scholarly journals Persistent oxidative stress and inflammasome activation in CD14highCD16- monocytes from COVID-19 patients

2021 ◽  
Author(s):  
Silvia Lucena Lage ◽  
Eduardo Pinheiro Amaral ◽  
kerry L. Hilligan ◽  
Elizabeth Laidlaw ◽  
Adam Rupert ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Stress Responses ◽  
Inflammasome Activation ◽  
Strongly Correlated ◽  
Long Term Outcomes ◽  
Caspase 1 ◽  
Mitochondrial Superoxide

The poor outcome of the coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, is associated with systemic hyperinflammatory response and immunopathology. Although inflammasome and oxidative stress have independently been implicated in COVID-19, it is poorly understood whether these two pathways cooperatively contribute to disease severity. Herein, we found an enrichment of CD14highCD16- monocytes displaying inflammasome activation evidenced by caspase-1/ASC-speck formation in severe COVID-19 patients when compared to mild ones and healthy controls, respectively. Those cells also showed aberrant levels of mitochondrial superoxide (MitoSOX) and lipid peroxidation, both hallmarks of the oxidative stress response, which strongly correlated with caspase-1 activity. In addition, we found that NLRP3 inflammasome-derived IL-1β secretion by SARS-CoV-2-exposed monocytes in vitro was partially dependent on lipid peroxidation. Importantly, altered inflammasome and stress responses persisted after short-term patient recovery. Collectively, our findings suggest oxidative stress/NLRP3 signaling pathway as a potential target for host-directed therapy to mitigate early COVID-19 hyperinflammation as well as its long-term outcomes.

scholarly journals Persistent Oxidative Stress and Inflammasome Activation in CD14highCD16− Monocytes From COVID-19 Patients

2022 ◽  
Vol 12 ◽  
Author(s):  
Silvia Lucena Lage ◽  
Eduardo Pinheiro Amaral ◽  
Kerry L. Hilligan ◽  
Elizabeth Laidlaw ◽  
Adam Rupert ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Stress Responses ◽  
Inflammasome Activation ◽  
Strongly Correlated ◽  
Long Term Outcomes ◽  
Caspase 1 ◽  
Mitochondrial Superoxide

The poor outcome of the coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, is associated with systemic hyperinflammatory response and immunopathology. Although inflammasome and oxidative stress have independently been implicated in COVID-19, it is poorly understood whether these two pathways cooperatively contribute to disease severity. Herein, we found an enrichment of CD14highCD16− monocytes displaying inflammasome activation evidenced by caspase-1/ASC-speck formation in severe COVID-19 patients when compared to mild ones and healthy controls, respectively. Those cells also showed aberrant levels of mitochondrial superoxide and lipid peroxidation, both hallmarks of the oxidative stress response, which strongly correlated with caspase-1 activity. In addition, we found that NLRP3 inflammasome-derived IL-1β secretion by SARS-CoV-2-exposed monocytes in vitro was partially dependent on lipid peroxidation. Importantly, altered inflammasome and stress responses persisted after short-term patient recovery. Collectively, our findings suggest oxidative stress/NLRP3 signaling pathway as a potential target for host-directed therapy to mitigate early COVID-19 hyperinflammation and also its long-term outcomes.

scholarly journals Fn14 Exacerbates Acute Lung Injury by Activating the NLRP3 Inflammasome in Mice

2021 ◽  
Author(s):  
Xin-Xin Guan ◽  
Hui-Hui Yang ◽  
Wen-Jing Zhong ◽  
Jia-Xi Duan ◽  
Chen-Yu Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Lung Injury ◽  
Survival Rate ◽  
Lung Injury ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Inflammatory Factor ◽  
Caspase 1 ◽  
Primary Mouse

Abstract Background: Uncontrolled inflammation is an important factor in the occurrence and development of acute lung injury (ALI). Fibroblast growth factor-inducible 14 (Fn14) takes part in the pathological process of a variety of inflammatory diseases. However, the role of Fn14 in ALI has not yet been elucidated. Methods: C57BL/6J mice were used in this study. ALI model was induced by intratracheal injection of lipopolysaccharide (LPS, 5 mg/kg). The effects of Fn14 receptor blocker ATA (20 mg/kg) on lung injury, inflammatory cell infiltration, inflammatory factor secretion, and oxidative stress in mice were observed. The activation of NLRP3 inflammasome was detected by qPCR, Western blot, and ELISA. Prophylactic or therapeutic ATA was administered to observe its effect on the survival rate of ALI mice. In vitro, primary mouse peritoneal macrophages were used to activate the NLRP3 inflammasome by LPS or LPS+ATP. Fn14 was activated by recombinant TWEAK, or knockdown by lentivirus, and the effects on NLRP3 inflammasome activation was detected.Results: We found that ATA significantly downregulated the expression of Fn14 in the lungs and improved the survival rate of mice receiving a lethal dose of LPS. ATA also attenuated lung tissue damage by decreasing the infiltration of macrophages and neutrophils, reducing inflammation, and suppressing oxidative stress. Interestingly, we found that ATA strongly inhibited the activation of NLRP3 inflammasome in the lungs of ALI mice. Furthermore, in vitro, exogenous TWEAK, a natural ligand of Fn14, enhanced the levels of NLRP3 and Caspase-1 p10 and the maturation and secretion of IL-1β in the primary murine macrophages, eventually leading to the activation of NLRP3 inflammasome. In addition, the expression of Fn14, NLRP3, and Caspase-1 p10 and the production of IL-1β were effectively blocked by Fn14 shRNA in macrophages. In mechanism, the activation of Fn14 promoted the production of reactive oxygen species in activated macrophages. Conclusion：Our study first reports that the activation of Fn14 aggravates ALI by amplifying the activation of NLRP3 inflammasome. Therefore, blocking Fn14 may be a potential way to treat ALI.

scholarly journals Crosstalk between Long-Term Sublethal Oxidative Stress and Detrimental Inflammation as Potential Drivers for Age-Related Retinal Degeneration

Antioxidants ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 25
Author(s):  
Lara Macchioni ◽  
Davide Chiasserini ◽  
Letizia Mezzasoma ◽  
Magdalena Davidescu ◽  
Pier Luigi Orvietani ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Age Related Macular Degeneration ◽  
Inflammasome Activation ◽  
Related Factor ◽  
Nuclear Factor ◽  
Rpe Cells ◽  
Age Related ◽  
Oxidative Insult

Age-related retinal degenerations, including age-related macular degeneration (AMD), are caused by the loss of retinal pigmented epithelial (RPE) cells and photoreceptors. The pathogenesis of AMD, deeply linked to the aging process, also involves oxidative stress and inflammatory responses. However, the molecular mechanisms contributing to the shift from healthy aging to AMD are still poorly understood. Since RPE cells in the retina are chronically exposed to a pro-oxidant microenvironment throughout life, we simulated in vivo conditions by growing ARPE-19 cells in the presence of 10 μM H2O2 for several passages. This long-term oxidative insult induced senescence in ARPE-19 cells without affecting cell proliferation. Global proteomic analysis revealed a dysregulated expression in proteins involved in antioxidant response, mitochondrial homeostasis, and extracellular matrix organization. The analyses of mitochondrial functionality showed increased mitochondrial biogenesis and ATP generation and improved response to oxidative stress. The latter, however, was linked to nuclear factor-κB (NF-κB) rather than nuclear factor erythroid 2–related factor 2 (Nrf2) activation. NF-κB hyperactivation also resulted in increased pro-inflammatory cytokines expression and inflammasome activation. Moreover, in response to additional pro-inflammatory insults, senescent ARPE-19 cells underwent an exaggerated inflammatory reaction. Our results indicate senescence as an important link between chronic oxidative insult and detrimental chronic inflammation, with possible future repercussions for therapeutic interventions.

scholarly journals Rabeprazole inhibits inflammatory reaction by inhibition of cell pyroptosis in gastric epithelial cells

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Jing Xie ◽  
Long Fan ◽  
Liya Xiong ◽  
Peiyu Chen ◽  
Hongli Wang ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Clinical Sample ◽  
Critical Role ◽  
Enzyme Linked Immunosorbent Assay ◽  
Inflammasome Activation ◽  
Peptic Ulcers ◽  
Gastric Epithelial Cells ◽  
Caspase 1 ◽  
H Pylori

Abstract Background Helicobacter pylori (H. pylori) is a common pathogen in development of peptic ulcers with pyroptosis. Rabeprazole, a critical component of standard triple therapy, has been widely used as the first-line regimen for H. pylori infectious treatment. The aim of this study to explore the function of Rabeprazole on cell pyroptosis in vitro. Methods The clinical sample from patients diagnosed with or without H. pylori-infection were collected to analyze by Immunohistochemistry (IHC). Real-time quantitative PCR (qPCR), western blot (WB) and enzyme linked immunosorbent assay (Elisa) were performed to analyze the effect of Rabeprazole on cell pyroptosis, including LDH, IL-1β and IL-18. Results In this study, we showed that Rabeprazole regulated a phenomenon of cell pyroptosis as confirmed by lactate dehydrogenase (LDH) assay. Further results showed that Rabeprazole inhibited cell pyroptosis in gastric epithelial cells by alleviating GSDMD-executed pyroptosis, leading to decrease IL-1β and IL-18 mature and secretion, which is attributed to NLRP3 inflammasome activation inhibition. Further analysis showed that ASC, NLRP3 and Caspase-1, was significantly repressed in response to Rabeprazole stimulation, resulting in decreasing cleaved-caspase-1 expression. Most important, NLRP3 and GSDMD is significantly increased in gastric tissue of patients with H. pylori infection. Conclusion These findings revealed a critical role of Rabeprazole in cell pyroptosis in patients with H. pylori infection, suggesting that targeting cell pyroptosis is an alternative strategy in improving H. pylori treatment.

scholarly journals Toxicological Implications of Platinum Nanoparticle Exposure: Stimulation of Intracellular Stress, Inflammatory Response, and Akt Signaling In Vitro

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Claudia J. Labrador-Rached ◽  
Rebecca T. Browning ◽  
Laura K. Braydich-Stolle ◽  
Kristen K. Comfort
Keyword(s):  
Stress Responses ◽  
Health And Safety ◽  
Cellular Responses ◽  
Cellular Interactions ◽  
Platinum Nanoparticle ◽  
Liver Model ◽  
Dependent Signal ◽  
Cell Functionality

Due to their distinctive physicochemical properties, platinum nanoparticles (PtNPs) have emerged as a material of interest for a number of biomedical therapeutics. However, in some instances NP exposure has been correlated to health and safety concerns, including cytotoxicity, activation of cellular stress, and modification to normal cell functionality. As PtNPs have induced differential cellular responses in vitro, the goal of this study was to further characterize the behavior and toxicological potential of PtNPs within a HepG2 liver model. This study identified that a high PtNP dosage induced HepG2 cytotoxicity. However, lower, subtoxic PtNP concentrations were able to elicit multiple stress responses, secretion of proinflammatory cytokines, and modulation of insulin-like growth factor-1 dependent signal transduction. Taken together, this work suggests that PtNPs would not be overtly toxic for acute exposures, but sustained cellular interactions might produce long term health consequences.

scholarly journals The Essential Oil of Artemisia argyi H.Lév. and Vaniot Attenuates NLRP3 Inflammasome Activation in THP-1 Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Pengxiao Chen ◽  
Qi Bai ◽  
Yanting Wu ◽  
Qiongzhen Zeng ◽  
Xiaowei Song ◽  
...  
Keyword(s):  
Essential Oil ◽  
Nlrp3 Inflammasome ◽  
Therapeutic Potential ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Artemisia Argyi ◽  
Nlrp3 Inflammasome Activation ◽  
Long Time

Artemisia argyi H. Lév. and Vaniot is a traditional medical herb that has been used for a long time in China and other Asian counties. Essential oil is the main active fraction of Artemisia argyi H. Lév. and Vaniot, and its anti-inflammatory potential has been observed in vitro and in vivo. Here, we found that the essential oil of Artemisia argyi H. Lév. and Vaniot (EOAA) inhibited monosodium urate (MSU)- and nigericin-induced NLRP3 inflammasome activation. EOAA suppressed caspase-1 and IL-1β processing and pyroptosis. NF-κB p65 phosphorylation and translocation were also inhibited. In addition, EOAA suppressed nigericin-induced NLRP3 inflammasome activation without blocking ASC oligomerization, suggesting that it may inhibit NLRP3 inflammasome activation by preventing caspase-1 processing. Our study thus indicates that EOAA inhibits NLRP3 inflammasome activation and has therapeutic potential against NLRP3-driven diseases.

scholarly journals Activation of GSDME compensates for GSDMD deficiency in a mouse model of NLRP3 inflammasomopathy

2021 ◽  
Author(s):  
Chun Wang ◽  
Tong Yang ◽  
Jianqiu Xiao ◽  
Canxin Xu ◽  
Yael Alippe ◽  
...  
Keyword(s):  
Inflammatory Disease ◽  
Early Death ◽  
Organ Damage ◽  
Caspase 8 ◽  
Inflammasome Activation ◽  
Inflammatory Pathway ◽  
Disease Symptoms ◽  
Caspase 1 ◽  
Inflammatory Stimuli

AbstractThe D301N NLRP3 mutation in mice (D303N in humans) causes severe multi-organ damage and early death driven by the constitutively activated NLRP3 (NLRP3ca) inflammasome. Triggered inflammasomes activate caspase-1 to process IL-1 family cytokines and gasdermin D (GSDMD), generating N-terminal fragments, which oligomerize within the plasma membrane to form pores, which cause inflammatory cell death (pyroptosis) and through which IL-1β and IL-18 are secreted. GSDMD activation is central to disease symptoms since spontaneous inflammation in Nlrp3ca;Gsdmd-/- mice is negligible. Unexpectedly, when Nlrp3ca;Gsdmd-/- mice were challenged with LPS or TNF-α, they secreted high amounts of IL-1β and IL-18, suggesting an alternative GSDMD-independent inflammatory pathway. Here we show that GSDMD deficient macrophages subjected to inflammatory stimuli activate caspase-8, -3 and GSDME-dependent cytokine release and pyroptosis. Caspase-8, -3 and GSDME also activated pyroptosis when NLRP3 was stimulated in caspase-1 deficient macrophages. Thus, a salvage caspase-8, -3-GSDME inflammatory pathway is activated following NLRP3 activation when the canonical NLRP3-caspase-1-GSDMD is blocked. Surprisingly, the active metabolite of the GSDMD-inhibitor disulfiram, inhibited not only GSDMD but also GSDME-mediated inflammation in vitro and suppressed severe inflammatory disease symptoms in Nlrp3ca mice, a model for severe neonatal multisystem inflammatory disease. Although disulfiram did not directly inhibit GSDME, it suppressed inflammasome activation in GSDMD-deficient cells. Thus, the combination of inflammatory signals and NLRP3ca overwhelmed the protection provided by GSDMD deficiency, rewiring signaling cascades through caspase-8, -3 and GSDME to propagate inflammation. This functional redundancy suggests that concomitant inhibition of GSDMD and GSDME may be necessary to suppress disease in inflammasomopathy patients.

scholarly journals Callicarpa Nudiflora Extract Exerts Anti-Inflammatory Effect on H. Pylori-Associated Gastritis Through Repression of ROS/NLRP3/Caspase-1/IL-1β Signaling Axis

2021 ◽  
Author(s):  
Lili Li ◽  
Xiaohui Zhu ◽  
Xingxing Chai ◽  
Xiaoyu Chen ◽  
Xiaohua Su ◽  
...  
Keyword(s):  
Cell Damage ◽  
Underlying Mechanism ◽  
Inflammatory Factors ◽  
Inflammasome Activation ◽  
Ros Production ◽  
Gastric Diseases ◽  
Caspase 1 ◽  
Signaling Axis ◽  
H Pylori

Abstract Helicobacter pylori ( H. pylori ) is a major pathogenic factor for the development of gastric diseases including chronic gastritis and gastric cancer. Callicarpa nudiflora (CN), an air-dried leaves extract of Callicarpa nudiflora Hook. & Arn., has been found to exhibit a broad-spectrum antibacterial effect. In our study, we extracted the active ingredient from air-dried leaves of Callicarpa nudiflora, detected the effect of CN against H. pylori -infected GES-1 cells in vitro , and elucidated the underlying mechanism. GES-1 cells were cocultured with HPSS1 at MOI = 100:1 and treated with different concentrations of CN. Results indicated that CN not only significantly decreased cellular lactate dehydrogenase leakage, but also markedly attenuated H. pylori -induced cell apoptosis and ROS production in GSE-1 cells, therefore protecting gastric epithelial cells against injuries caused by H. pylori . CN also inhibited the secretions of inflammatory factors, such as tumor necrosis factor-α (TNF-α), IL-1β, IL-6 and IL-8. Furthermore, CN remarkably decreased the expression levels of NLRP3, PYCARD, active Caspase-1. In conclusion, CN exhibited highly efficient protective effect against H. pylori -induced gastritis and cell damage; Mechanismly, CN suppressed H. pylori -triggered inflammatory response and pyroptosis through depressing ROS production and NLRP3 inflammasome activation via ROS/NLRP3/IL-1β signaling axis.

scholarly journals Macrophage Uptake of Necrotic Cell DNA Activates the AIM2 Inflammasome to Regulate a Proinflammatory Phenotype in CKD

2018 ◽  
Vol 29 (4) ◽  
pp. 1165-1181 ◽  
Author(s):  
Takanori Komada ◽  
Hyunjae Chung ◽  
Arthur Lau ◽  
Jaye M. Platnich ◽  
Paul L. Beck ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Inflammasome Activation ◽  
Dna Uptake ◽  
Chronic Injury ◽  
Caspase 1 ◽  
Double Stranded Dna ◽  
Molecular Pattern ◽  
Macrophage Uptake

Nonmicrobial inflammation contributes to CKD progression and fibrosis. Absent in melanoma 2 (AIM2) is an inflammasome-forming receptor for double-stranded DNA. AIM2 is expressed in the kidney and activated mainly by macrophages. We investigated the potential pathogenic role of the AIM2 inflammasome in kidney disease. In kidneys from patients with diabetic or nondiabetic CKD, immunofluorescence showed AIM2 expression in glomeruli, tubules, and infiltrating leukocytes. In a mouse model of unilateral ureteral obstruction (UUO), Aim2 deficiency attenuated the renal injury, fibrosis, and inflammation observed in wild-type (WT) littermates. In bone marrow chimera studies, UUO induced substantially more tubular injury and IL-1β cleavage in Aim2−/− or WT mice that received WT bone marrow than in WT mice that received Aim2−/− bone marrow. Intravital microscopy of the kidney in LysM(gfp/gfp) mice 5–6 days after UUO demonstrated the significant recruitment of GFP+ proinflammatory macrophages that crawled along injured tubules, engulfed DNA from necrotic cells, and expressed active caspase-1. DNA uptake occurred in large vacuolar structures within recruited macrophages but not resident CX3CR1+ renal phagocytes. In vitro, macrophages that engulfed necrotic debris showed AIM2-dependent activation of caspase-1 and IL-1β, as well as the formation of AIM2+ ASC specks. ASC specks are a hallmark of inflammasome activation. Cotreatment with DNaseI attenuated the increase in IL-1β levels, confirming that DNA was the principal damage-associated molecular pattern in this process. Therefore, the activation of the AIM2 inflammasome by DNA from necrotic cells drives a proinflammatory phenotype that contributes to chronic injury in the kidney.

Over IFI16 expression increased inflammation in Hepatitis B Virus-Associated Glomerulonephritis by Regulating Caspase-1 and IL-1 ß

2020 ◽  
Author(s):  
zhaoqing zeng ◽  
yuyang li ◽  
jinhong yu ◽  
jing liu ◽  
shijun chen ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Cell Line ◽  
Renal Damage ◽  
Hbv Infection ◽  
Inflammatory Factors ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
B Virus

Abstract Aims & background: IFI16 plays an important role in innate immunity against invasive microbial infection by sensing double-stranded DNA viruses due to caspase-1-dependent inflammasome activation and subsequent maturation and secretion of IL-1β. However, the role of IFI16 in regulating the immune response to viruses in vivo and in vitro, especially in sensing hepatitis B virus (HBV), has not been examined. We hypothesized that the expression of IFI16 increases corresponding to HBV-mediated inflammation in patients with hepatitis B virus associated glomerulonephritis (HBV-GN), a condition which activates inflammatory mechanisms and causes renal damage. To test this hypothesis, we therefore analyzed the expression of IFI16 and inflammatory factors in HBV-GN tissues and cell lines relative to the inflammatory response to HBV infection. Methods: A total 75 patients with chronic nephritis(CN) including 50 with HBV-GN and 25 with chronic glomerulonephritis (CCN) involved in this study. Each CN patient received renal biopsy, and immunohistochemistry(IHC) was used to detect the expression of IFI16 and inflammatory factors Caspase-1 and IL-1β in the biopsy specimens. Following IFI16 was transfected in HBV-infected and HBV-uninfected human glomerular mesangial (HGM) cell line and HEK-293T cell line, expression of Caspase-1 and IL-1β were detected by Western blot and qRT- PCR. Results: IFI16 expression in HBV-GN biopsies (80.0%) was significantly higher than in CGN (24.0%) and positively correlated with caspase-1 and IL-1𝛽 expression in HBV-GN. In vitro, over expression IFI16 increased caspase-1 and IL-1𝛽 expression in HBV -infected HGM and HEK-293T. Conclusions: The elevation of IFI16 during HBV infection or replication may contribute to renal damage due to inflammation, thus providing a putative therapeutic target and a new avenue for researching the pathogenesis of HBV-GN.

Sign in / Sign up

Export Citation Format

Share Document