Activation of the Pyrin Inflammasome by Intracellular <i>Burkholderia cenocepacia</i>

Gavrilin, Mikhail A.; Abdelaziz, Dalia H.; Mostafa, Mahmoud; Abdulrahman, Basant; Grandhi, Jaykumar; Akhter, Anwari; Khweek, Arwa Abu; Aubert, Daniel; Valvano, Miguel A.; Wewers, Mark D.; Amer, Amal O.

doi:10.4049/jimmunol.1102272

Cited by 109 publications

(88 citation statements)

References 69 publications

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“…Because the PYRIN inflammasome also plays a role in the detection of B. cenocepacia in human and mouse macrophages [20,31,32], we next compared B. cenocepacia -induced CASP4 expression and the activation of CASP1 in WT, mefv −/- , and casp4 −/- macrophages at 6 h post infection via immunoblot. Expression of CASP4 in response to B. cenocepacia was markedly induced in WT and mefv −/- macrophages (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Although, CASP4 has been implicated in the restriction of L. pneumophila and the closely related Burkholderia species B. pseudomallei and B. thailandensis , the exact mechanism is still unclear [16,38]. Recognition of intracellular B. cenocepacia in murine macrophages is mediated through NOD-like receptors including NLRP3 and MEFV/PYRIN [19,20]. Non-canonical NLRP3-PYCARD/ASC-dependent inflammasome activation in response to Gram-negative pathogens requires CASP4 [15].…”

Section: Discussionmentioning

confidence: 99%

“…As part of the non-canonical inflammasome, CASP4/caspase-11 contributes to cytokine release and bacterial restriction either upstream or independently of CASP1 [15–18]. B. cenocepacia activates CASP1 via NLRP3 in murine macrophages [19] and via MEFV/PYRIN in human monocytes [20] in a type VI secretion system (T6SS)-dependent manner, resulting in pronounced inflammation. A potential role for CASP4 during B. cenocepacia infection, however, has not yet been investigated.…”

Section: Introductionmentioning

confidence: 99%

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CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection

Krause¹,

Caution²,

Badr³

et al. 2018

Autophagy

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CASP4/caspase-11-dependent inflammasome activation is important for the clearance of various Gram-negative bacteria entering the host cytosol. Additionally, CASP4 modulates the actin cytoskeleton to promote the maturation of phagosomes harboring intracellular pathogens such as Legionella pneumophila but not those enclosing nonpathogenic bacteria. Nevertheless, this non-inflammatory role of CASP4 regarding the trafficking of vacuolar bacteria remains poorly understood. Macroautophagy/autophagy, a catabolic process within eukaryotic cells, is also implicated in the elimination of intracellular pathogens such as Burkholderia cenocepacia. Here we show that CASP4-deficient macrophages exhibit a defect in autophagosome formation in response to B. cenocepacia infection. The absence of CASP4 causes an accumulation of the small GTPase RAB7, reduced colocalization of B. cenocepacia with LC3 and acidic compartments accompanied by increased bacterial replication in vitro and in vivo. Together, our data reveal a novel role of CASP4 in regulating autophagy in response to B. cenocepacia infection.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection

Krause¹,

Caution²,

Badr³

et al. 2018

Autophagy

Self Cite

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show abstract

“…A recent study has elegantly shown that pyrin is a specific immune sensor for bacterial modifications of Rho GTPases and responds to Clostridium difficile which is a frequent cause of nosocomial diarrhea [22]. Burkholderia cenocepacia is another microorganism modifying Rho GTPases and leading to the activation of pyrin [23,22]. Pyrin does not directly recognize the microbial products but detects pathogen virulence activity [22].…”

Section: Introductionmentioning

confidence: 99%

The myths we believed in familial Mediterranean fever: what have we learned in the past years?

Özen

Batu

2015

Semin Immunopathol

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Familial Mediterranean fever is the most common monogenic periodic fever syndrome over the world especially in the eastern Mediterranean. It presents with recurrent and self-limited inflammatory attacks of fever and polyserositis along with high acute-phase reactants. The disease is associated with mutations in the MEFV gene that encodes pyrin, a component of inflammasome, which leads to exaggerated inflammatory response through uncontrolled production of interleukin 1. With the identification of the gene associated with the disease, we believed that everything was solved and that this was an ordinary monogenic disease with autosomal recessive inheritance. However, through the breathtaking progress in the basic research field as well as the clinical care of these patients, we have understood that the picture for this monogenic disorder was more complicated than we had anticipated. In this review, we have discussed the myths we believed in familial Mediterranean fever and how they have evolved during the past years.

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“…Thus, mutated pyrin loses the ability to negatively regulate the NLRP3 inflammasome, resulting in higher inflammasome activity and more IL-1β production. Other studies suggest pyrin can assemble a ‘pyrin inflammasome’ together with ASC and caspase-1 to facilitate IL-1β processing independently of NLRP3 [88–90], and in the mutated form, the caspase-1 activity is constitutively activated. Recently, both of these contrasting models have gained support, implicating a complex regulatory network.…”

Section: Autophagy In Classic Auidsmentioning

confidence: 99%

Autophagy dysfunction in autoinflammatory diseases

Hua

Shen

McDonald

et al. 2018

Journal of Autoimmunity

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Autoinflammatory diseases (AUIDs) are a genetically heterogeneous group of rheumatic diseases characterized by episodic inflammation linked with dysregulated innate immune responses. In this review, we summarize the molecular mechanisms altered by disease-associated variants in several AUIDs, including NOD2-associated diseases, TNF receptor-associated periodic syndrome (TRAPS), familial Mediterranean fever (FMF) and hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), and highlight the roles dysregulated autophagy plays in disease pathogenesis. Autophagy is a conserved eukaryotic pathway for the elimination of cellular stressors, such as misfolded proteins, damaged organelles, or intracellular microorganisms. It is now recognized that autophagy also functions to control inflammation through regulatory interactions with innate immune signaling pathways. AUID-associated genetic variants are known to directly activate inflammatory signaling pathways. Recent evidence also indicates that these variants may also cause impairment of autophagy, thus augmenting inflammatory responses indirectly. Intriguingly, these variants can impair autophagy by different mechanisms, further implicating the autophagic response pathway in AUIDs. These discoveries provide evidence that autophagy could be investigated as a new therapeutic target for AUIDs.

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Activation of the Pyrin Inflammasome by Intracellular Burkholderia cenocepacia

Cited by 109 publications

References 69 publications

CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection

CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection

The myths we believed in familial Mediterranean fever: what have we learned in the past years?

Autophagy dysfunction in autoinflammatory diseases

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