scholarly journals Viral Glycoproteins Induce NLRP3 Inflammasome Activation and Pyroptosis in Macrophages

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2076
Author(s):  
Hannah S. Eisfeld ◽  
Alexander Simonis ◽  
Sandra Winter ◽  
Jason Chhen ◽  
Luisa J. Ströh ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Cell Death ◽  
Nlrp3 Inflammasome ◽  
Vaccine Development ◽  
Viral Pathogenesis ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Viral Pathogens ◽  
Nlrp3 Inflammasome Activation ◽  
Viral Glycoproteins

Infections with viral pathogens are widespread and can cause a variety of different diseases. In-depth knowledge about viral triggers initiating an immune response is necessary to decipher viral pathogenesis. Inflammasomes, as part of the innate immune system, can be activated by viral pathogens. However, viral structural components responsible for inflammasome activation remain largely unknown. Here we analyzed glycoproteins derived from SARS-CoV-1/2, HCMV and HCV, required for viral entry and fusion, as potential triggers of NLRP3 inflammasome activation and pyroptosis in THP-1 macrophages. All tested glycoproteins were able to potently induce NLRP3 inflammasome activation, indicated by ASC-SPECK formation and secretion of cleaved IL-1β. Lytic cell death via gasdermin D (GSDMD), pore formation, and pyroptosis are required for IL-1β release. As a hallmark of pyroptosis, we were able to detect cleavage of GSDMD and, correspondingly, cell death in THP-1 macrophages. CRISPR-Cas9 knockout of NLRP3 and GSDMD in THP-1 macrophages confirmed and strongly support the evidence that viral glycoproteins can act as innate immunity triggers. With our study, we decipher key mechanisms of viral pathogenesis by showing that viral glycoproteins potently induce innate immune responses. These insights could be beneficial in vaccine development and provide new impulses for the investigation of vaccine-induced innate immunity.

scholarly journals Sendai Virus V Protein Inhibits the Secretion of Interleukin-1β by Preventing NLRP3 Inflammasome Assembly

2018 ◽  
Vol 92 (19) ◽  
Author(s):  
Takayuki Komatsu ◽  
Yukie Tanaka ◽  
Yoshinori Kitagawa ◽  
Naoki Koide ◽  
Yoshikazu Naiki ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Sendai Virus ◽  
Nipah Virus ◽  
Innate Immune ◽  
Parainfluenza Virus ◽  
Inflammasome Activation ◽  
V Protein ◽  
Nlrp3 Inflammasome Activation ◽  
Human Parainfluenza Virus

ABSTRACT Inflammasomes play a key role in host innate immune responses to viral infection by caspase-1 (Casp-1) activation to facilitate interleukin-1β (IL-1β) secretion, which contributes to the host antiviral defense. The NLRP3 inflammasome consists of the cytoplasmic sensor molecule NLRP3, adaptor protein ASC, and effector protein pro-caspase-1 (pro-Casp-1). NLRP3 and ASC promote pro-Casp-1 cleavage, leading to IL-1β maturation and secretion. However, as a countermeasure, viral pathogens have evolved virulence factors to antagonize inflammasome pathways. Here we report that V gene knockout Sendai virus [SeV V(−)] induced markedly greater amounts of IL-1β than wild-type SeV in infected THP1 macrophages. Deficiency of NLRP3 in cells inhibited SeV V(−)-induced IL-1β secretion, indicating an essential role for NLRP3 in SeV V(−)-induced IL-1β activation. Moreover, SeV V protein inhibited the assembly of NLRP3 inflammasomes, including NLRP3-dependent ASC oligomerization, NLRP3-ASC association, NLRP3 self-oligomerization, and intermolecular interactions between NLRP3 molecules. Furthermore, a high correlation between the NLRP3-binding capacity of V protein and the ability to block inflammasome complex assembly was observed. Therefore, SeV V protein likely inhibits NLRP3 self-oligomerization by interacting with NLRP3 and inhibiting subsequent recruitment of ASC to block NLRP3-dependent ASC oligomerization, in turn blocking full activation of the NLRP3 inflammasome and thus blocking IL-1β secretion. Notably, the inhibitory action of SeV V protein on NLRP3 inflammasome activation is shared by other paramyxovirus V proteins, such as Nipah virus and human parainfluenza virus type 2. We thus reveal a mechanism by which paramyxovirus inhibits inflammatory responses by inhibiting NLRP3 inflammasome complex assembly and IL-1β activation. IMPORTANCE The present study demonstrates that the V protein of SeV, Nipah virus, and human parainfluenza virus type 2 interacts with NLRP3 to inhibit NLRP3 inflammasome activation, potentially suggesting a novel strategy by which viruses evade the host innate immune response. As all members of the Paramyxovirinae subfamily carry similar V genes, this new finding may also lead to identification of novel therapeutic targets for paramyxovirus infection and related diseases.

scholarly journals The Zα2 domain of ZBP1 is a molecular switch regulating influenza-induced PANoptosis and perinatal lethality during development

2020 ◽  
Vol 295 (24) ◽  
pp. 8325-8330 ◽  
Author(s):  
Sannula Kesavardhana ◽  
R. K. Subbarao Malireddi ◽  
Amanda R. Burton ◽  
Shaina N. Porter ◽  
Peter Vogel ◽  
...  
Keyword(s):  
Cell Death ◽  
Nucleic Acids ◽  
Influenza A Virus ◽  
Nlrp3 Inflammasome ◽  
Influenza A ◽  
Defense Responses ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Perinatal Lethality

Z-DNA-binding protein 1 (ZBP1) is an innate immune sensor of nucleic acids that regulates host defense responses and development. ZBP1 activation triggers inflammation and pyroptosis, necroptosis, and apoptosis (PANoptosis) by activating receptor-interacting Ser/Thr kinase 3 (RIPK3), caspase-8, and the NLRP3 inflammasome. ZBP1 is unique among innate immune sensors because of its N-terminal Zα1 and Zα2 domains, which bind to nucleic acids in the Z-conformation. However, the specific role of these Zα domains in orchestrating ZBP1 activation and subsequent inflammation and cell death is not clear. Here we generated Zbp1ΔZα2/ΔZα2 mice that express ZBP1 lacking the Zα2 domain and demonstrate that this domain is critical for influenza A virus–induced PANoptosis and underlies perinatal lethality in mice in which the RIP homotypic interaction motif domain of RIPK1 has been mutated (Ripk1mRHIM/mRHIM). Deletion of the Zα2 domain in ZBP1 abolished influenza A virus–induced PANoptosis and NLRP3 inflammasome activation. Furthermore, deletion of the Zα2 domain of ZBP1 was sufficient to rescue Ripk1mRHIM/mRHIM mice from perinatal lethality caused by ZBP1-driven cell death and inflammation. Our findings identify the essential role of the Zα2 domain of ZBP1 in several physiological functions and establish a link between Z-RNA sensing via the Zα2 domain and promotion of influenza-induced PANoptosis and perinatal lethality.

scholarly journals Paclitaxel Enhances the Innate Immunity by Promoting NLRP3 Inflammasome Activation in Macrophages

2019 ◽  
Vol 10 ◽  
Author(s):  
Qiong-zhen Zeng ◽  
Fan Yang ◽  
Chen-guang Li ◽  
Li-hui Xu ◽  
Xian-hui He ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation

scholarly journals DDX3X Links NLRP11 to the Regulation of Type I Interferon Responses and NLRP3 Inflammasome Activation

2021 ◽  
Vol 12 ◽  
Author(s):  
Ioannis Kienes ◽  
Sarah Bauer ◽  
Clarissa Gottschild ◽  
Nora Mirza ◽  
Jens Pfannstiel ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Cytokine ◽  
Inflammasome Activation ◽  
Type I ◽  
Dependent Manner ◽  
Type I Ifn ◽  
Central Target ◽  
Nlrp3 Inflammasome Activation ◽  
Lrr Domain

Tight regulation of inflammatory cytokine and interferon (IFN) production in innate immunity is pivotal for optimal control of pathogens and avoidance of immunopathology. The human Nod-like receptor (NLR) NLRP11 has been shown to regulate type I IFN and pro-inflammatory cytokine responses. Here, we identified the ATP-dependent RNA helicase DDX3X as a novel binding partner of NLRP11, using co-immunoprecipitation and LC-MS/MS. DDX3X is known to enhance type I IFN responses and NLRP3 inflammasome activation. We demonstrate that NLRP11 can abolish IKKϵ-mediated phosphorylation of DDX3X, resulting in lower type I IFN induction upon viral infection. These effects were dependent on the LRR domain of NLRP11 that we mapped as the interaction domain for DDX3X. In addition, NLRP11 also suppressed NLRP3-mediated caspase-1 activation in an LRR domain-dependent manner, suggesting that NLRP11 might sequester DDX3X and prevent it from promoting NLRP3-induced inflammasome activation. Taken together, our data revealed DDX3X as a central target of NLRP11, which can mediate the effects of NLRP11 on type I IFN induction as well as NLRP3 inflammasome activation. This expands our knowledge of the molecular mechanisms underlying NLRP11 function in innate immunity and suggests that both NLRP11 and DDX3X might be promising targets for modulation of innate immune responses.

scholarly journals NLRP3 Inflammasome in Diabetic Cardiomyopathy and Exercise Intervention

2021 ◽  
Vol 22 (24) ◽  
pp. 13228
Author(s):  
Yi Sun ◽  
Shuzhe Ding
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Nlrp3 Inflammasome ◽  
Exercise Intervention ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Low Grade ◽  
Chronic Exercise ◽  
Nlrp3 Inflammasome Activation ◽  
Low Grade Inflammation

Diabetic cardiomyopathy (DCM), as a common complication of diabetes, is characterized by chronic low-grade inflammation. The NLRP3 inflammasome is a key sensor mediating innate immune and inflammatory responses. However, the mechanisms initiating and promoting NLRP3 inflammasome activation in DCM is largely unexplored. The aim of the present review is to describe the link between NLRP3 inflammasome and DCM, and to provide evidence highlighting the importance of exercise training in DCM intervention. Collectively, this evidence suggests that DCM is an inflammatory disease aggravated by NLRP3 inflammasome-mediated release of IL-1β and IL-18. In addition, chronic exercise intervention is an effective preventive and therapeutic method to alleviate DCM via modulating the NLRP3 inflammasome.

scholarly journals Mycotoxin Zearalenone Attenuates Innate Immune Responses and Suppresses NLRP3 Inflammasome Activation in LPS-Activated Macrophages

Toxins ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 593
Author(s):  
Po-Yen Lee ◽  
Ching-Chih Liu ◽  
Shu-Chi Wang ◽  
Kai-Yin Chen ◽  
Tzu-Chieh Lin ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Adverse Effects ◽  
Signaling Pathways ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Mammalian Species ◽  
Inflammasome Activation ◽  
Amino Terminal ◽  
Proinflammatory Mediators ◽  
Nlrp3 Inflammasome Activation

Zearalenone (ZEA) is a mycotoxin that has several adverse effects on most mammalian species. However, the effects of ZEA on macrophage-mediated innate immunity during infection have not been examined. In the present study, bacterial lipopolysaccharides (LPS) were used to induce the activation of macrophages and evaluate the effects of ZEA on the inflammatory responses and inflammation-associated signaling pathways. The experimental results indicated that ZEA suppressed LPS-activated inflammatory responses by macrophages including attenuating the production of proinflammatory mediators (nitric oxide (NO) and prostaglandin E2 (PGE2)), decreased the secretion of proinflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6), inhibited the activation of c-Jun amino-terminal kinase (JNK), p38 and nuclear factor-κB (NF-κB) signaling pathways, and repressed the nucleotide-binding and oligomerization domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. These results indicated that mycotoxin ZEA attenuates macrophage-mediated innate immunity upon LPS stimulation, suggesting that the intake of mycotoxin ZEA-contaminated food might result in decreasing innate immunity, which has a higher risk of adverse effects during infection.

scholarly journals IRF8 Regulates Gram-Negative Bacteria–Mediated NLRP3 Inflammasome Activation and Cell Death

2020 ◽  
Vol 204 (9) ◽  
pp. 2514-2522 ◽  
Author(s):  
Rajendra Karki ◽  
Ein Lee ◽  
Bhesh R. Sharma ◽  
Balaji Banoth ◽  
Thirumala-Devi Kanneganti
Keyword(s):  
Cell Death ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Nlrp3 Inflammasome Activation
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