a critical role in host defense against Toxoplasma gondii. Immunity 37, 302–313 (2012).
Wandel, M. P. et al. GBPs inhibit motility of Shigella flexneri but are targeted for degradation by the bacterial ubiquitin ligase IpaH9.8. Cell Host Microbe 22, 507–518.e5 (2017).
Li, P. et al. Ubiquitination and degradation of GBPs by a Shigella effector to suppress host defence. Nature 551, 378–383 (2017).
Pilla-Moffett, D., Barber, M. F., Taylor, G. A. & Coers, J. Interferon-inducible GTPases in host resistance, inflammation and disease. J. Mol. Biol. 428, 3495–3513 (2016).
Meunier, E. et al. Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases. Nature 509, 366–370 (2014).
Pilla, D. M. et al. Guanylate binding proteins promote caspase-11-dependent pyroptosis in response to cytoplasmic LPS. Proc. Natl Acad. Sci. USA 111, 6046–6051 (2014).
Meunier, E. et al. Guanylate-binding proteins promote activation of the AIM2 inflammasome during infection with Francisella novicida. Nat. Immunol. 16, 476–484 (2015).
Man, S. M. et al. The transcription factor IRF1 and guanylate-binding proteins target activation of the AIM2 inflammasome by Francisella infection. Nat. Immunol. 16, 467–475 (2015).
Man, S. M. et al. IRGB10 liberates bacterial ligands for sensing by the AIM2 and caspase-11-NLRP3 inflammasomes. Cell 167, 382–396.e17 (2016).
Deng, M. et al. The endotoxin delivery protein HMGB1 mediates caspase-11-dependent lethality in sepsis. Immunity 49, 740–753.e7 (2018).
Lamkanfi, M. et al. Inflammasome-dependent release of the alarmin HMGB1 in endotoxemia. J. Immunol. 185, 4385–4392 (2010).
Yanai, H. et al. Conditional ablation of HMGB1 in mice reveals its protective function against endotoxemia and bacterial infection. Proc. Natl Acad. Sci. USA 110, 20699–20704 (2013).
Yokoyama, S. et al. A novel pathway of LPS uptake through syndecan-1 leading to pyroptotic cell death. eLife 7, e37854 (2018).
Kang, R. et al. Lipid peroxidation drives gasdermin D-mediated pyroptosis in lethal polymicrobial sepsis. Cell Host Microbe 24, 97–108 e4 (2018).
Russo, A. J. & Rathinam, V. A. K. Lipid peroxidation adds fuel to pyr(optosis). Cell Host Microbe 24, 8–9 (2018).
Chu, L. H. et al. The oxidized phospholipid oxPAPC protects from septic shock by targeting the non-canonical inflammasome in macrophages. Nat. Commun. 9, 996 (2018).
Zanoni, I. et al. An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells. Science 352, 1232–1236 (2016).
Li, W. et al. Stearoyl lysophosphatidylcholine inhibits endotoxin-induced caspase-11 activation. Shock 50, 339–345 (2018).
Rühl, S. et al. ESCRT-dependent membrane repair negatively regulates pyroptosis downstream of GSDMD activation. Science 362, 956–960 (2018).
Kobayashi, T. et al. The Shigella OspC3 effector inhibits caspase-4, antagonizes inflammatory cell death, and promotes epithelial infection. Cell Host Microbe 13, 570–583 (2013).
Zhou, P. et al. Alpha-kinase 1 is a cytosolic innate immune receptor for bacterial ADP-heptose. Nature 561, 122–126 (2018).
We thank J. Snyder for editing the manuscript. Research in the Shao laboratory is supported by the Basic Science Center Project of the National Natural Science Foundation of China (81788101) and National Key Research and Development Program of China (2016YFA0501500 and 2017YFA0505900). Research in the Rathinam laboratory is supported by the US National Institutes of Health (R01AI119015 and R21AI 135528).