Coronaviruses: Innate Immunity, Inflammasome Activation, Inflammatory Cell Death, and Cytokines.
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ABSTRACT:
SUBMITTER: Lee S
PROVIDER: S-EPMC7561287 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Inflammatory and apoptotic caspases are central players in inflammation and apoptosis, respectively. However, recent studies have revealed that these caspases have functions beyond their established roles. In addition to mediating cleavage of the inflammasome-associated cytokines interleukin-1β (IL-1β) and IL-18, inflammatory caspases modulate distinct forms of programmed cell death and coordinate cell-autonomous immunity and other fundamental cellular processes. Certain apoptotic caspases assemble structurally diverse and dynamic complexes that direct inflammasome and interferon responses to fine-tune inflammation. In this Review, we discuss the expanding and interconnected roles of caspases that highlight new aspects of this family of cysteine proteases in innate immunity.
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Project description:Microtubules play critical roles in regulating the activation of NLRP3 inflammasome and microtubule-destabilizing agents such as colchicine have been shown to suppress the activation of this inflammasome. However, it remains largely unknown whether paclitaxel, a microtubule-stabilizing agent being used in cancer therapy, has any influences on NLRP3 inflammasome activation. Here we showed that paclitaxel pre-treatment greatly enhanced ATP- or nigericin-induced NLRP3 inflammasome activation as indicated by increased release of cleaved caspase-1 and mature IL-1β, enhanced formation of ASC speck, and increased gasdermin D cleavage and pyroptosis. Paclitaxel time- and dose-dependently induced α-tubulin acetylation in LPS-primed murine and human macrophages and further increased ATP- or nigericin-induced α-tubulin acetylation. Such increased α-tubulin acetylation was significantly suppressed either by resveratrol or NAD+ (coenzyme required for deacetylase activity of SIRT2), or by genetic knockdown of MEC-17 (gene encoding α-tubulin acetyltransferase 1). Concurrently, the paclitaxel-mediated enhancement of NLRP3 inflammasome activation was significantly suppressed by resveratrol, NAD+, or MEC-17 knockdown, indicating the involvement of paclitaxel-induced α-tubulin acetylation in the augmentation of NLRP3 inflammasome activation. Similar to paclitaxel, epothilone B that is another microtubule-stabilizing agent also induced α-tubulin acetylation and increased NLRP3 inflammasome activation in macrophages in response to ATP treatment. Consistent with the in vitro results, intraperitoneal administration of paclitaxel significantly increased serum IL-1β levels, reduced bacterial burden, dampened infiltration of inflammatory cells in the liver, and improved animal survival in a mouse model of bacterial infection. Collectively, our data indicate that paclitaxel potentiated NLRP3 inflammasome activation by inducing α-tubulin acetylation and thereby conferred enhanced antibacterial innate responses, suggesting its potential application against pathogenic infections beyond its use as a chemotherapeutic agent.
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Project description:ObjectiveTo determine the protective effect of Shengmai injection (SMI) on myocardial injury in diabetic rats and its mechanism based on NLRP3/Caspase1 signaling pathway.Materials and methodsRat H9c2 cardiomyocytes were cultured in vitro, and the cell survival rate of different concentrations of palmitate acid (PA) and different concentrations of SMI were detected by CCK-8. The myocardial injury cell model was induced with PA, treated with SMI, and combined with NLRP3 specific inhibitor (MCC950) to interfere with the high-fat-induced rat H9c2 myocardial cell injury model. The cell changes were observed by Hoechst/PI staining and the expression levels of MDA, SOD, and ROS in each group were detected. The protein and gene changes of the NLRP3/Caspase-1 signaling pathway were detected by Western blot and RT-qPCR, respectively.Results200 μmol/L of PA were selected to induce the myocardial injury cell model and 25 μL/mL of SMI was selected for intervention concentration. SMI could significantly reduce MDA expression, increase SOD level, and decrease ROS production. SMI could decrease the gene expression levels of NLRP3, ASC, Caspase-1, and GSDMD, and the protein expressions of NLRP3, ASC, Cleaved Caspase-1, GSDMD, and GSDMD-N.ConclusionSMI can inhibit the high-fat-induced activation of the NLRP3/Caspase-1 signaling pathway, intervene in cardiomyocyte pyroptosis, and prevent diabetic cardiomyopathy.
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Project description:Background Bergenin, an active constituent of plants of the genus Bergenia, has been reported to have antidiabetic properties. This study investigated whether bergenin is beneficial for treating type 2 diabetes mellitus (T2DM) via regulating NOD-like receptor family-pyrin domain containing 3 (NLRP3) inflammasome. Methods Two pancreatic β-cell lines, INS-1 and MIN6, were treated with 1, 3, or 10 µM bergenin in the absence or presence of palmitic acid (PA). Cell Counting Kit (CCK)-8, flow cytometry, quantitative reverse transcription-polymerase chain reaction, western blotting, and immunofluorescent staining were performed. Results Bergenin with concentrations of 1, 3, and 10 µM had no cytotoxicity in INS-1 and MIN6 cells. However, bergenin dose-dependently relieved PA-induced pancreatic β‑cell loss and apoptosis. Bergenin dose-dependently inhibited NLRP3 inflammasome-related inflammation, as observed by the downregulation of NLRP3, apoptosis associated speck like protein (ASC), cleaved caspase-1, and gasdermin-D (GSDMD)-N, as well as the decreased release of cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-1β, and IL-18. The NOD-like receptor signaling pathway was predicted to be a downstream signaling pathway regulated by bergenin. Autodock Vina software docked bergenin with NLRP3. The binding energy of interaction was −5.101 kcal/mol and the root-mean-square deviation (RMSD) score was 1.5901A. Treating pancreatic β‑cells with bergenin accelerated the degeneration of NLRP3. Furthermore, restoration of NLRP3 expression using plasmid transfection reversed the protective effects of bergenin on pancreatic β-cells. Conclusions Our data suggests that bergenin is a potential agent for treating T2DM through preventing NLRP3 inflammasome-related inflammation in pancreatic β-cells.
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Project description:BACKGROUND:In models of COPD, environmental stressors induce innate immune responses, inflammasome activation and inflammation. However, the interaction between these responses and their role in driving pulmonary inflammation in stable COPD is unknown. OBJECTIVES:To investigate the activation of innate immunity and inflammasome pathways in the bronchial mucosa and bronchoalveolar lavage (BAL) of patients with stable COPD of different severity and control healthy smokers and non-smokers. METHODS:Innate immune mediators (interleukin (IL)-6, IL-7, IL-10, IL-27, IL-37, thymic stromal lymphopoietin (TSLP), interferon ? and their receptors, STAT1 and pSTAT1) and inflammasome components (NLRP3, NALP7, caspase 1, IL-1? and its receptors, IL-18, IL-33, ST2) were measured in the bronchial mucosa using immunohistochemistry. IL-6, soluble IL-6R, sgp130, IL-7, IL-27, HMGB1, IL-33, IL-37 and soluble ST2 were measured in BAL using ELISA. RESULTS:In bronchial biopsies IL-27+ and pSTAT1+ cells are increased in patients with severe COPD compared with control healthy smokers. IL-7+ cells are increased in patients with COPD and control smokers compared with control non-smokers. In severe stable COPD IL-7R+, IL-27R+ and TSLPR+ cells are increased in comparison with both control groups. The NALP3 inflammasome is not activated in patients with stable COPD compared with control subjects. The inflammasome inhibitory molecules NALP7 and IL-37 are increased in patients with COPD compared with control smokers. IL-6 levels are increased in BAL from patients with stable COPD compared with control smokers with normal lung function whereas IL-1? and IL-18 were similar across all groups. CONCLUSIONS:Increased expression of IL-27, IL-37 and NALP7 in the bronchial mucosa may be involved in progression of stable COPD.
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Project description:Caspases regulate cell death, immune responses, and homeostasis. Caspase-6 is categorized as an executioner caspase but shows key differences from the other executioners. Overall, little is known about the functions of caspase-6 in biological processes apart from apoptosis. Here, we show that caspase-6 mediates innate immunity and inflammasome activation. Furthermore, we demonstrate that caspase-6 promotes the activation of programmed cell death pathways including pyroptosis, apoptosis, and necroptosis (PANoptosis) and plays an essential role in host defense against influenza A virus (IAV) infection. In addition, caspase-6 promoted the differentiation of alternatively activated macrophages (AAMs). Caspase-6 facilitated the RIP homotypic interaction motif (RHIM)-dependent binding of RIPK3 to ZBP1 via its interaction with RIPK3. Altogether, our findings reveal a vital role for caspase-6 in facilitating ZBP1-mediated inflammasome activation, cell death, and host defense during IAV infection, opening additional avenues for treatment of infectious and autoinflammatory diseases and cancer.
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