Pore Formation Triggered by<i>Legionella</i>spp. Is an Nlrc4 Inflammasome-Dependent Host Cell Response That Precedes Pyroptosis

Silveira, Tatiana N.; Zamboni, Dario S.

doi:10.1128/iai.00905-09

Cited by 96 publications

(107 citation statements)

References 59 publications

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“…These secretion systems allow the delivery of bacterial products directly into the host cell cytoplasm. In experimental models, Nlrc4-and Naip5-induced caspase-1 activation can be achieved by delivering purified flagellin into the host cell cytosol by means of cationic liposomes or by transducing cells with appropriated gene-expression systems (10,27,28). Consistent with this view, TLR5 stimulation primarily leads to the activation of microbicidal effector mechanisms that are supposedly effective in controlling less aggressive, non-pathogenic bacterial infection.…”

Section: Discussionmentioning

confidence: 93%

A Novel Pathway for Inducible Nitric-oxide Synthase Activation through Inflammasomes

Buzzo

Campopiano

Massis

et al. 2010

Journal of Biological Chemistry

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Innate immune recognition of flagellin is shared by transmembrane TLR5 and cytosolic Nlrc4 (NOD-like receptor family CARD (caspase activation recruitment domain) domain containing 4)/Naip5 (neuronal apoptosis inhibitory protein 5). TLR5 activates inflammatory genes through MYD88 pathway, whereas Nlrc4 and Naip5 assemble multiprotein complexes called inflammasomes, culminating in caspase-1 activation, IL-1␤/IL-18 secretion, and pyroptosis. Although both TLR5 and Naip5/Nlrc4 pathways cooperate to clear infections, little is known about the relative anti-pathogen effector mechanisms operating through each of them. Here we show that the cytosolic flagellin (FLA-BSDot) was able to activate iNOS, an enzyme previously associated with TLR5 pathway. Using Nlrc4-or Naip5-deficient macrophages, we found that both receptors are involved in iNOS activation by FLA-BSDot. Moreover, distinct from extracellular flagellin (FLA-BS), iNOS activation by intracellular flagellin is completely abrogated in the absence of caspase-1. Interestingly, IL-1␤ and IL-18 do not seem to be important for FLA-BSDot-mediated iNOS production. Together, our data defined an additional anti-pathogen effector mechanism operated through Naip5 and Nlrc4 inflammasomes and illustrated a novel signaling transduction pathway that activates iNOS.

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Section: Discussionmentioning

confidence: 93%

A Novel Pathway for Inducible Nitric-oxide Synthase Activation through Inflammasomes

Buzzo

Campopiano

Massis

et al. 2010

Journal of Biological Chemistry

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“…The non-pneumophila Legionella strains used included Legionella micdadei (ATCC 33218) and Legionella bozemanii (ATCC 33217) as previously described (20). Additionally, a streptomycin mutant of Legionella gratiana (ATCC 49413) was generated (DZ571) and used in this study.…”

Section: Bacterial Strainsmentioning

confidence: 99%

“…Moreover, this inflammasome was reported to be the key for restriction of L. pneumophila replication in mouse macrophages and in vivo (11,13,(16)(17)(18)(19). Once activated, this inflammasome promotes the formation of pores in the macrophage membrane (16,17,20); this process culminates in the induction of an inflammatory form of cell death termed pyroptosis (reviewed in Ref. 21).…”

mentioning

confidence: 99%

Caspase-1 but Not Caspase-11 Is Required for NLRC4-Mediated Pyroptosis and Restriction of Infection by Flagellated Legionella Species in Mouse Macrophages and In Vivo

Cerqueira

Pereira

Silva

et al. 2015

The Journal of Immunology

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Gram-negative bacteria from the Legionella genus are intracellular pathogens that cause a severe form of pneumonia called Legionnaires’ disease. The bacteria replicate intracellularly in macrophages, and the restriction of bacterial replication by these cells is critical for host resistance. The activation of the NAIP5/NLRC4 inflammasome, which is readily triggered in response to bacterial flagellin, is essential for the restriction of bacterial replication in murine macrophages. Once activated, this inflammasome induces pore formation and pyroptosis and facilitates the restriction of bacterial replication in macrophages. Because investigations related to the NLRC4-mediated restriction of Legionella replication were performed using mice double deficient for caspase-1 and caspase-11, we assessed the participation of caspase-1 and caspase-11 in the functions of the NLRC4 inflammasome and the restriction of Legionella replication in macrophages and in vivo. By using several species of Legionella and mice singly deficient for caspase-1 or caspase-11, we demonstrated that caspase-1 but not caspase-11 was required for pore formation, pyroptosis, and restriction of Legionella replication in macrophages and in vivo. By generating F1 mice in a mixed 129 × C57BL/6 background deficient (129 × Casp-11−/−) or sufficient (129 × C57BL/6) for caspase-11 expression, we found that caspase-11 was dispensable for the restriction of Legionella pneumophila replication in macrophages and in vivo. Thus, although caspase-11 participates in flagellin-independent noncanonical activation of the NLRP3 inflammasome, it is dispensable for the activities of the NLRC4 inflammasome. In contrast, functional caspase-1 is necessary and sufficient to trigger flagellin/NLRC4-mediated restriction of Legionella spp. infection in macrophages and in vivo.

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“…The cell-free supernatants and cellular lysate were collected after 12, 24, and 48 h of incubation, and the caspase-1 and IL-1b production was detected by Western blotting, as described previously (26). The BMMs incubated with ATP (5 mM) plus 100 ng/ml LPS (both from Sigma-Aldrich) were used as the positive control.…”

Section: Detection Of Activated Caspase-1 and Il-1bmentioning

confidence: 99%

Apoptosis-Associated Speck–like Protein Containing a Caspase Recruitment Domain Inflammasomes Mediate IL-1β Response and Host Resistance to Trypanosoma cruzi Infection

Silva

Sesti-Costa

Silveira

et al. 2013

The Journal of Immunology

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The innate immune response to Trypanosoma cruzi infection comprises several pattern recognition receptors (PRRs), including TLR-2, -4, -7, and -9, as well as the cytosolic receptor Nod1. However, there are additional PRRs that account for the host immune responses to T. cruzi. In this context, the nucleotide-binding oligomerization domain–like receptors (NLRs) that activate the inflammasomes are candidate receptors that deserve renewed investigation. Following pathogen infection, NLRs form large molecular platforms, termed inflammasomes, which activate caspase-1 and induce the production of active IL-1β and IL-18. In this study, we evaluated the involvement of inflammasomes in T. cruzi infection and demonstrated that apoptosis-associated speck–like protein containing a caspase recruitment domain (ASC) inflammasomes, including NLR family, pyrin domain–containing 3 (NLRP3), but not NLR family, caspase recruitment domain–containing 4 or NLR family, pyrin domain–containing 6, are required for triggering the activation of caspase-1 and the secretion of IL-1β. The mechanism by which T. cruzi mediates the activation of the ASC/NLRP3 pathway involves K+ efflux, lysosomal acidification, reactive oxygen species generation, and lysosomal damage. We also demonstrate that despite normal IFN-γ production in the heart, ASC−/− and caspase-1−/− infected mice exhibit a higher incidence of mortality, cardiac parasitism, and heart inflammation. These data suggest that ASC inflammasomes are critical determinants of host resistance to infection with T. cruzi.

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Pore Formation Triggered byLegionellaspp. Is an Nlrc4 Inflammasome-Dependent Host Cell Response That Precedes Pyroptosis

Cited by 96 publications

References 59 publications

A Novel Pathway for Inducible Nitric-oxide Synthase Activation through Inflammasomes

A Novel Pathway for Inducible Nitric-oxide Synthase Activation through Inflammasomes

Caspase-1 but Not Caspase-11 Is Required for NLRC4-Mediated Pyroptosis and Restriction of Infection by Flagellated Legionella Species in Mouse Macrophages and In Vivo

Apoptosis-Associated Speck–like Protein Containing a Caspase Recruitment Domain Inflammasomes Mediate IL-1β Response and Host Resistance to Trypanosoma cruzi Infection

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