Cutting Edge: Cytosolic Bacterial DNA Activates the Inflammasome via Aim2

Warren, Sarah; Armstrong, Abraham; Hamilton, M. Kristina; Mao, Dat P.; Leaf, Irina A.; Miao, Edward A.; Aderem, Alan

doi:10.4049/jimmunol.1000724

Cited by 128 publications

(98 citation statements)

References 20 publications

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“…Pyroptosis is thought to expose intracellular bacteria to extracellular immune surveillance, thus allowing their destruction by antimicrobial peptides, Igs, and the complement system, as well as their uptake by neutrophils and other immune cells. Finally, AIM2 responds to F. tularensis, Listeria monocytogenes, and certain DNA viruses such as CMV and vaccinia virus to induce caspase-1 activation (26)(27)(28)(29)(30)(31). The increased susceptibility of caspase-1-deficient mice to infection with F. tularensis, the causative agent of tularaemia, illustrates the critical role the AIM2 inflammasome plays in host defense responses to microbial pathogens (32).…”

Section: Modulation Of Inflammasome Pathways By Bacterial and Viral Pmentioning

confidence: 99%

Modulation of Inflammasome Pathways by Bacterial and Viral Pathogens

Lamkanfi

Dixit²

2011

The Journal of Immunology

204

175

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Inflammasomes are emerging as key regulators of the host response against microbial pathogens. These cytosolic multiprotein complexes recruit and activate the cysteine protease caspase-1 when microbes invade sterile tissues or elicit cellular damage. Inflammasome-activated caspase-1 induces inflammation by cleaving the proinflammatory cytokines IL-1β and IL-18 into their biologically active forms and by releasing the alarmin HMGB1 into the extracellular milieu. Additionally, inflammasomes counter bacterial replication and clear infected immune cells through an inflammatory cell death program termed pyroptosis. As a countermeasure, bacterial and viral pathogens evolved virulence factors to antagonize inflammasome pathways. In this review, we discuss recent progress on how inflammasomes contribute to host defense against bacterial and viral pathogens, and we review how viruses and bacteria modulate inflammasome function to their benefit.

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Section: Modulation Of Inflammasome Pathways By Bacterial and Viral Pmentioning

confidence: 99%

Modulation of Inflammasome Pathways by Bacterial and Viral Pathogens

Lamkanfi

Dixit²

2011

The Journal of Immunology

204

175

View full text Add to dashboard Cite

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“…Additionally, a recently identified pattern-recognition receptor termed AIM2 was found to recognize cytoplasmic dsDNA through its HIN-200 domain and ASC via its pyrin domain. Franciscella tularensis and L. monocytogenes DNA activate AIM2 inflammasome by their interaction with ASC to induce caspase-1 (6,22). Further, studies using knockout (KO) mice revealed the importance of AIM2 in host defense against cytosolic bacteria, such as Franciscella spp.…”

mentioning

confidence: 99%

Critical Role of ASC Inflammasomes and Bacterial Type IV Secretion System in Caspase-1 Activation and Host Innate Resistance to Brucella abortus Infection

Gomes

Campos

Oliveira

et al. 2013

The Journal of Immunology

107

133

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Pathogens are detected by innate immune receptors that, upon activation, orchestrate an appropriate immune response. Recent studies revealed the intracellular signaling cascades involved in the TLR-initiated immune response to Brucella abortus infection. However, no report has elucidated the role of inflammasome receptors in Brucella recognition. Therefore, we decided to investigate the function of NLRC4, NLRP3, and AIM2 in sensing Brucella. In this study, we showed that NLRC4 is not required to induce caspase-1 activation and further secretion of IL-1β by B. abortus in macrophages. In contrast, we determined that AIM2, which senses Brucella DNA, and NLRP3 are partially required for caspase-1 activation and IL-1β secretion. Additionally, mitochondrial reactive oxygen species induced by Brucella were implicated in IL-1β production. Furthermore, AIM2, NLRP3, ASC, and caspase-1 knockout mice were more susceptible to B. abortus infection than were wild-type animals, suggesting that multiple ASC-dependent inflammasomes contribute to host protection against infection. This protective effect is due to the inflammatory response caused by IL-1β and IL-18 rather than pyroptosis, because we observed augmented bacterial burden in IL-1R and IL-18 knockout mice. Finally, we determined that bacterial type IV secretion system VirB and live, but not heat-killed, Brucella are required for full inflammasome activation in macrophages during infection. Taken together, our results indicate that Brucella is sensed by ASC inflammasomes that collectively orchestrate a robust caspase-1 activation and proinflammatory response.

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“…5,[8][9][10][11] Recent studies have shown that L. monocytogenes infection of myeloid cells triggers AIM2-mediated pyroptosis via caspase-1 activation. [12][13][14][15] Using Aim2-deficient mice, Rathinam et al demonstrated that the AIM2 inflammasome is critical for innate defense against L. monocytogenes and DNA viruses, and indicated that AIM2 can sense the double-stranded DNA from these microbes. MEF cells stably expressing GFP-LC3 (p62 -/-) are infected with the ΔactA2 strain for 2 h, the number of Ub-positive ΔactA2 bacteria in p62 -/-cells is similar to that in p62 -/-cells stably expressing GFP-LC3 and p62-3xMyc (p62 -/-/p62); however, the amount of LC3 associated with ΔactA2 bacteria in p62 -/-cells is less than half of that in p62 -/-/p62 cells.…”

mentioning

confidence: 99%