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-1? (IL-1?) 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-1?, enhanced formation of ASC speck, and increased gasdermin D cleavage and pyroptosis. Paclitaxel time- and dose-dependently induced ?-tubulin acetylation in LPS-primed murine and human macrophages and further increased ATP- or nigericin-induced ?-tubulin acetylation. Such increased ?-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 ?-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 ?-tubulin acetylation in the augmentation of NLRP3 inflammasome activation. Similar to paclitaxel, epothilone B that is another microtubule-stabilizing agent also induced ?-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-1? 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 ?-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: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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