AIM2 Engages Active but Unprocessed Caspase-1 to Induce Noncanonical Activation of the NLRP3 Inflammasome

Cunha, Larissa D.; Silva, Alexandre L. N.; Ribeiro, Juliana Martins; Mascarenhas, Danielle P. A.; Quirino, Gustavo F. S.; Santos, Leonardo Lima dos; Flavell, Richard A.; Zamboni, Dario S.

doi:10.1016/j.celrep.2017.06.086

Cited by 72 publications

(51 citation statements)

References 58 publications

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“…We acknowledge that addition of LPS to study inflammasome activation in macrophages infected with Leishmania does not mimic natural infection. However, priming isolated cells prior infection is a common strategy to boost gene regulation and to synchronize inflammasome activation upon infection with many microbes including parasites, bacteria, and viruses . It is important to highlight that, in vivo, Leishmania parasites activate the inflammasome without the requirement of priming or LPS injection .…”

Section: Discussionmentioning

confidence: 99%

“…However, priming isolated cells prior infection is a common strategy to boost gene regulation and to synchronize inflammasome activation upon infection with many microbes including parasites, bacteria, and viruses. 26,[45][46][47][48] It is important to highlight that, in vivo, Leishmania parasites activate the inflammasome without the requirement of priming or LPS injection. 25,27,29,49 We believe that this occur because of tissue damage caused during infection, the release of alarmins, such as ATP, IL-1 , and high mobility group box 1 (HMGB1), and also other inflammatory mediators such as IFN-and TNF-, which can boost NF-B signaling and are extremely important in the pathogenesis of Leishmania infections.…”

Section: Discussionmentioning

confidence: 99%

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Macrophage priming is dispensable for NLRP3 inflammasome activation and restriction of Leishmania amazonensis replication

Carvalho

Silva

Santos

et al. 2019

Journal of Leukocyte Biology

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The NLRP3 inflammasome is activated in response to multiple stimuli and triggers activation of caspase‐1 (CASP1), IL‐1β production, and inflammation. NLRP3 activation requires two signals. The first leads to transcriptional regulation of specific genes related to inflammation, and the second is triggered when pathogens, toxins, or specific compounds damage cellular membranes and/or trigger the production of reactive oxygen species (ROS). Here, we assess the requirement of the first signal (priming) for the activation of the NLRP3 inflammasome in bone marrow‐derived macrophages (BMDMs) infected with Leishmania amazonensis. We found that BMDMs express the inflammasome components NLRP3, ASC, and CASP1 at sufficient levels to enable the assembly and activation of NLRP3 inflammasome in response to infection. Therefore, priming was not required for the formation of ASC specks, CASP1 activation (measured by fluorescent dye FAM‐YVAD), and restriction of L. amazonensis replication via the NLRP3 inflammasome. By contrast, BMDM priming was required for CASP1 cleavage (p20) and IL‐1β secretion, because priming triggers robust up‐regulation of pro‐IL‐1β and CASP11 that are important for efficient processing of CASP1 and IL‐1β. Taken together, our data shed light into the cellular and molecular processes involved in activation of the NLRP3 in macrophages by Leishmania, a process that is important for the outcome of Leishmaniasis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Macrophage priming is dispensable for NLRP3 inflammasome activation and restriction of Leishmania amazonensis replication

Carvalho

Silva

Santos

et al. 2019

Journal of Leukocyte Biology

Self Cite

View full text Add to dashboard Cite

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“…Various recent studies reported clues about the caspase-11 non-canonical inflammasome-mediated activation of the NLRP3 canonical inflammasome. Potassium ion (K + ) efflux is a critical determinant for the activation of NLRP3 canonical inflammasome, and caspase-11 non-canonical inflammasome activated NLRP3 canonical inflammasome by facilitating K + efflux through cell membrane damage and the pores generated by N-GSDMD, bacterial pore-forming toxins, and P2X 7 [37,[39][40][41].…”

Section: Caspase-11 Non-canonical Inflammasome-activated Inflammatorymentioning

confidence: 99%

Caspase-11 Non-Canonical Inflammasome: Emerging Activator and Regulator of Infection-Mediated Inflammatory Responses

2020

IJMS

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Inflammation is a body's protective mechanism to eliminate invading pathogens and cellular damaging signals. The inflammatory response consists of two main consecutive steps-a priming step preparing the inflammatory responses and a triggering step boosting the inflammatory responses. The main feature of the triggering step is the activation of the inflammasome, an intracellular multiprotein complex facilitating the inflammatory responses. The regulatory roles of 'canonical' inflammasomes in the inflammatory responses and diseases have been largely investigated, so far. New types of inflammasomes have been recently discovered and named as 'non-canonical' inflammasomes since their roles to induce inflammatory responses are similar to those of canonical inflammasomes, however, the stimulating ligands and the underlying mechanisms are different. Therefore, a growing number of studies have actively investigated the novel roles of non-canonical inflammasomes in inflammatory responses and diseases. This review summarizes and discusses the recent studies exploring the regulatory roles of caspase-11 non-canonical inflammasome during the inflammatory responses and provides insight into the development of novel therapeutics for infectious and inflammatory diseases by targeting caspase-11 non-canonical inflammasome.

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“…pneumophila indirectly activates NLRP3 through the caspase-11 and absent in melanoma 2 (AIM2) inflammasomes. 57,58 Bacterially-induced metabolic changes may also indirectly affect NLRP3 activation and innate immune function more broadly.…”

Section: Bacterial Infectionmentioning

confidence: 99%

The rOX‐stars of inflammation: links between the inflammasome and mitochondrial meltdown

Holley

Schroder

2020

Clin & Trans Imm

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The nod-like receptor protein 3 (NLRP3) inflammasome drives inflammation in response to mitochondrial dysfunction. As metabolic powerhouses with prokaryotic ancestry, mitochondria are a cache for danger-associated molecular patterns and pathogen-associated molecular pattern-like molecules that elicit potent innate immune responses. Persistent mitochondrial damage caused by infection, or genetic or environmental factors, can lead to inappropriate or sustained inflammasome signalling. Here, we review the features of mitochondria that drive inflammatory signalling, with a particular focus on mitochondrial activation of the NLRP3 inflammasome. Given that mitochondrial network dynamics, metabolic activity and redox state are all intricately linked to each other and to NLRP3 inflammasome activity, we highlight the importance of a holistic approach to investigations of NLRP3 activation by dysfunctional mitochondria.

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AIM2 Engages Active but Unprocessed Caspase-1 to Induce Noncanonical Activation of the NLRP3 Inflammasome

Cited by 72 publications

References 58 publications

Macrophage priming is dispensable for NLRP3 inflammasome activation and restriction of Leishmania amazonensis replication

Macrophage priming is dispensable for NLRP3 inflammasome activation and restriction of Leishmania amazonensis replication

Caspase-11 Non-Canonical Inflammasome: Emerging Activator and Regulator of Infection-Mediated Inflammatory Responses

The rOX‐stars of inflammation: links between the inflammasome and mitochondrial meltdown

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