Perfluoroalkyl substance pollutants activate the innate immune system through the AIM2 inflammasome

Wang, Liqiu; Liu, Tao; Yang, Shuai; Sun, Lin; Zhao, Zhiyao; Li, Li-Yue; She, Yuanchu; Zheng, Yanyan; Ye, Xiaoyan; Bao, Qing; Dong, Guang‐Hui; Li, Chunwei; Cui, Jun

doi:10.1038/s41467-021-23201-0

Cited by 118 publications

(79 citation statements)

References 78 publications

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“…For example, elevated lysozyme activity, an antimicrobial enzyme and important biomarker of innate immune system function, has been reported in both mammalian and non-mammalian species exposed to PFAS ( Guillette et al, 2020 ; Peden-Adams et al, 2009 , 2008 ). Furthermore, in vivo and in vitro experiments have demonstrated that PFAS exposure can lead to severe inflammation in organs, including the liver, kidneys, and nervous system ( Qian et al, 2010 ; Dong et al, 2012 ; Qazi et al, 2013 ; Xing et al, 2016 ; Xu et al, 2019 ; Wang et al, 2021 ). Systemic inflammation can disrupt the integrity of the BBB through modification of tight junctions, endothelial damage, degradation of extracellular matrix components, and changes in astrocytes ( Varatharaj and Galea, 2017 ).…”

Section: Neurophysiological and Neurochemical Mechanisms Driving Pfas...mentioning

confidence: 99%

A Critical Review and Meta-Analysis of Impacts of Per- and Polyfluorinated Substances on the Brain and Behavior

et al. 2022

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Per- and polyfluoroalkyl substances (PFAS) are a class of structurally diverse synthetic organic chemicals that are chemically stable, resistant to degradation, and persistent in terrestrial and aquatic environments. Widespread use of PFAS in industrial processing and manufacturing over the last 70 years has led to global contamination of built and natural environments. The brain is a lipid rich and highly vascularized organ composed of long-lived neurons and glial cells that are especially vulnerable to the impacts of persistent and lipophilic toxicants. Generally, PFAS partition to protein-rich tissues of the body, primarily the liver and blood, but are also detected in the brains of humans, wildlife, and laboratory animals. Here we review factors impacting the absorption, distribution, and accumulation of PFAS in the brain, and currently available evidence for neurotoxic impacts defined by disruption of neurochemical, neurophysiological, and behavioral endpoints. Emphasis is placed on the neurotoxic potential of exposures during critical periods of development and in sensitive populations, and factors that may exacerbate neurotoxicity of PFAS. While limitations and inconsistencies across studies exist, the available body of evidence suggests that the neurobehavioral impacts of long-chain PFAS exposures during development are more pronounced than impacts resulting from exposure during adulthood. There is a paucity of experimental studies evaluating neurobehavioral and molecular mechanisms of short-chain PFAS, and even greater data gaps in the analysis of neurotoxicity for PFAS outside of the perfluoroalkyl acids. Whereas most experimental studies were focused on acute and subchronic impacts resulting from high dose exposures to a single PFAS congener, more realistic exposures for humans and wildlife are mixtures exposures that are relatively chronic and low dose in nature. Our evaluation of the available human epidemiological, experimental, and wildlife data also indicates heightened accumulation of perfluoroalkyl acids in the brain after environmental exposure, in comparison to the experimental studies. These findings highlight the need for additional experimental analysis of neurodevelopmental impacts of environmentally relevant concentrations and complex mixtures of PFAS.

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Section: Neurophysiological and Neurochemical Mechanisms Driving Pfas...mentioning

confidence: 99%

A Critical Review and Meta-Analysis of Impacts of Per- and Polyfluorinated Substances on the Brain and Behavior

et al. 2022

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“…When dsDNA binds to the AIM2 receptor, ASC and pro-caspase-1 are recruited for inflammasome complex formation and activation ( 30 , 31 ). Previous studies have found that the AIM2 inflammasome induction in hepatocytes and macrophages participates in chronic liver diseases via the pyroptosis pathway ( 32 – 35 ). However, the mechanism of AIM2 inflammasome regulation is not well-studied.…”

Section: Inflammasome Biology and Activationmentioning

confidence: 99%

“…Assembly of the AIM2 inflammasome in KCs led to the processing of IL-1β and IL-18 in response to hepatitis B virus infection, aggregating the development of liver cirrhosis ( 34 , 101 ). Moreover, perfluorooctane sulfonate (PFOS), a chemical that causes chronic systematic inflammation, activated the AIM2 inflammasome via the Ca(2+)–PKC–NF-κB/JNK–BAX/BAK axis ( 35 ). In contrast, deletion of the AIM2 suppressed PFOS-induced inflammation and fibrosis in the liver and other organs ( 35 ).…”

Section: Inflammasome and Pyroptosis In Liver Fibrosismentioning

confidence: 99%

Inflammasomes and Pyroptosis of Liver Cells in Liver Fibrosis

et al. 2022

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Inflammasomes are multiprotein complexes that can sense danger signals and activate caspase-1 to mediate pro-inflammatory cytokines release and pyroptotic cell death. There are two main canonical and non-canonical signaling pathways that trigger inflammasome activation. Inflammasomes are expressed and assembled in parenchymal and nonparenchymal cells in response to liver injury in the liver. Additionally, the hepatocytes, biliary epithelial cells (cholangiocytes), hepatic stellate cells (HSCs), hepatic macrophages, and liver sinusoidal endothelial cells (LSECs) contribute to liver fibrosis via different mechanisms. However, the underlying mechanism of the inflammasome and pyroptosis in these liver cells in liver fibrosis remains elusive. This review summarizes the activation and function of inflammasome complexes and then discusses the association between inflammasomes, pyroptosis, and liver fibrosis. Unlike other similar reviewers, we will focus on the effect of inflammasome activation and pyroptosis in the various liver cells during the development of liver fibrosis. We will also highlight the latest progress of pharmacological intervention in inflammasome-mediated liver fibrosis.

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“…The pathogen DNA can be accumulating in the cytosol due to infection of the cell with viruses or they can be generated by degrading bacteria in the cytosol via action of GBPs and IRGB10 ( 73 – 76 ). Cell stress leading to the release of non-oxidized mitochondrial DNA can also activate the AIM2 inflammasome ( 83 ) ( Figure 1 ).…”

Section: Signal 2: Activation Of the Nlrp3 And Aim2 Inflammasomesmentioning

confidence: 99%

Interaction of Mycobacteria With Host Cell Inflammasomes

Rastogi

Briken

2022

Front. Immunol.

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The inflammasome complex is important for host defense against intracellular bacterial infections. Mycobacterium tuberculosis (Mtb) is a facultative intracellular bacterium which is able to survive in infected macrophages. Here we discuss how the host cell inflammasomes sense Mtb and other related mycobacterial species. Furthermore, we describe the molecular mechanisms of NLRP3 inflammasome sensing of Mtb which involve the type VII secretion system ESX-1, cell surface lipids (TDM/TDB), secreted effector proteins (LpqH, PPE13, EST12, EsxA) and double-stranded RNA acting on the priming and/or activation steps of inflammasome activation. In contrast, Mtb also mediates inhibition of the NLRP3 inflammasome by limiting exposure of cell surface ligands via its hydrolase, Hip1, by inhibiting the host cell cathepsin G protease via the secreted Mtb effector Rv3364c and finally, by limiting intracellular triggers (K+ and Cl- efflux and cytosolic reactive oxygen species production) via its serine/threonine kinase PknF. In addition, Mtb inhibits the AIM2 inflammasome activation via an unknown mechanism. Overall, there is good evidence for a tug-of-war between Mtb trying to limit inflammasome activation and the host cell trying to sense Mtb and activate the inflammasome. The detailed molecular mechanisms and the importance of inflammasome activation for virulence of Mtb or host susceptibility have not been fully investigated.

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Perfluoroalkyl substance pollutants activate the innate immune system through the AIM2 inflammasome

Cited by 118 publications

References 78 publications

A Critical Review and Meta-Analysis of Impacts of Per- and Polyfluorinated Substances on the Brain and Behavior

A Critical Review and Meta-Analysis of Impacts of Per- and Polyfluorinated Substances on the Brain and Behavior

Inflammasomes and Pyroptosis of Liver Cells in Liver Fibrosis

Interaction of Mycobacteria With Host Cell Inflammasomes

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