Mitochondrial damage contributes to<i>Pseudomonas aeruginosa</i>activation of the inflammasome and is downregulated by autophagy

Jabir, Majid S.; Hopkins, Lee; Ritchie, Neil D.; Ullah, Ihsan; Bayes, Hannah; Liu, Dong; Tourlomousis, Panagiotis; Lupton, Alison; Puleston, Daniel J.; Simon, Anna Katharina; Bryant, Clare E.; Evans, Thomas J.

doi:10.4161/15548627.2014.981915

Cited by 146 publications

(126 citation statements)

References 42 publications

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“…Overexpression of the NLRP3 inflammasome core molecules or treatment with IL-1␤ promoted autophagy in P. aeruginosa-infected macrophages, which is consistent with the findings of others showing that caspase1 increases the autophagic influx by upregulating Beclin1 expression (43). Jabir et al demonstrated that the DNA released from damaged mitochondria contributes to P. aeruginosa-mediated activation of the IPAF inflammasome and is downregulated by autophagy (31). These findings indicate the cross talk between inflammasome and autophagy.…”

Section: Figsupporting

confidence: 78%

Pseudomonas aeruginosa Triggers Macrophage Autophagy To Escape Intracellular Killing by Activation of the NLRP3 Inflammasome

et al. 2016

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Assembly of the inflammasome has recently been identified to be a critical event in the initiation of inflammation. However, its role in bacterial killing remains unclear. Our study demonstrates that Pseudomonas aeruginosa infection induces the assembly of the NLRP3 inflammasome and the sequential secretion of caspase1 and interleukin-1␤ (IL-1␤) in human macrophages. More importantly, activation of the NLRP3 inflammasome reduces the killing of P. aeruginosa in human macrophages, without affecting the generation of antimicrobial peptides, reactive oxygen species, and nitric oxide. In addition, our results demonstrate that P. aeruginosa infection increases the amount of the LC3-II protein and triggers the formation of autophagosomes in human macrophages. The P. aeruginosa-induced autophagy was enhanced by overexpression of NLRP3, ASC, or caspase1 but was reduced by knockdown of these core molecules of the NLRP3 inflammasome. Treatment with IL-1␤ enhanced autophagy in human macrophages. More importantly, IL-1␤ decreased the macrophage-mediated killing of P. aeruginosa, whereas knockdown of ATG7 or Beclin1 restored the IL-1␤-mediated suppression of bacterial killing. Collectively, our study explores a novel mechanism employed by P. aeruginosa to escape from phagocyte killing and may provide a better understanding of the interaction between P. aeruginosa and host immune cells, including macrophages.

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Section: Figsupporting

confidence: 78%

Pseudomonas aeruginosa Triggers Macrophage Autophagy To Escape Intracellular Killing by Activation of the NLRP3 Inflammasome

et al. 2016

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“…It is well known that mitochondria play a key role in the activation of the NLRP3 inflammasome [22][23][24]. Our work revealed that the decreased activity of mitochondrial respiratory chain complex I caused by ATP was restored by levornidazole (Fig.…”

Section: Levornidazole Suppresses the Nlrp3 Inflammasome By Protectinsupporting

confidence: 46%

A new pharmacological effect of levornidazole: Inhibition of NLRP3 inflammasome activation

Wang

et al. 2015

Biochemical Pharmacology

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“…adaptor, thus limiting TRIF signaling, could be a possible explanation (Jabir et al, 2014). Indeed, TRIF signaling was required not only to eventually restrain the inflammatory response in VVC but also to sustain IL-1Ra production in infection (unpublished data).…”

Section: Discussionmentioning

confidence: 94%

Pathogenic NLRP3 Inflammasome Activity during Candida Infection Is Negatively Regulated by IL-22 via Activation of NLRC4 and IL-1Ra

Borghi

Luca

Puccetti

et al. 2015

Cell Host & Microbe

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Candida albicans is a well-tolerated resident of human mucosal tissues. This implies that host defense mechanisms cooperate to limit inflammation while controlling fungal burden. The cytokine IL-22 and inflammasomes are essential components of the mucosal responses to C. albicans. How these components cooperate to mediate the balance of inflammation and host defense is not explored. We find that NLRP3 inflammasome activation promotes neutrophil recruitment and inflammation during infection and that this activity is counteracted by IL-22. Mechanistically, IL-22 activated NLRC4 for sustained production of the IL-1 receptor antagonist IL-1Ra, which restrained NLRP3 activity. Symptomatic infection in mice and humans occurred under conditions of IL-1Ra deficiency and was rescued in mice by replacement therapy with the recombinant IL-1Ra anakinra. Thus, pathogenic inflammasome activity during Candida infection is negatively regulated by the IL-22/NLRC4/IL-1Ra axis. Our findings offer insights into the pathogenesis of C. albicans and suggest therapeutic avenues for candidiasis.

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Mitochondrial damage contributes toPseudomonas aeruginosaactivation of the inflammasome and is downregulated by autophagy

Cited by 146 publications

References 42 publications

Pseudomonas aeruginosa Triggers Macrophage Autophagy To Escape Intracellular Killing by Activation of the NLRP3 Inflammasome

Pseudomonas aeruginosa Triggers Macrophage Autophagy To Escape Intracellular Killing by Activation of the NLRP3 Inflammasome

A new pharmacological effect of levornidazole: Inhibition of NLRP3 inflammasome activation

Pathogenic NLRP3 Inflammasome Activity during Candida Infection Is Negatively Regulated by IL-22 via Activation of NLRC4 and IL-1Ra

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