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

Buzzo, Carina L.; Campopiano, Julia Cortina; Massis, Liliana M.; Lage, Silvia Lucena; Cassado, Alexandra Anjos; Leme-Souza, Rafael; Cunha, Larissa D.; Russo, Marco; Zamboni, Dario S.; Amarante-Mendes, Gustavo P.; Bortoluci, Karina Ramalho

doi:10.1074/jbc.m110.124297

Cited by 49 publications

(57 citation statements)

References 47 publications

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“…The human GBP5 and its mouse ortholog are required for the NLRP3-dependent IL-1b secretion (45); therefore, we suggest that T. cruzi triggers GBP5, which induces the assembly of the NLRP3/ASC inflammasome that is important for killing the parasite. Furthermore, we demonstrated that the ASC 2/2 and caspase-1 2/2 macrophages primed with IFN-g and infected with T. cruzi exhibited increased numbers of parasites and reduced levels of NO compared with the WT macrophages, thus reinforcing our hypothesis that the caspase-1 pathway is somehow connected to the production of NO, as reported previously (46). Notably, we showed that IL-1b triggered robust NO production by macrophages and controlled T. cruzi growth in BMMs.…”

Section: Discussionsupporting

confidence: 73%

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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Section: Discussionsupporting

confidence: 73%

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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“…29 Resident peritoneal macrophages were collected from naïve animals by RPMI 1640 lavage, resuspended in RPMI 1640 containing 10% fetal bovine serum and seeded at a density of 1310 5 cells/well in 96-well plates. After an overnight incubation, the cells were washed to remove non-adherent cells.…”

Section: Mcp-1 and Il-8 Releasing Assaysmentioning

confidence: 99%

Over-activation of TLR5 signaling by high-dose flagellin induces liver injury in mice

et al. 2014

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Flagellin is a potent activator of a broad range of cell types that are involved in innate and adaptive immunity. Therefore, it is a good adjuvant candidate for vaccines, and it might function as a biological protectant against both major acute radiation syndrome during cancer radiotherapy and a mitigator of radiation emergencies. However, accumulating evidence has implicated flagellin in the occurrence of some inflammatory diseases, such as acute lung inflammation, cardiovascular collapse and inflammatory bowel disease. The aim of this study was to elucidate whether only flagellin-TLR5 signaling activation plays a role in the pathophysiology of liver or whether some other flagellin activity also contributes to liver injury either via bacterial infections or during clinical applications. Recombinant flagellin proteins with or without TLR5-stimulating activity were used to evaluate the role of flagellin-TLR5 signaling in liver injury in wild-type and TLR5 KO mice. Gross lesions and large areas of hepatocellular necrosis were observed in liver tissue 12 h after the intraperitoneal administration of 100 or 200 mg flagellin (FliC) in a dose-and time-dependent manner in wild-type mice, but not in TLR5 KO mice. Deletion of the N-terminal or TLR5 binding domain of flagellin inhibited flagellin-induced inflammatory responses and the subsequent acute liver function abnormality and damage. These data confirmed that flagellin is an essential determinant of liver injury and demonstrated that the over-activation of TLR5 signaling by high-dose flagellin caused acute inflammatory responses, neutrophil accumulation and oxidative stress in the liver, which contributes to the progression and severity of flagellin-induced liver injury.

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“…Both of these effector mechanisms lead to the inhibition of Legionella pneumophila replication. Importantly, caspase-1-induced IL-1β and IL-18 are not involved in phagosome maturation (4,12), induction of pyroptosis (14), or iNOS activation (13), suggesting that caspase-1 mediates independent effects that cooperate to clear infections.…”

mentioning

confidence: 99%

“…The activation of caspase-1 in response to cytosolic flagellin by the NAIP5/NLRC4 inflammasome complex can also induce other effector mechanisms to restrict infections, such as caspase-7-dependent phagosome maturation (4,12) and the activation of inducible nitric oxide synthase (iNOS) by macrophages (13). Both of these effector mechanisms lead to the inhibition of Legionella pneumophila replication.…”

mentioning

confidence: 99%

Cytosolic flagellin-induced lysosomal pathway regulates inflammasome-dependent and -independent macrophage responses

Lage

Buzzo

Amaral³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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NAIP5/NLRC4 (neuronal apoptosis inhibitory protein 5/nucleotide oligomerization domain-like receptor family, caspase activation recruitment domain domain-containing 4) inflammasome activation by cytosolic flagellin results in caspase-1-mediated processing and secretion of IL-1β/IL-18 and pyroptosis, an inflammatory cell death pathway. Here, we found that although NLRC4, ASC, and caspase-1 are required for IL-1β secretion in response to cytosolic flagellin, cell death, nevertheless, occurs in the absence of these molecules. Cytosolic flagellin-induced inflammasome-independent cell death is accompanied by IL-1α secretion and is temporally correlated with the restriction of Salmonella Typhimurium infection. Despite displaying some apoptotic features, this peculiar form of cell death do not require caspase activation but is regulated by a lysosomal pathway, in which cathepsin B and cathepsin D play redundant roles. Moreover, cathepsin B contributes to NAIP5/NLRC4 inflammasome-induced pyroptosis and IL-1α and IL-1β production in response to cytosolic flagellin. Together, our data describe a pathway induced by cytosolic flagellin that induces a peculiar form of cell death and regulates inflammasome-mediated effector mechanisms of macrophages.

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

Cited by 49 publications

References 47 publications

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

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

Over-activation of TLR5 signaling by high-dose flagellin induces liver injury in mice

Cytosolic flagellin-induced lysosomal pathway regulates inflammasome-dependent and -independent macrophage responses

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