The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis

Franchi, Luigi; Eigenbrod, Tatjana; Muñoz-Planillo, Raúl; Núñez, Gabriel

doi:10.1038/ni.1703

Cited by 1,601 publications

(1,408 citation statements)

References 101 publications

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“…The NLR family member proteins NLRP3 and NLRC4 are known to mediate caspase-1 activation by forming a macromolecular complex (also called an inflammasome) with the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) [18]. To explore the mechanisms responsible for the activation of caspase-1 by A. hydrophila, we investigated the roles of NLRP3, NLRC4 and ASC.…”

Section: Caspase-1 Activation By a Hydrophila Occurs Via Nlrp3-asc Imentioning

confidence: 99%

“…However, accumulating evidence indicates that infection with many pathogens including bacteria, viruses and fungi induces the proinflammatory cell death of infected macrophages through the activation of caspase-1 [5][6][7][8][9][10][11][12][13][14][15][16][17]. The Nod-like receptor (NLR) family, pyrin domain containing 3 (NLRP3) is critical for caspase-1 activation and the secretion of IL-1b and IL-18 in response to multiple microbial molecules and endogenous danger molecules, whereas the NLR family, CARD domain containing 4 (NLRC4) protein is believed to sense bacterial flagellin and induce caspase-1 activation [18,19].…”

Section: Introductionmentioning

confidence: 99%

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Cytotoxins of the human pathogen Aeromonas hydrophila trigger, via the NLRP3 inflammasome, caspase‐1 activation in macrophages

et al. 2010

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Aeromonas hydrophila is a Gram-negative pathogen that causes serious infectious disease in humans. A. hydrophila induces apoptosis in infected macrophages, but the host proinflammatory responses triggered by macrophage death are largely unknown. Here, we demonstrate that the infection of mouse macrophages with A. hydrophila triggers the activation of caspase-1 and release of IL-1b. Caspase-1 activation was abrogated in macrophages deficient in Nod-like receptor family, pyrin domain containing 3 (NLRP3) and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), but not NLR family, CARD domain containing 4 (NLRC4). The activation of the NLRP3 inflammasome was mediated by three cytotoxins (aerolysin, hemolysin and multifunctional repeat-in-toxin) produced by A. hydrophila. Our results indicated that the NLRP3 inflammasome senses A. hydrophila infection through the action of bacterial cytotoxins.Key words: Aeromonas . Caspase-1 . Nod-like receptor Supporting Information available online IntroductionThe genus Aeromonas is responsible for a significant number of animal and human infections. Aeromonas are opportunistic human pathogens that can cause intestinal and extraintestinal, wound, soft tissue, skin, and blood infections and septicemia. The most common human disease associated with Aeromonas infection is gastroenteritis with diarrhea symptoms. Among the 21 species that have been differentiated based on DNA-DNA hybridization, A. caviae, A. veronii biotype sobria and A. hydrophila are most commonly associated with human infections and account for more than 85% of all clinical isolates [1,2].Recently, it has been reported that infection with A. hydrophila induces apoptosis in macrophages [3,4]. Although the cytotoxicity by the bacteria is believed to enable the bacteria to evade eradication and clearance by the macrophages, the host proinflammatory responses triggered by the death of the macrophages remain unknown.Induction of apoptosis is considered a virulence mechanism of pathogenic bacteria that can cause tissue damage and Here, we investigated the cell death of macrophages infected with A. hydrophila and demonstrate that the bacteria cause pyroptosis with caspase-1 activation via the NLRP3 inflammasome. Aerolysin, hemolysin (HlyA) and multifunctional repeat-intoxin (RtxA) produced by A. hydrophila are required to elicit the NLRP3 inflammasome and necrotic cell death. We identify the essential bacterial and host factors for eliciting caspase-1 activation and proinflammatory responses. SHORT COMMUNICATION Results and discussionInfection with A. hydrophila induces caspase-1 activation, IL-1b release and pyroptosis It has been reported that aerolysin produced by A. salmonicida induces caspase-1 activation in CHO cells [20,21]. However, whether whole bacterial infection by A. hydrophila leads to caspase-1 activation in macrophages has not been elucidated. We examined caspase-1 activation in infected primary mouse BMderived macrophages (BMM) and observed that BMM infected with WT strai...

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Section: Caspase-1 Activation By a Hydrophila Occurs Via Nlrp3-asc Imentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cytotoxins of the human pathogen Aeromonas hydrophila trigger, via the NLRP3 inflammasome, caspase‐1 activation in macrophages

et al. 2010

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“…The main task of the active enzyme is the conversion of pro-IL-1β into its mature form, IL-1β. 3,61 In LPS and LPSÀQD treated microglia, we found significantly increased levels of IL-1β as determined by ELISA assays ( Figure 4A). 43 The viability of the cells exposed to LPS and/or LPSÀQD (100 ng/mL and 10 μg/mL) in the presence of serum was within 10% from the control.…”

Section: Articlementioning

confidence: 89%

Caspase-1 Activity in Microglia Stimulated by Pro-Inflammagen Nanocrystals

Moquin¹,

Hutter

Choi

et al. 2013

ACS Nano

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These authors share equal first authorship.A n acute inflammatory response to an insult is largely a protective cellular response. An unopposed acute inflammatory process persists, leading to the characteristic chronic inflammation. Commonly, the sequel would be a deterioration of physiological function. An early intervention is therefore important to reduce or eliminate this undesirable consequence. To this end, several biomarkers of inflammation have been measured and tested; these biomarkers are mainly the products of enzymatic reactions. Caspase-1 is one of the most prominent of the enzymes involved in inflammation. 1 Inflammation can be induced by numerous exogenous agents, including airborne particles, biological aggregates, nanocrystals (quantum dots (QDs)) and lipopolysaccharides (LPS). 2 These inflammagens are recognized by macrophages and microglia and some of them bind to cell surface receptors such as Toll-like receptors (TLR). In particular, endotoxins, including LPS, bind TLR-4 and trigger receptor dimerization at the plasma membrane, which, in turn, activate signal transduction cascades to induce inflammation. 1 TLR-4 activation initiates both genomic and nongenomic inflammatory responses (i) by activating the transcription factor NF-κB, which translocates to the nucleus and induces the expression of pro-inflammatory cytokines (e.g., pro-interleukins), and (ii) by internalizing the bound endotoxin stimuli, fusing with lysosomes and triggering the formation of inflammasomes ( Figure 1A). Nod-like receptor protein-3 (NLRP-3) inflammasome 3À6 is one of the most wellstudied inflammasomes and contains the precursor pro-caspase-1, which is cleaved following inflammatory stimuli and releases its active form, caspase-1. 7 Caspase-1 is a cysteine protease which converts * Address correspondence to dusica.maysinger@mcgill.ca.Received for review January 14, 2013 and accepted October 9, 2013. Published online 10.1021/nn404473gABSTRACT Although caspase-1 is a key participant in inflammation, there is no sensitive assay to measure its enzymatic activity in real time in cells or animals. Here we describe a nanosensor for caspase-1 ratiometric measurements, consisting of a rhodamine-labeled, caspase-1 cleavable peptide linked to quantum dots (QDs). Microglia cells were stimulated by lipopolysaccharide (LPS) and by hybrid nanoparticles LPSÀQDs. These stimuli activated caspase-1 in microglia monolayers and in the mouse brain, while a selected caspase inhibitor markedly reduced it. LPSÀQDs entered into the lysosomal compartment and led to an enlargement of these cellular organelles in the exposed microglia. Both lysosomal swelling and mitochondrial impairment contributed to caspase-1 activation and to the consequent interleukin-1β release. The results from these studies highlight how the unique properties of QDs can be used to create versatile biotools in the study of inflammation in real time in vivo.

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“…Amongst the various inflammasomes, the NALP3 inflammasome is particularly effective at sensing a plethora of diverse molecules, including bacterial and viral PAMPs, stressassociated danger signals, such as ATP or monosodium urate crystals (MSU), as well as asbestos, silica, alum and -amyloid [43].…”

Section: Nod-like Receptors (Nlrs)mentioning

confidence: 99%

“…Caspase-1 cleaves pro-IL-1 into active mature IL-1β, which is then secreted into the extracellular space [43]. It is now generally accepted that activation and release of IL-1…”

Section: Nod-like Receptors (Nlrs)mentioning

confidence: 99%

TLR, NLR Agonists, and Other Immune Modulators as Infectious Disease Vaccine Adjuvants

Higgins

Mills

2010

Curr Infect Dis Rep

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Vaccines based on attenuated or killed viruses and bacteria are highly effective in preventing infection with a range of pathogens, but can have safety issues. Therefore, there is a move towards subunit vaccines based on recombinant proteins or naked DNA. However, protein subunit vaccines are typically poorly immunogenic when administered alone and therefore require co-administration with adjuvants to boost the immune response.

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The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis

Cited by 1,601 publications

References 101 publications

Cytotoxins of the human pathogen Aeromonas hydrophila trigger, via the NLRP3 inflammasome, caspase‐1 activation in macrophages

Cytotoxins of the human pathogen Aeromonas hydrophila trigger, via the NLRP3 inflammasome, caspase‐1 activation in macrophages

Caspase-1 Activity in Microglia Stimulated by Pro-Inflammagen Nanocrystals

TLR, NLR Agonists, and Other Immune Modulators as Infectious Disease Vaccine Adjuvants

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