Regulation of Caspase-8 Activity at the Crossroads of Pro-Inflammation and Anti-Inflammation

Caspase-8 has been classified as an apoptotic caspase, and its initial definition was an initiator of extrinsic cell death. During the past decade, the concept of caspase-8 functioning has been changed by findings of its additional roles in diverse biological processes. Although caspase-8 was not originally thought to be involved in the inflammation process, many recent works have determined that caspase-8 plays an important role in the regulatory functions of inflammatory processes. In this review, we describe the recent advances in knowledge regarding the manner in which caspase-8 modulates the inflammatory responses concerning inflammasome activation, cell death, and cytokine induction.

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The cell biology of inflammasomes: Mechanisms of inflammasome activation and regulation

The Journal of Cell Biology ◽

10.1083/jcb.201602089 ◽

2016 ◽

Vol 213 (6) ◽

pp. 617-629 ◽

Cited By ~ 256

Author(s):

Deepika Sharma ◽

Thirumala-Devi Kanneganti

Keyword(s):

Cell Death ◽

Inflammatory Response ◽

Cell Biology ◽

Inflammasome Activation ◽

Biological Processes ◽

Biological Functions ◽

Cellular Processes ◽

The Past ◽

Functional Output ◽

Made In

Over the past decade, numerous advances have been made in the role and regulation of inflammasomes during pathogenic and sterile insults. An inflammasome complex comprises a sensor, an adaptor, and a zymogen procaspase-1. The functional output of inflammasome activation includes secretion of cytokines, IL-1β and IL-18, and induction of an inflammatory form of cell death called pyroptosis. Recent studies have highlighted the intersection of this inflammatory response with fundamental cellular processes. Novel modulators and functions of inflammasome activation conventionally associated with the maintenance of homeostatic biological functions have been uncovered. In this review, we discuss the biological processes involved in the activation and regulation of the inflammasome.

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ZBP1 promotes LPS-induced cell death and IL-1β release via RHIM-mediated interactions with RIPK1

Nature Communications ◽

10.1038/s41467-020-20357-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Hayley I. Muendlein ◽

Wilson M. Connolly ◽

Zoie Magri ◽

Irina Smirnova ◽

Vladimir Ilyukha ◽

...

Keyword(s):

Immune Response ◽

Cell Death ◽

Complex Formation ◽

Complex I ◽

Yersinia Pseudotuberculosis ◽

Caspase 8 ◽

Inflammasome Activation ◽

Inflammatory Signaling ◽

Complex Ii ◽

Dependent Model

AbstractInflammation and cell death are closely linked arms of the host immune response to infection, which when carefully balanced ensure host survival. One example of this balance is the tightly regulated transition from TNFR1-associated pro-inflammatory complex I to pro-death complex II. By contrast, here we show that a TRIF-dependent complex containing FADD, RIPK1 and caspase-8 (that we have termed the TRIFosome) mediates cell death in response to Yersinia pseudotuberculosis and LPS. Furthermore, we show that constitutive binding between ZBP1 and RIPK1 is essential for the initiation of TRIFosome interactions, caspase-8-mediated cell death and inflammasome activation, thus positioning ZBP1 as an effector of cell death in the context of bacterial blockade of pro-inflammatory signaling. Additionally, our findings offer an alternative to the TNFR1-dependent model of complex II assembly, by demonstrating pro-death complex formation reliant on TRIF signaling.

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Innate immune priming in the absence of TAK1 drives RIPK1 kinase activity–independent pyroptosis, apoptosis, necroptosis, and inflammatory disease

Journal of Experimental Medicine ◽

10.1084/jem.20191644 ◽

2019 ◽

Vol 217 (3) ◽

Cited By ~ 21

Author(s):

R.K. Subbarao Malireddi ◽

Prajwal Gurung ◽

Sannula Kesavardhana ◽

Parimal Samir ◽

Amanda Burton ◽

...

Keyword(s):

Cell Death ◽

Severe Sepsis ◽

Kinase Activity ◽

Innate Immune ◽

Caspase 8 ◽

Inflammasome Activation ◽

Unknown Mechanism ◽

Immune Priming ◽

Signaling Axis

RIPK1 kinase activity has been shown to be essential to driving pyroptosis, apoptosis, and necroptosis. However, here we show a kinase activity–independent role for RIPK1 in these processes using a model of TLR priming in a TAK1-deficient setting to mimic pathogen-induced priming and inhibition. TLR priming of TAK1-deficient macrophages triggered inflammasome activation, including the activation of caspase-8 and gasdermin D, and the recruitment of NLRP3 and ASC into a novel RIPK1 kinase activity–independent cell death complex to drive pyroptosis and apoptosis. Furthermore, we found fully functional RIPK1 kinase activity–independent necroptosis driven by the RIPK3–MLKL pathway in TAK1-deficient macrophages. In vivo, TAK1 inactivation resulted in RIPK3–caspase-8 signaling axis–driven myeloid proliferation and a severe sepsis-like syndrome. Overall, our study highlights a previously unknown mechanism for RIPK1 kinase activity–independent inflammasome activation and pyroptosis, apoptosis, and necroptosis (PANoptosis) that could be targeted for treatment of TAK1-associated myeloid proliferation and sepsis.

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The BH3-only protein Bad is dispensable for TNF-mediated cell death

Cell Death and Disease ◽

10.1038/cddis.2014.575 ◽

2015 ◽

Vol 6 (1) ◽

pp. e1611-e1611 ◽

Cited By ~ 4

Author(s):

E Ottina ◽

M Sochalska ◽

R Sgonc ◽

A Villunger

Keyword(s):

Cell Death ◽

Tumor Necrosis ◽

Inflammatory Responses ◽

Apoptotic Cell ◽

Caspase 8 ◽

Tnf Receptor ◽

Bh3 Domain ◽

Rate Limiting ◽

Tnf Receptor I ◽

Necrosis Factor

Abstract Tumor necrosis factor (TNF) is a key signaling molecule orchestrating immune and inflammatory responses and possesses the capacity to trigger apoptotic as well as necroptotic cell death. Apoptotic cell death elicited by TNF has been demonstrated to engage pro-apoptotic Bcl-2 family proteins, most prominently the BH3-only protein Bid, a key substrate of caspase-8, the key effector protease downstream of TNF receptor I. Most recently, the BH3 domain-containing protein Bad (Bcl-2-antagonist of cell death) has been shown to be rate limiting for TNF-mediated cell death, suggesting possible synergy with Bid, but genetic analyses presented here demonstrate that it is dispensable for this process.

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Dynamics of ASC speck formation during skin inflammatory responses in vivo

10.1101/111542 ◽

2017 ◽

Author(s):

Paola Kuri ◽

Nicole L. Schieber ◽

Thomas Thumberger ◽

Joachim Wittbrodt ◽

Yannick Schwab ◽

...

Keyword(s):

Cell Death ◽

Real Time ◽

Inflammatory Responses ◽

Full Length ◽

Inflammasome Activation ◽

Endogenous Gene ◽

Effector Caspase

AbstractActivated danger or pathogen sensors trigger assembly of the inflammasome adaptor ASC into specks, large signalling platforms considered hallmarks of inflammasome activation. Because a lack of in vivo tools has prevented the study of endogenous ASC dynamics, we generated a live ASC reporter through CRISPR/Cas9 tagging of the endogenous gene in zebrafish. We see strong ASC expression in the skin and other epithelia that act as barriers to insult. A toxic stimulus triggered speck formation and rapid pyroptosis in keratinocytes in vivo. Macrophages engulfed and digested this speck-containing pyroptotic debris. A 3D ultrastructural reconstruction based on CLEM of in vivo assembled specks revealed a compact network of highly intercrossed filaments, whereas PYD or CARD alone formed filamentous aggregates. The effector caspase is recruited through PYD, whose overexpression induced pyroptosis, but after substantial delay. Therefore, formation of a single compact speck and rapid cell death induction in vivo requires full-length ASC.One Sentence SummaryWith a new endogenous ASC real-time reporter we characterize speck dynamics in vivo as well as the concomitant pyroptosis speck formation causes in keratinocytes.

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SARS-CoV-2 triggers inflammatory responses and cell death through caspase-8 activation

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-020-00334-0 ◽

2020 ◽

Vol 5 (1) ◽

Cited By ~ 4

Author(s):

Shufen Li ◽

Yulan Zhang ◽

Zhenqiong Guan ◽

Huiling Li ◽

Meidi Ye ◽

...

Keyword(s):

Cell Death ◽

Inflammatory Cytokine ◽

Inflammatory Responses ◽

Interstitial Fibrosis ◽

Clinical Manifestations ◽

Respiratory Illness ◽

Lung Epithelial Cells ◽

Lung Damage ◽

Caspase 8 ◽

Pulmonary Interstitial Fibrosis

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to respiratory illness and multi-organ failure in critically ill patients. Although the virus-induced lung damage and inflammatory cytokine storm are believed to be directly associated with coronavirus disease 2019 (COVID-19) clinical manifestations, the underlying mechanisms of virus-triggered inflammatory responses are currently unknown. Here we report that SARS-CoV-2 infection activates caspase-8 to trigger cell apoptosis and inflammatory cytokine processing in the lung epithelial cells. The processed inflammatory cytokines are released through the virus-induced necroptosis pathway. Virus-induced apoptosis, necroptosis, and inflammation activation were also observed in the lung sections of SARS-CoV-2-infected HFH4-hACE2 transgenic mouse model, a valid model for studying SARS-CoV-2 pathogenesis. Furthermore, analysis of the postmortem lung sections of fatal COVID-19 patients revealed not only apoptosis and necroptosis but also massive inflammatory cell infiltration, necrotic cell debris, and pulmonary interstitial fibrosis, typical of immune pathogenesis in the lung. The SARS-CoV-2 infection triggered a dual mode of cell death pathways and caspase-8-dependent inflammatory responses may lead to the lung damage in the COVID-19 patients. These discoveries might assist the development of therapeutic strategies to treat COVID-19.

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Impaired NLRP3 inflammasome activation/pyroptosis leads to robust inflammatory cell death via caspase-8/RIPK3 during coronavirus infection

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.015036 ◽

2020 ◽

Vol 295 (41) ◽

pp. 14040-14052 ◽

Cited By ~ 13

Author(s):

Min Zheng ◽

Evan Peter Williams ◽

R. K. Subbarao Malireddi ◽

Rajendra Karki ◽

Balaji Banoth ◽

...

Keyword(s):

Cell Death ◽

Nlrp3 Inflammasome ◽

Inflammatory Cell ◽

Hepatitis Virus ◽

Caspase 8 ◽

Inflammasome Activation ◽

Negative Consequences ◽

Zoonotic Infections ◽

Nlrp3 Inflammasome Activation ◽

Coronavirus Infection

Coronaviruses have caused several zoonotic infections in the past two decades, leading to significant morbidity and mortality globally. Balanced regulation of cell death and inflammatory immune responses is essential to promote protection against coronavirus infection; however, the underlying mechanisms that control these processes remain to be resolved. Here we demonstrate that infection with the murine coronavirus mouse hepatitis virus (MHV) activated the NLRP3 inflammasome and inflammatory cell death in the form of PANoptosis. Deleting NLRP3 inflammasome components or the downstream cell death executioner gasdermin D (GSDMD) led to an initial reduction in cell death followed by a robust increase in the incidence of caspase-8– and receptor-interacting serine/threonine-protein kinase 3 (RIPK3)–mediated inflammatory cell deathafter coronavirus infection. Additionally, loss of GSDMD promoted robust NLRP3 inflammasome activation. Moreover, the amounts of some cytokines released during coronavirus infection were significantly altered in the absence of GSDMD. Altogether, our findings show that inflammatory cell death, PANoptosis, is induced by coronavirus infection and that impaired NLRP3 inflammasome function or pyroptosis can lead to negative consequences for the host. These findings may have important implications for studies of coronavirus-induced disease.

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Extracellular histones trigger disseminated intravascular coagulation by lytic cell death

10.1101/2020.06.11.144683 ◽

2020 ◽

Author(s):

Congqing Wu ◽

Yan Zhang ◽

Lan Li ◽

Ankit Pandeya ◽

Guoying Zhang ◽

...

Keyword(s):

Cell Death ◽

Tissue Factor ◽

Inflammatory Responses ◽

Inflammasome Activation ◽

List Type ◽

Coagulation Activation ◽

Eukaryotic Chromatin ◽

Extracellular Histones ◽

Dependent Mechanism

AbstractHistones are cationic nuclear proteins that are essential for the structure and functions of eukaryotic chromatin. However, extracellular histones trigger inflammatory responses and contribute to death in sepsis by unknown mechanisms. We recently reported that inflammasome activation and pyroptosis trigger coagulation activation through a tissue factor (TF)-dependent mechanism. Here, we show that histones trigger coagulation activation in vivo as evidenced by coagulation parameters and fibrin deposition in tissues. However, histone-induced coagulopathy was neither dependent on caspase 1/11 and gasdermin D (GSDMD), nor on TLR2 and TLR4, as deficiency of these genes in mice did not protect against histone-induced coagulopathy. Incubation of histones with macrophages induced lytic cell death and phosphatidylserine (PS) exposure, which is required for TF activity, a key initiator of coagulation. Neutralization of TF diminished histone-induced coagulation. Our findings reveal lytic cell death as a novel mechanism of histone-induce coagulation activation and thrombosis.Key PointsHistones trigger DIC in a tissue factor dependent mechanismHistones induce tissue factor activation through lytic cell death

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Autophagy and Macrophage Functions: Inflammatory Response and Phagocytosis

Cells ◽

10.3390/cells9010070 ◽

2019 ◽

Vol 9 (1) ◽

pp. 70 ◽

Cited By ~ 10

Author(s):

Ming-Yue Wu ◽

Jia-Hong Lu

Keyword(s):

Inflammatory Responses ◽

Macrophage Polarization ◽

Innate Immune ◽

Inflammasome Activation ◽

Recycling Process ◽

Macrophage Function ◽

The Past ◽

Cellular Debris ◽

Regulation Mechanisms

Autophagy is a conserved bulk degradation and recycling process that plays important roles in multiple biological functions, including inflammatory responses. As an important component of the innate immune system, macrophages are involved in defending cells from invading pathogens, clearing cellular debris, and regulating inflammatory responses. During the past two decades, accumulated evidence has revealed the intrinsic connection between autophagy and macrophage function. This review focuses on the role of autophagy, both as nonselective and selective forms, in the regulation of the inflammatory and phagocytotic functions of macrophages. Specifically, the roles of autophagy in pattern recognition, cytokine release, inflammasome activation, macrophage polarization, LC3-associated phagocytosis, and xenophagy are comprehensively reviewed. The roles of autophagy receptors in the macrophage function regulation are also summarized. Finally, the obstacles and remaining questions regarding the molecular regulation mechanisms, disease association, and therapeutic applications are discussed.

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Huanglian-Wendan Decoction Inhibits NF-κB/NLRP3 Inflammasome Activation in Liver and Brain of Rats Exposed to Chronic Unpredictable Mild Stress

Mediators of Inflammation ◽

10.1155/2018/3093516 ◽

2018 ◽

Vol 2018 ◽

pp. 1-15 ◽

Cited By ~ 10

Author(s):

Ke-Ke Jia ◽

Hong Ding ◽

Han-Wen Yu ◽

Tie-Jun Dong ◽

Ying Pan ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Inflammatory Responses ◽

Common Mental Disorder ◽

Interleukin 1 ◽

Water Extract ◽

Inflammasome Activation ◽

Mild Stress ◽

Chronic Unpredictable Mild Stress ◽

Nlrp3 Inflammasome Activation ◽

Anti Inflammation

Depression is a common mental disorder in modern society. A traditional Chinese medicine Huanglian-Wendan decoction with potential anti-inflammation is used as a clinical antidepressant. Our previous study showed central and peripheral inflammatory responses in a rat model of depression developed by chronic unpredictable mild stress (CUMS). Here, we investigated the anti-inflammatory activity and mechanism of Huanglian-Wendan decoction in CUMS rats. LC-MS/MS and HPLC were performed to determine the major compounds in water extract of this decoction. This study showed that Huanglian-Wendan decoction significantly increased sucrose consumption and reduced serum levels of interleukin-1 beta (IL-1β), IL-6, and alanine aminotransferase (ALT) in CUMS rats. Moreover, this decoction inhibited nuclear entry of nuclear factor-kappa B (NF-κB) with the reduction of phosphorylated protein of NF-κB (p-NF-κB) and inhibitor of NF-κB alpha (p-IκBα) and downregulated protein of nod-like receptor family pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein containing CARD (ASC), cysteinyl aspartate-specific proteinase-1 (Caspase-1), and IL-1β in liver and brain regions of CUMS rats. These findings demonstrated that Huanglian-Wendan decoction had antidepressant activity with hepatoprotection in CUMS rats coinciding with its anti-inflammation in both periphery and central. The inhibitory modulation of NF-κB and NLRP3 inflammasome activation by Huanglian-Wendan decoction may mediate its antidepressant action.

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