Post-translational regulation of inflammasomes

Yang, Jie; Liu, Zhonghua; Xiao, Tsan Sam

doi:10.1038/cmi.2016.29

Cited by 175 publications

(150 citation statements)

References 200 publications

(250 reference statements)

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“…[42][43][44] It was also observed that 3-MA particularly abolished AIM2 inhibition by RGFP966 in our study, indicating plausible autophagosome regulations between RGFP966 and AIM2. [42][43][44] It was also observed that 3-MA particularly abolished AIM2 inhibition by RGFP966 in our study, indicating plausible autophagosome regulations between RGFP966 and AIM2.…”

Section: Discussionsupporting

confidence: 82%

The HDAC3 inhibitor RGFP966 ameliorated ischemic brain damage by downregulating the AIM2 inflammasome

et al. 2019

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contributed equally to the research work.Abbreviations: AIM2, absent in melanoma 2; ASC, apoptosis speck-like protein; BBB, brain-blood barrier; DAMPs, damaged-associated molecular patterns; ECA, external carotid artery; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFAP, glial fibrillary acidic protein; HDAC3, histone deacetylases 3; Iba-1, ionized calcium binding adaptor molecule 1; LPS, lipopolysaccharide; MCAO, middle cerebral artery occlusion; NeuN, neuronal nuclei; Nrf2, nuclear factor E2-related factor-2; PYD, N-terminal pyrin domain; TTC, 2,3,5-triphenyltetrazolium chloride AbstractHistone deacetylases 3 (HDAC3) modulates the acetylation state of histone and nonhistone proteins and could be a powerful regulator of the inflammatory process in stroke. Inflammasome activation is a ubiquitous but poorly understood consequence of acute ischemic stroke. Here, we investigated the potential contributions of HDAC3 to inflammasome activation in primary cultured microglia and experimental stroke models. In this study, we documented that HDAC3 expression was increased in microglia of mouse experimental stroke model. Intraperitoneal injection of RGFP966 (a selective inhibitor of HDAC3) decreased infarct size and alleviated neurological deficits after the onset of middle cerebral artery occlusion (MCAO). In vitro data indicated that LPS stimulation evoked a time-dependent increase of HDAC3 and absent in melanoma 2 (AIM2) inflammasome in primary cultured microglia.Interestingly, AIM2 was subjected to spatiotemporal regulation by RGFP966. The ability of RGFP966 to inhibit the AIM2 inflammasome was confirmed in an experimental mouse model of stroke. As expected, AIM2 knockout mice also demonstrated significant resistance to ischemia injury compared with their wild-type littermates. RGFP966 failed to exhibit extra protective effects in AIM2−/− stroke mice. Furthermore, we found that RGFP966 enhanced STAT1 acetylation and subsequently attenuated STAT1 phosphorylation, which may at least partially contributed to the negative regulation of AIM2 by RGFP966. Together, we initially found that RGFP966 alleviated the inflammatory response and protected against ischemic stroke by regulating the AIM2 inflammasome. K E Y W O R D SAIM2 inflammasome, HDAC3, microglia, STAT1, stroke | 649 ZHANG et Al.

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Section: Discussionsupporting

confidence: 82%

The HDAC3 inhibitor RGFP966 ameliorated ischemic brain damage by downregulating the AIM2 inflammasome

et al. 2019

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“…The recruitment of this machinery to AIM2 leads to AIM2 degradation via selective autophagy . These findings demonstrate that post‐translational modifications contribute to inflammasomes regulation and may be key at regulating the intensity and duration of the inflammatory responses …”

Section: Regulation Of Aim2mentioning

confidence: 78%

The AIM2 inflammasome: Sensor of pathogens and cellular perturbations

Lugrin

Martinon

2017

Immunological Reviews

290

205

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Recognition of pathogens and altered self must be efficient and highly specific to orchestrate appropriate responses while limiting excessive inflammation and autoimmune reaction to normal self. AIM2 is a member of innate immune sensors that detects the presence of DNA, arguably the most conserved molecules in living organisms. However, AIM2 achieves specificity by detecting altered or mislocalized DNA molecules. It can detect damaged DNA, and the aberrant presence of DNA within the cytosolic compartment such as genomic DNA released into the cytosol upon loss of nuclear envelope integrity. AIM2 is also a key sensor of pathogens that detects the presence of foreign DNA accumulating in the cytosol during the life cycle of intracellular pathogens including viruses, bacteria, and parasites. AIM2 activation initiates the assembly of the inflammasome, an innate immune complex that leads to the activation of inflammatory caspases. This triggers the maturation and secretion of the cytokines IL-1β and IL-18. It can also initiate pyroptosis, a proinflammatory form of cell death. The AIM2 inflammasome contributes to physiological responses and diseases. It is a key player in host defenses, but its deregulation can contribute immune-linked diseases, such as autoinflammatory and autoimmune pathologies. Moreover, AIM2 may play a role in cancer development. Recent studies have shown that the detection of self-DNA species by AIM2 is an important factor that contributes to diseases associated with perturbation of cellular homeostasis. Thus, in addition of being a sensor of pathogen associated molecular patterns (PAMPs), the AIM2 inflammasome is emerging as a key guardian of cellular integrity.

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“…6 To date, several inflammasomes have been described, including NLRP1, NLRC4, AIM2, and NLRP3 inflammasome, and the NLRP3 inflammasome is the most characterized one. 9,10 It is reported that NLRP3 inflammasome can be activated by many different stimuli including PAMPs and DAMPs. In addition, a newly identified protein NEK7 (NIMA-related kinase 7), which can directly bind to NLRP3 protein, is also thought to be the component of NLRP3 inflammasome.…”

Section: Introductionmentioning

confidence: 99%

Ginsenoside Rg3 suppresses the NLRP3 inflammasome activation through inhibition of its assembly

et al. 2019

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Ginsenoside Rg3 is one of the main constituents of Panax ginseng. Compelling evidence has demonstrated that ginsenoside Rg3 is capable of inhibiting inflammation.However, the mechanism mediating its anti-inflammatory effects remain unclear.Here we show that ginsenoside Rg3 blocks IL-1β secretion and caspase-1 activation through inhibiting LPS priming and the NLRP3 inflammasome activation in human and mouse macrophages. Rg3 specifically inhibits activation of NLRP3 but not the NLRC4 or AIM2 inflammasomes. In addition, Rg3 has no effect on upstream regulation of NLRP3 inflammasome, such as K + efflux, ROS production, or mitochondrial membrane potential. Mechanistically, Rg3 abrogates NEK7-NLRP3 interaction, and subsequently inhibits NLRP3-ASC interaction, ASC oligomerization, and speckle formation. More importantly, Rg3 can reduce IL-1β secretion induced by LPS in mice and protect mice from lethal endotoxic shock. Thus, our findings reveal an anti-inflammatory mechanism for Rg3 and suggest its potential use in NLRP3-driven diseases. K E Y W O R D Santi-inflammation, ginsenoside Rg3, inflammasome, NLRP3 inflammasome | 209 SHI et al. SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section.

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Post-translational regulation of inflammasomes

Cited by 175 publications

References 200 publications

The HDAC3 inhibitor RGFP966 ameliorated ischemic brain damage by downregulating the AIM2 inflammasome

The HDAC3 inhibitor RGFP966 ameliorated ischemic brain damage by downregulating the AIM2 inflammasome

The AIM2 inflammasome: Sensor of pathogens and cellular perturbations

Ginsenoside Rg3 suppresses the NLRP3 inflammasome activation through inhibition of its assembly

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