Differential Regulation of Caspase-1 Activation, Pyroptosis, and Autophagy via Ipaf and ASC in Shigella-Infected Macrophages

Division of Bacterial Pathogenesis, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
PLoS Pathogens (Impact Factor: 7.56). 09/2007; 3(8):e111. DOI: 10.1371/journal.ppat.0030111
Source: PubMed


Author Summary

Shigella are bacterial pathogens that are the cause of bacillary dysentery known as shigellosis. A crucial aspect of the propensity of Shigella to cause diseases lies in its ability to invade the cytoplasm of epithelial cells as well as macrophages. The bacterial invasion of macrophages induces pyroptosis, the proinflammatory cell death associated with caspase-1 activation. Activated caspase-1 then cleaves and activates prointerleukin (proIL)-1β and proIL-18, which are proinflammatory cytokines involved in host inflammatory responses. However, the precise mechanisms of caspase-1 activation induced by Shigella infection remain poorly understood. Ipaf, a cytosolic pattern-recognition receptor of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family, is a crucial host factor that activates caspase-1 through the sensing of flagellin produced by some bacteria, such as Salmonella or Legionella. We discovered that Ipaf and the adaptor protein ASC are required for caspase-1 activation induced by non-flagellated Shigella infection. Thus, Ipaf and ASC mediate caspase-1 activation by sensing an unknown bacterial factor, but not flagellin. Autophagy, a cellular system for eliminating intracellular pathogens, was dramatically enhanced in Shigella-infected macrophages by the absence of caspase-1 or Ipaf, but not ASC. The inhibition of autophagy promoted Shigella-induced cell death, suggesting that autophagy protects infected macrophages from pyroptosis. This study provides evidence that in Shigella-infected macrophages, autophagy is inhibited by Ipaf and caspase-1, but positively regulated by ASC, providing a novel function for NLR proteins in bacterial–host interactions.

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Available from: Naohiro Inohara, Jul 09, 2014
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    • "Gram-positive bacteria like Listeria can trigger the NLRsinduced inflammasome activation by secreting pore-forming proteins leading to leakage of phagolysosomal constituents such as cathepsins into the cytosol that are then recognized by NLRP3 (Meixenberger et al, 2010). Gram-negative bacteria such as Salmonella (Mariathasan et al, 2004) or Shigella (Suzuki et al, 2007) use type III secretion systems for cytosolic delivery of flagellin that is detected by NLRC4 (Franchi et al, 2009). Furthermore, the DNA-recognizing PRR Aim2 is reported to sense DNA of several intracellular bacteria, such as Listeria monocytogenes (Fernandes- Alnemri et al, 2009) and Legionella pneumonia (Ge et al, 2012). "
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    ABSTRACT: Macrophages detect bacterial infection through pattern recognition receptors (PRRs) localized at the cell surface, in intracellular vesicles or in the cytosol. Discrimination of viable and virulent bacteria from non-virulent bacteria (dead or viable) is necessary to appropriately scale the anti-bacterial immune response. Such scaling of anti-bacterial immunity is necessary to control the infection, but also to avoid immunopathology or bacterial persistence. PRR-mediated detection of bacterial constituents in the cytosol rather than at the cell surface along with cytosolic recognition of secreted bacterial nucleic acids indicates viability and virulence of infecting bacteria. The effector responses triggered by activation of cytosolic PRRs, in particular the RIG-I-induced simultaneous rapid type I IFN induction and inflammasome activation, are crucial for timely control of bacterial infection by innate and adaptive immunity. The knowledge on the PRRs and the effector responses relevant for control of infection with intracellular bacteria will help to develop strategies to overcome chronic infection.
    The EMBO Journal 09/2014; 33(20). DOI:10.15252/embj.201489055 · 10.43 Impact Factor
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    • "Accordingly, the transfection of purified flagellin from L. pneumophila and S. typhimurium directly into the cell cytosol is sufficient to trigger caspase-1-dependent pore formation, pyroptosis, and IL-1β secretion (45, 46). Importantly, infection with the non-flagellated bacteria S. flexneri also induces NLRC4-mediated pyroptosis, most likely in response to the inner rod component of T3SS (36). "
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    ABSTRACT: Neuronal apoptosis inhibitory protein (NAIP)/NOD-like receptor (NLR) containing a caspase activating and recruitment domain (CARD) 4 (NLRC4) inflammasome complexes are acti-vated in response to proteins from virulent bacteria that reach the cell cytosol. Specific NAIP proteins bind to the agonists and then physically associate with NLRC4 to form an inflammasome complex able to recruit and activate pro-caspase-1. NAIP5 and NAIP6 sense flagellin, component of flagella from motile bacteria, whereas NAIP1 and NAIP2 detect needle and rod components from bacterial type III secretion systems, respectively. Active caspase-1 mediates the maturation and secretion of the pro-inflammatory cytokines, IL-1β and IL-18, and is responsible for the induction of pyroptosis, a pro-inflammatory form of cell death. In addition to these well-known effector mechanisms, novel roles have been described for NAIP/NLRC4 inflammasomes, such as phagosomal maturation, activation of inducible nitric oxide synthase, regulation of autophagy, secretion of inflammatory media-tors, antibody production, activation of T cells, among others. These effector mechanisms mediated by NAIP/NLRC4 inflammasomes have been extensively studied in the context of resistance of infections and the potential of their agonists has been exploited in therapeutic strategies to non-infectious pathologies, such as tumor protection. Thus, this review will discuss current knowledge about the activation of NAIP/NLRC4 inflammasomes and their effector mechanisms.
    Frontiers in Immunology 07/2014; 5. DOI:10.3389/fimmu.2014.00309
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    • "Induction of pyroptosis was so far essentially described as a mechanism of cell death of various host cell types, preferentially macrophages, triggered by opportunistic pathogenic bacteria infection including Salmonella typhimurium, Salmonella enterica (Fink and Cookson, 2007), Legionella pneumophila (Pereira et al., 2011), Listeria monocytogenes (Sauer et al., 2010), Yersinia species (Bergsbaken and Cookson, 2007) and Shigella species (Suzuki et al., 2007). It remains to investigate if targeted pyroptosis may also provide an effective cell death mechanism in cancer and if distinct natural products have the ability to mediate this cell death modality. "
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    ABSTRACT: Over the past decades, apoptosis emerged as a leading strategy to eliminate cancer cells. Nowadays, it becomes progressively clear that apoptosis is not the only programmed cell death mechanism implicated in the elimination of malignant cells. This review will discuss non-apoptotic cell death modalities and will focus on natural compounds acting as inducers of these recently described processes. We will describe the major molecular characteristics of each individual death mechanism and we will detail the effects of natural and naturally-derived compounds on these cellular mechanisms.
    Phytochemistry Reviews 03/2014; 13(1). DOI:10.1007/s11101-013-9318-0 · 2.41 Impact Factor
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