Bacterial Outer Membrane Vesicles Mediate Cytosolic Localization of LPS and Caspase-11 Activation

Vanaja, Sivapriya Kailasan; Russo, Ashley J.; Behl, Bharat; Banerjee, Ishita; Yankova, Maya; Deshmukh, S. D.; Rathinam, Vijay

doi:10.1016/j.cell.2016.04.015

Cited by 521 publications

(562 citation statements)

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“…Studies of cytoplasmic LPS signaling have used LPS encapsulated by transfection reagents such as lipofectamine to mimic plasma membrane breaching by LPS in the setting of endotoxemia (10,12,22). Further, delivery of LPS packaged within bacterial microvesicles, which fuse with the plasma membrane without causing breach, resulted in intracellular LPS release and also activated inflammatory caspase signaling and pyroptosis (23,24).…”

Section: Introductionmentioning

confidence: 99%

Caspase-11–mediated endothelial pyroptosis underlies endotoxemia-induced lung injury

Cheng¹,

Xiong²,

Ye³

et al. 2017

Journal of Clinical Investigation

324

348

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Acute lung injury is a leading cause of death in bacterial sepsis due to the wholesale destruction of the lung endothelial barrier, which results in protein-rich lung edema, influx of proinflammatory leukocytes, and intractable hypoxemia. Pyroptosis is a form of programmed lytic cell death that is triggered by inflammatory caspases, but little is known about its role in EC death and acute lung injury. Here, we show that systemic exposure to the bacterial endotoxin lipopolysaccharide (LPS) causes severe endothelial pyroptosis that is mediated by the inflammatory caspases, human caspases 4/5 in human ECs, or the murine homolog caspase-11 in mice in vivo. In caspase-11-deficient mice, BM transplantation with WT hematopoietic cells did not abrogate endotoxemia-induced acute lung injury, indicating a central role for nonhematopoietic caspase-11 in endotoxemia. Additionally, conditional deletion of caspase-11 in ECs reduced endotoxemia-induced lung edema, neutrophil accumulation, and death. These results establish the requisite role of endothelial pyroptosis in endotoxemic tissue injury and suggest that endothelial inflammatory caspases are an important therapeutic target for acute lung injury.Caspase-11-mediated endothelial pyroptosis underlies endotoxemia-induced lung injury The Journal of Clinical Investigation R E S E A R C H A R T I C L E4 1 2 5 jci.org Volume 127 Number 11 November 2017the complex process of inflammation involves multiple programmed cell death pathways, depending on the type and magnitude of the inciting stimulus and cell type. From an evolutionary perspective, pyroptosis of cells harboring intracellular bacteria or in which LPS has breached the plasma membrane is an effective means of eliminating an intracellular bacterial niche and activating the host through release of inflammatory mediators such as IL-1β, while sparing uninfected neighboring cells (13,(28)(29)(30). Thus, pyroptosis induced by inflammatory caspases 1/4/5/11 is an innate immune response distinct from the canonical inflammasome activation pathway via cell-surface TLR4 (11,(31)(32)(33)(34). However, caspase-11 can also be immunopathologic in sepsis (35). Caspase-11-deficient mice were protected in endotoxemic shock (10,11), suggesting that in the setting of an overwhelming inflammatory response, the potentially protective pyroptotic mechanism activates an exaggerated pathologic response due to overwhelming cell lysis. The role of the inflammatory caspases 4/5/11 in mediating cytoplasmic LPS signaling and pyroptosis has until now been primarily studied in macrophages or dendritic cells (11,12,14,28,32,36). Their role in destroying the endothelial barrier through widespread endothelial death and pathogenesis of ALI remains unknown. Here, we tested the hypothesis that lung ECs are a primary target for pyroptosis via intracellular sensing of LPS by the inflammatory caspases 4/5/11 and that endothelial pyroptosis is required for the induction of ALI. Results LPS in ECs induces pyroptotic cell death via activation of inflammatory cas...

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Section: Introductionmentioning

confidence: 99%

Caspase-11–mediated endothelial pyroptosis underlies endotoxemia-induced lung injury

Cheng¹,

Xiong²,

Ye³

et al. 2017

Journal of Clinical Investigation

324

348

View full text Add to dashboard Cite

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“…During bacterial infections, LPS accesses the cytosol through membrane damage inflicted in the host cells by virulence-associated secretion systems or pore-forming toxins [45]. However, outer membrane vesicles derived from non-pathogenic bacteria can also induce caspase-11 dependent responses [52], and injection of free LPS into mice induces caspase-11 dependent responses [53]. Under these conditions, where no virulent bacteria are present, we have minimal understanding of how LPS gains access to the cytosol.…”

Section: Lps Detection In Mammals: Diverse Pathways Are Coordinated Bmentioning

confidence: 99%

Lipopolysaccharide Detection across the Kingdoms of Life

Kagan

2017

Trends in Immunology

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Studies in recent years have uncovered a diverse set of eukaryotic receptors that recognize lipopolysaccharide (LPS), the major outer-membrane component of gram-negative bacteria. Indeed, Toll-like Receptors, G-protein coupled receptors, Integrins, Receptor-like kinases, and caspases have emerged as important LPS-interacting proteins. In this Review, the mammalian receptors that detect LPS are described. I highlight how no host protein is involved in all LPS responses, but a single lipid (phosphatidylinositol 4,5-bisphosphate) regulates many LPS responses, including endocytosis, phagocytosis, inflammation and pyroptosis. I further describe LPS response systems that operate specifically in plants, and discuss potentially new LPS response systems that await discovery. This diversity of receptors for a single microbial product underscores the importance of host-microbe interactions in multiple kingdoms of life.

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“…Caspase-11-dependent cleavage of GSDMD and subsequent pore formation also triggers activation of the canonical NLRP3 inflammasome by inducing potassium efflux (22)(23)(24). Caspase-11 activation can also be triggered by endocytosis of Gram-negative bacterial outer membrane vesicles (25), the activity of type III and type IV secretion systems of Gram-negative pathogens like Legionella and Yersinia (26,27), or disruption of bacterial cell-containing vacuolar compartments by members of the interferon (IFN)-inducible GTPases known as guanylate binding proteins (GBPs) (28)(29)(30)(31)(32).…”

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confidence: 99%

Guanylate Binding Proteins Regulate Inflammasome Activation in Response to Hyperinjected Yersinia Translocon Components

et al. 2017

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Gram-negative bacterial pathogens utilize virulence-associated secretion systems to inject, or translocate, effector proteins into host cells to manipulate cellular processes and promote bacterial replication. However, translocated bacterial products are sensed by nucleotide binding domain and leucine-rich repeat-containing proteins (NLRs), which trigger the formation of a multiprotein complex called the inflammasome, leading to secretion of interleukin-1 (IL-1) family cytokines, pyroptosis, and control of pathogen replication. Pathogenic Yersinia bacteria inject effector proteins termed Yops, as well as pore-forming proteins that comprise the translocon itself, into target cells. The Yersinia translocation regulatory protein YopK promotes bacterial virulence by limiting hyperinjection of the translocon proteins YopD and YopB into cells, thereby limiting cellular detection of Yersinia virulence activity. How hyperinjection of translocon proteins leads to inflammasome activation is currently unknown. We found that translocated YopB and YopD colocalized with the late endosomal/lysosomal protein LAMP1 and that the frequency of YopD and LAMP1 association correlated with the level of caspase-1 activation in individual cells. We also observed colocalization between YopD and Galectin-3, an indicator of endosomal membrane damage. Intriguingly, YopK limited the colocalization of Galectin-3 with YopD, suggesting that YopK limits the induction or sensing of endosomal membrane damage by components of the type III secretion system (T3SS) translocon. Furthermore, guanylate binding proteins (GBPs) encoded on chromosome 3 (Gbp Chr3 ), which respond to pathogen-induced damage or alteration of host membranes, were necessary for inflammasome activation in response to hyperinjected YopB/-D. Our findings indicate that lysosomal damage by Yersinia translocon proteins promotes inflammasome activation and implicate GBPs as key regulators of this process.

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Bacterial Outer Membrane Vesicles Mediate Cytosolic Localization of LPS and Caspase-11 Activation

Cited by 521 publications

References 45 publications

Caspase-11–mediated endothelial pyroptosis underlies endotoxemia-induced lung injury

Caspase-11–mediated endothelial pyroptosis underlies endotoxemia-induced lung injury

Lipopolysaccharide Detection across the Kingdoms of Life

Guanylate Binding Proteins Regulate Inflammasome Activation in Response to Hyperinjected Yersinia Translocon Components

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