The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Rongbin Zhou - One of the best experts on this subject based on the ideXlab platform.

  • plant lectins activate the NLRP3 Inflammasome to promote inflammatory disorders
    Journal of Immunology, 2017
    Co-Authors: Tao Gong, Xiaqiong Wang, Chenggong Yu, Yanqing Yang, Rongbin Zhou, Wei Jiang
    Abstract:

    Plant-derived dietary lectins have been reported to be involved in the pathogenesis of several inflammatory diseases, including inflammatory bowel disease, diabetes, rheumatoid arthritis, and celiac disease, but little is known about the molecular mechanisms underlying lectin-induced inflammation. In this study, we showed that plant lectins can induce caspase-1 activation and IL-1β secretion via the NLRP3 Inflammasome. Lectins were internalized and subsequently escaped from the lysosome and then translocated to the endoplasmic reticulum. Endoplasmic reticulum–loaded plant lectins then triggered Ca 2+ release and mitochondrial damage, and inhibition of Ca 2+ release and mitochondrial reactive oxygen species by chemical inhibitors significantly suppressed NLRP3 Inflammasome activation. In vivo, plant lectin–induced inflammation and tissue damage also depended on the NLRP3 Inflammasome. Our findings indicate that plant lectins can act as an exogenous “danger signal” that can activate the NLRP3 Inflammasome and suggest that dietary lectins might promote inflammatory diseases via the NLRP3 Inflammasome.

  • dopamine controls systemic inflammation through inhibition of NLRP3 Inflammasome
    Cell, 2015
    Co-Authors: Wei Jiang, Xiaqiong Wang, Chen Ding, Zhigang Tian, Rongbin Zhou
    Abstract:

    Summary Inflammasomes are involved in diverse inflammatory diseases, so the activation of Inflammasomes needs to be tightly controlled to prevent excessive inflammation. However, the endogenous regulatory mechanisms of Inflammasome activation are still unclear. Here, we report that the neurotransmitter dopamine (DA) inhibits NLRP3 Inflammasome activation via dopamine D1 receptor (DRD1). DRD1 signaling negatively regulates NLRP3 Inflammasome via a second messenger cyclic adenosine monophosphate (cAMP), which binds to NLRP3 and promotes its ubiquitination and degradation via the E3 ubiquitin ligase MARCH7. Importantly, in vivo data show that DA and DRD1 signaling prevent NLRP3 Inflammasome-dependent inflammation, including neurotoxin-induced neuroinflammation, LPS-induced systemic inflammation, and monosodium urate crystal (MSU)-induced peritoneal inflammation. Taken together, our results reveal an endogenous mechanism of Inflammasome regulation and suggest DRD1 as a potential target for the treatment of NLRP3 Inflammasome-driven diseases.

  • rna viruses promote activation of the NLRP3 Inflammasome through a rip1 rip3 drp1 signaling pathway
    Nature Immunology, 2014
    Co-Authors: Xiaqiong Wang, Tao Gong, Wei Jiang, Zhigang Tian, Yiqing Yan, Jiahuai Han, Rongbin Zhou
    Abstract:

    The NLRP3 Inflammasome functions as a crucial component of the innate immune system in recognizing viral infection, but the mechanism by which viruses activate this Inflammasome remains unclear. Here we found that inhibition of the serine-threonine kinases RIP1 (RIPK1) or RIP3 (RIPK3) suppressed RNA virus-induced activation of the NLRP3 Inflammasome. Infection with an RNA virus initiated assembly of the RIP1-RIP3 complex, which promoted activation of the GTPase DRP1 and its translocation to mitochondria to drive mitochondrial damage and activation of the NLRP3 Inflammasome. Notably, the RIP1-RIP3 complex drove the NLRP3 Inflammasome independently of MLKL, an essential downstream effector of RIP1-RIP3-dependent necrosis. Together our results reveal a specific role for the RIP1-RIP3-DRP1 pathway in RNA virus-induced activation of the NLRP3 Inflammasome and establish a direct link between inflammation and cell-death signaling pathways.

  • er stress activates the NLRP3 Inflammasome via an upr independent pathway
    Cell Death and Disease, 2012
    Co-Authors: Philippe Menu, Rongbin Zhou, Annick Mayor, Aubry Tardivel, Hidenori Ichijo, Kazutoshi Mori, J Tschopp
    Abstract:

    Uncontrolled endoplasmic reticulum (ER) stress responses are proposed to contribute to the pathology of chronic inflammatory diseases such as type 2 diabetes or atherosclerosis. However, the connection between ER stress and inflammation remains largely unexplored. Here, we show that ER stress causes activation of the NLRP3 Inflammasome, with subsequent release of the pro-inflammatory cytokine interleukin-1β. This ER-triggered proinflammatory signal shares the same requirement for reactive oxygen species production and potassium efflux compared with other known NLRP3 Inflammasome activators, but is independent of the classical unfolded protein response (UPR). We thus propose that the NLRP3 Inflammasome senses and responds to ER stress downstream of a previously uncharacterized ER stress response signaling pathway distinct from the UPR, thus providing mechanistic insight to the link between ER stress and chronic inflammatory diseases.

  • a role for mitochondria in NLRP3 Inflammasome activation
    Nature, 2011
    Co-Authors: Rongbin Zhou, Philippe Menu, Amir S Yazdi, Jurg Tschopp
    Abstract:

    An inflammatory response initiated by the NLRP3 Inflammasome is triggered by a variety of situations of host 'danger', including infection and metabolic dysregulation. Previous studies suggested that NLRP3 Inflammasome activity is negatively regulated by autophagy and positively regulated by reactive oxygen species (ROS) derived from an uncharacterized organelle. Here we show that mitophagy/autophagy blockade leads to the accumulation of damaged, ROS-generating mitochondria, and this in turn activates the NLRP3 Inflammasome. Resting NLRP3 localizes to endoplasmic reticulum structures, whereas on Inflammasome activation both NLRP3 and its adaptor ASC redistribute to the perinuclear space where they co-localize with endoplasmic reticulum and mitochondria organelle clusters. Notably, both ROS generation and Inflammasome activation are suppressed when mitochondrial activity is dysregulated by inhibition of the voltage-dependent anion channel. This indicates that NLRP3 Inflammasome senses mitochondrial dysfunction and may explain the frequent association of mitochondrial damage with inflammatory diseases.

Alan Aderem - One of the best experts on this subject based on the ideXlab platform.

  • the NLRP3 Inflammasome detects encephalomyocarditis virus and vesicular stomatitis virus infection
    Journal of Virology, 2011
    Co-Authors: Jayant V Rajan, David Rodriguez, Edward A Miao, Alan Aderem
    Abstract:

    Inflammasomes are cytosolic protein complexes that regulate caspase-1 activation and the secretion of interleukin-1β (IL-1β) and IL-18. Several different Inflammasome complexes have been identified, but the NLRP3 Inflammasome is particularly notable because of its central role in diseases of inflammation. Recent work has demonstrated an essential role for the NLRP3 Inflammasome in host defense against influenza virus. We show here that two other RNA viruses, encephalomyocarditis virus (EMCV) and vesicular stomatitis virus (VSV), activate the NLRP3 Inflammasome in dendritic cells and macrophages through a mechanism requiring viral replication. Inflammasome activation in response to both viruses does not require MDA5 or RIG-I signaling. Despite the ability of the NLRP3 Inflammasome to detect EMCV and VSV, wild-type and caspase-1-deficient mice were equally susceptible to infection with both viruses. These findings indicate that the NLRP3 Inflammasome may be a common pathway for RNA virus detection, but its precise role in the host response may be variable.

  • the NLRP3 Inflammasome detects encephalomyocarditis virus and vesicular stomatitis virus infection
    Journal of Virology, 2011
    Co-Authors: Jayant V Rajan, David Rodriguez, Edward A Miao, Alan Aderem
    Abstract:

    Inflammasomes are cytosolic protein complexes that regulate caspase-1 activation and the secretion of interleukin-1β (IL-1β) and IL-18. Several different Inflammasome complexes have been identified, but the NLRP3 Inflammasome is particularly notable because of its central role in diseases of inflammation. Recent work has demonstrated an essential role for the NLRP3 Inflammasome in host defense against influenza virus. We show here that two other RNA viruses, encephalomyocarditis virus (EMCV) and vesicular stomatitis virus (VSV), activate the NLRP3 Inflammasome in dendritic cells and macrophages through a mechanism requiring viral replication. Inflammasome activation in response to both viruses does not require MDA5 or RIG-I signaling. Despite the ability of the NLRP3 Inflammasome to detect EMCV and VSV, wild-type and caspase-1-deficient mice were equally susceptible to infection with both viruses. These findings indicate that the NLRP3 Inflammasome may be a common pathway for RNA virus detection, but its precise role in the host response may be variable.

Damien Arnoult - One of the best experts on this subject based on the ideXlab platform.

  • rna viruses promote activation of the NLRP3 Inflammasome through cytopathogenic effect induced potassium efflux
    Cell Death and Disease, 2019
    Co-Authors: Leandro Silva Da Costa, Ahmed Outlioua, Adrienne Anginot, Khadija Akarid, Damien Arnoult
    Abstract:

    Early detection of viruses by the innate immune system is crucial for host defense. The NLRP3 Inflammasome, through activation of caspase-1, promotes the maturation of IL-1β and IL-18, which are critical for antiviral immunity and inflammatory response. However, the mechanism by which viruses activate this Inflammasome is still debated. Here, we report that the replication of cytopathogenic RNA viruses such as vesicular stomatitis virus (VSV) or encephalomyocarditis virus (EMCV) induced a lytic cell death leading to potassium efflux, the common trigger of NLRP3 Inflammasome activation. This lytic cell death was not prevented by a chemical or genetic inhibition of apoptosis, pyroptosis, or necroptosis but required the viral replication. Hence, the viruses that stimulated type I IFNs production after their sensing did not activate NLRP3 Inflammasome due to an inhibition of their replication. In contrast, NLRP3 Inflammasome activation induced by RNA virus infection was stimulated in IFNAR-deficient or MAVS-deficient cells consequently to an increased viral replication and ensuing lytic cell death. Therefore, in a context of inefficient IFN response, viral replication-induced lytic cell death activates of the NLRP3 Inflammasome to fight against infection.

Jayant V Rajan - One of the best experts on this subject based on the ideXlab platform.

  • the NLRP3 Inflammasome detects encephalomyocarditis virus and vesicular stomatitis virus infection
    Journal of Virology, 2011
    Co-Authors: Jayant V Rajan, David Rodriguez, Edward A Miao, Alan Aderem
    Abstract:

    Inflammasomes are cytosolic protein complexes that regulate caspase-1 activation and the secretion of interleukin-1β (IL-1β) and IL-18. Several different Inflammasome complexes have been identified, but the NLRP3 Inflammasome is particularly notable because of its central role in diseases of inflammation. Recent work has demonstrated an essential role for the NLRP3 Inflammasome in host defense against influenza virus. We show here that two other RNA viruses, encephalomyocarditis virus (EMCV) and vesicular stomatitis virus (VSV), activate the NLRP3 Inflammasome in dendritic cells and macrophages through a mechanism requiring viral replication. Inflammasome activation in response to both viruses does not require MDA5 or RIG-I signaling. Despite the ability of the NLRP3 Inflammasome to detect EMCV and VSV, wild-type and caspase-1-deficient mice were equally susceptible to infection with both viruses. These findings indicate that the NLRP3 Inflammasome may be a common pathway for RNA virus detection, but its precise role in the host response may be variable.

  • the NLRP3 Inflammasome detects encephalomyocarditis virus and vesicular stomatitis virus infection
    Journal of Virology, 2011
    Co-Authors: Jayant V Rajan, David Rodriguez, Edward A Miao, Alan Aderem
    Abstract:

    Inflammasomes are cytosolic protein complexes that regulate caspase-1 activation and the secretion of interleukin-1β (IL-1β) and IL-18. Several different Inflammasome complexes have been identified, but the NLRP3 Inflammasome is particularly notable because of its central role in diseases of inflammation. Recent work has demonstrated an essential role for the NLRP3 Inflammasome in host defense against influenza virus. We show here that two other RNA viruses, encephalomyocarditis virus (EMCV) and vesicular stomatitis virus (VSV), activate the NLRP3 Inflammasome in dendritic cells and macrophages through a mechanism requiring viral replication. Inflammasome activation in response to both viruses does not require MDA5 or RIG-I signaling. Despite the ability of the NLRP3 Inflammasome to detect EMCV and VSV, wild-type and caspase-1-deficient mice were equally susceptible to infection with both viruses. These findings indicate that the NLRP3 Inflammasome may be a common pathway for RNA virus detection, but its precise role in the host response may be variable.

Kiichi Nakahira - One of the best experts on this subject based on the ideXlab platform.

  • nox4 dependent fatty acid oxidation promotes NLRP3 Inflammasome activation in macrophages
    Nature Medicine, 2016
    Co-Authors: Jong Seok Moon, Gina M Denicola, Kiichi Nakahira, Kueipin Chung, Michael Jakun Koo, Maria A Pabon
    Abstract:

    Altered metabolism has been implicated in the pathogenesis of inflammatory diseases. NADPH oxidase 4 (NOX4), a source of cellular superoxide anions, has multiple biological functions that may be of importance in inflammation and in the pathogenesis of human metabolic diseases, including diabetes. However, the mechanisms by which NOX4-dependent metabolic regulation affect the innate immune response remain unclear. Here we show that deficiency of NOX4 resulted in reduced expression of carnitine palmitoyltransferase 1A (CPT1A), which is a key mitochondrial enzyme in the fatty acid oxidation (FAO) pathway. The reduced FAO resulted in less activation of the nucleotide-binding domain, leucine-rich-repeat-containing receptor (NLR), pyrin-domain-containing 3 (NLRP3) Inflammasome in human and mouse macrophages. In contrast, NOX4 deficiency did not inhibit the activation of the NLR family, CARD-domain-containing 4 (NLRC4), the NLRP1 or the absent in melanoma 2 (AIM2) Inflammasomes. We also found that inhibition of FAO by etomoxir treatment suppressed NLRP3 Inflammasome activation. Furthermore, Nox4-deficient mice showed substantial reduction in caspase-1 activation and in interleukin (IL)-1β and IL-18 production, and there was improved survival in a mouse model of NLRP3-mediated Streptococcus pneumoniae infection. The pharmacologic inhibition of NOX4 by either GKT137831, which is currently in phase 2 clinical trials, or VAS-2870 attenuated NLRP3 Inflammasome activation. Our results suggest that NOX4-mediated FAO promotes NLRP3 Inflammasome activation.

  • mtorc1 induced hk1 dependent glycolysis regulates NLRP3 Inflammasome activation
    Cell Reports, 2015
    Co-Authors: Stefan W. Ryter, Jong Seok Moon, Shu Hisata, Gina M Denicola, Kiichi Nakahira, Miae Park
    Abstract:

    The mammalian target of rapamycin complex 1 (mTORC1) regulates activation of immune cells and cellular energy metabolism. Although glycolysis has been linked to immune functions, the mechanisms by which glycolysis regulates NLRP3 Inflammasome activation remain unclear. Here, we demonstrate that mTORC1-induced glycolysis provides an essential mechanism for NLRP3 Inflammasome activation. Moreover, we demonstrate that hexokinase 1 (HK1)-dependent glycolysis, under the regulation of mTORC1, represents a critical metabolic pathway for NLRP3 Inflammasome activation. Downregulation of glycolysis by inhibition of Raptor/mTORC1 or HK1 suppressed both pro-IL-1β maturation and caspase-1 activation in macrophages in response to LPS and ATP. These results suggest that upregulation of HK1-dependent glycolysis by mTORC1 regulates NLRP3 Inflammasome activation.