Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 209
Filter
1.
Cell ; 186(11): 2288-2312, 2023 05 25.
Article in English | MEDLINE | ID: covidwho-20232943

ABSTRACT

Inflammasomes are critical sentinels of the innate immune system that respond to threats to the host through recognition of distinct molecules, known as pathogen- or damage-associated molecular patterns (PAMPs/DAMPs), or disruptions of cellular homeostasis, referred to as homeostasis-altering molecular processes (HAMPs) or effector-triggered immunity (ETI). Several distinct proteins nucleate inflammasomes, including NLRP1, CARD8, NLRP3, NLRP6, NLRC4/NAIP, AIM2, pyrin, and caspases-4/-5/-11. This diverse array of sensors strengthens the inflammasome response through redundancy and plasticity. Here, we present an overview of these pathways, outlining the mechanisms of inflammasome formation, subcellular regulation, and pyroptosis, and discuss the wide-reaching effects of inflammasomes in human disease.


Subject(s)
Inflammasomes , Humans , Apoptosis Regulatory Proteins/metabolism , CARD Signaling Adaptor Proteins/metabolism , Caspases/metabolism , Cell Death , Inflammasomes/metabolism , Neoplasm Proteins/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pyroptosis
2.
PLoS One ; 18(6): e0286211, 2023.
Article in English | MEDLINE | ID: covidwho-20232587

ABSTRACT

BACKGROUND AND PURPOSE: Cytokine storm invoked during acute and chronic lung injury promotes alveolar damage and remodeling. The current study shows that degraded elastin-targeted nanoparticles releasing doxycycline (Doxy NPs) are potent in mitigating cytokines storm, migration of immune cells in the lungs, and inhibiting inflammasome pathways in the LPS mouse model. EXPERIMENTAL APPROACH: Cytokine storm and lung injury were induced using LPS and elastase in C57BL/6 mice (rodent model for emphysema). The mice were then treated with I.V. Doxy NPs, blank NPs, or Doxy a day before LPS administration. Cytokine levels, immune cell population, and MMP activity were analyzed in broncheo-alveolar lavage fluid (BALF) 4 hours after LPS administration. Additionally, gene expression of IL-6, IL-1beta, MCP-1, NLRP3, Caspase 1 and MMPs were investigated in alveolar cells on day 3 after LPS administration. KEY RESULTS: Doxycycline NPs but not Doxycycline significantly decreased IL-6, TNF-α, IL-23 and were significantly more effective in decreasing the percentage of immune cells in the BALF. This is the first in-vivo study to demonstrate that Doxycycline can effectively inhibit inflammasome pathways in the lungs. CONCLUSION AND IMPLICATIONS: IV administration of elastin antibody conjugated Doxycycline-loaded albumin NPs can effectively modulate the local immune environment in the lungs, which is not achieved by IV Doxycycline even at 100-fold higher dose. This novel method of drug delivery can effectively lead to the repurposing of traditional Doxycycline as a potential adjunct treatment for managing the cytokine storm in the lungs in COPD and viral infections.


Subject(s)
Lung Injury , Nanoparticles , Pneumonia , Mice , Animals , Lipopolysaccharides/pharmacology , Inflammasomes/metabolism , Interleukin-6/metabolism , Cytokine Release Syndrome , Elastin/metabolism , Mice, Inbred C57BL , Pneumonia/metabolism , Lung/metabolism , Cytokines/metabolism , Lung Injury/metabolism
3.
J Virol ; 97(6): e0058923, 2023 Jun 29.
Article in English | MEDLINE | ID: covidwho-20236657

ABSTRACT

The inflammasome pathway is a critical early response mechanism of the host that detects pathogens, initiates the production of inflammatory cytokines, and recruits effector cells to the infection site. Nonetheless, the mechanism of inflammasome activation in coronavirus infection and its biological functions in host defense remain unclear. Transmissible gastroenteritis virus (TGEV), a member of the genus Alphacoronavirus, is a significant pathogen that mainly infects piglets and causes intestinal inflammation and inflammatory cell infiltration. Here, we investigated the mechanism of inflammasome activation in intestinal epithelial cells (IECs) infected with TGEV. We observed a substantial increase in interleukin 1ß (IL-1ß) and IL-18 levels in both IECs and TGEV-infected porcine intestinal tissues. Furthermore, TGEV infection resulted in increased activation of caspase-1 and the NLRP1 (NOD-like receptor [NLR]-containing pyrin domain [PYD]) inflammasome. Our findings revealed that TGEV infection impeded the interaction between porcine NLRP1 (pNLRP1) and porcine dipeptidyl peptidases 9 (pDPP9), yet it did not reduce the expression of pDPP9. Importantly, the ZU5 domain, not the function-to-find domain (FIIND) reported in human NLRP1, was identified as the minimal domain of pNLRP1 for pDPP9 binding. In addition, the robust type I IFN expression induced by TGEV infection also upregulated pNLRP1 expression and pNLRP1 itself acts as an interferon-stimulated gene to counteract TGEV infection. Our data demonstrate that pNLRP1 has antiviral capabilities against coronavirus infection, which highlights its potential as a novel therapeutic target for coronavirus antiviral therapy. IMPORTANCE Coronavirus primarily targets the epithelial cells of the respiratory and gastrointestinal tracts, leading to damage in both humans and animals. NLRP1 is a direct sensor for RNA virus infection which is highly expressed in epithelial barrier tissues. However, until recently, the precise molecular mechanisms underlying its activation in coronavirus infection and subsequent downstream events remained unclear. In this study, we demonstrate that the alphacoronavirus TGEV induces the production of IL-1ß and IL-18 and upregulates the expression of pNLRP1. Furthermore, we found that pNLRP1 can serve as an interferon-stimulated gene (ISG) to inhibit the infection of enterovirus TGEV. Our research highlights the crucial role of NLRP1 as a regulator of innate immunity in TGEV infection and shows that it may serve as a potential therapeutic target for the treatment of coronavirus infection.


Subject(s)
Gastroenteritis, Transmissible, of Swine , Inflammasomes , NLR Proteins , Transmissible gastroenteritis virus , Animals , Inflammasomes/immunology , Interferon Type I , Interleukin-18 , NLR Proteins/immunology , Swine , Gastroenteritis, Transmissible, of Swine/immunology , Gastroenteritis, Transmissible, of Swine/transmission
4.
Int J Mol Sci ; 24(11)2023 May 25.
Article in English | MEDLINE | ID: covidwho-20245103

ABSTRACT

Inflammation represents the innate immune response of the body tissues against invading microbes and cellular danger signals, and, in this way, it is beneficial [...].


Subject(s)
Inflammasomes , Inflammation , Humans , Immunity, Innate , Signal Transduction
5.
Front Immunol ; 14: 1185233, 2023.
Article in English | MEDLINE | ID: covidwho-20244458

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a contagious respiratory virus that is the cause of the coronavirus disease 2019 (COVID-19) pandemic which has posed a serious threat to public health. COVID-19 is characterized by a wide spectrum of clinical manifestations, ranging from asymptomatic infection to mild cold-like symptoms, severe pneumonia or even death. Inflammasomes are supramolecular signaling platforms that assemble in response to danger or microbial signals. Upon activation, inflammasomes mediate innate immune defense by favoring the release of proinflammatory cytokines and triggering pyroptotic cell death. Nevertheless, abnormalities in inflammasome functioning can result in a variety of human diseases such as autoimmune disorders and cancer. A growing body of evidence has showed that SARS-CoV-2 infection can induce inflammasome assembly. Dysregulated inflammasome activation and consequent cytokine burst have been associated with COVID-19 severity, alluding to the implication of inflammasomes in COVID-19 pathophysiology. Accordingly, an improved understanding of inflammasome-mediated inflammatory cascades in COVID-19 is essential to uncover the immunological mechanisms of COVID-19 pathology and identify effective therapeutic approaches for this devastating disease. In this review, we summarize the most recent findings on the interplay between SARS-CoV-2 and inflammasomes and the contribution of activated inflammasomes to COVID-19 progression. We dissect the mechanisms involving the inflammasome machinery in COVID-19 immunopathogenesis. In addition, we provide an overview of inflammasome-targeted therapies or antagonists that have potential clinical utility in COVID-19 treatment.


Subject(s)
COVID-19 , Humans , Inflammasomes/metabolism , SARS-CoV-2/physiology , COVID-19 Drug Treatment , Cytokines
6.
PLoS Biol ; 21(6): e3002144, 2023 Jun.
Article in English | MEDLINE | ID: covidwho-20243985

ABSTRACT

Hosts have evolved diverse strategies to respond to microbial infections, including the detection of pathogen-encoded proteases by inflammasome-forming sensors such as NLRP1 and CARD8. Here, we find that the 3CL protease (3CLpro) encoded by diverse coronaviruses, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), cleaves a rapidly evolving region of human CARD8 and activates a robust inflammasome response. CARD8 is required for cell death and the release of pro-inflammatory cytokines during SARS-CoV-2 infection. We further find that natural variation alters CARD8 sensing of 3CLpro, including 3CLpro-mediated antagonism rather than activation of megabat CARD8. Likewise, we find that a single nucleotide polymorphism (SNP) in humans reduces CARD8's ability to sense coronavirus 3CLpros and, instead, enables sensing of 3C proteases (3Cpro) from select picornaviruses. Our findings demonstrate that CARD8 is a broad sensor of viral protease activities and suggests that CARD8 diversity contributes to inter- and intraspecies variation in inflammasome-mediated viral sensing and immunopathology.


Subject(s)
COVID-19 , Picornaviridae , Humans , Inflammasomes/metabolism , Picornaviridae/genetics , Picornaviridae/metabolism , SARS-CoV-2/metabolism , Protease Inhibitors , Apoptosis Regulatory Proteins/metabolism , Neoplasm Proteins/metabolism , CARD Signaling Adaptor Proteins/metabolism
7.
Front Immunol ; 14: 1178662, 2023.
Article in English | MEDLINE | ID: covidwho-20234557

ABSTRACT

Gasdermin D (GSDMD)-mediated pyroptosis and downstream inflammation are important self-protection mechanisms against stimuli and infections. Hosts can defend against intracellular bacterial infections by inducing cell pyroptosis, which triggers the clearance of pathogens. However, pyroptosis is a double-edged sword. Numerous studies have revealed the relationship between abnormal GSDMD activation and various inflammatory diseases, including sepsis, coronavirus disease 2019 (COVID-19), neurodegenerative diseases, nonalcoholic steatohepatitis (NASH), inflammatory bowel disease (IBD), and malignant tumors. GSDMD, a key pyroptosis-executing protein, is linked to inflammatory signal transduction, activation of various inflammasomes, and the release of downstream inflammatory cytokines. Thus, inhibiting GSDMD activation is considered an effective strategy for treating related inflammatory diseases. The study of the mechanism of GSDMD activation, the formation of GSDMD membrane pores, and the regulatory strategy of GSDMD-mediated pyroptosis is currently a hot topic. Moreover, studies of the structure of caspase-GSDMD complexes and more in-depth molecular mechanisms provide multiple strategies for the development of GSDMD inhibitors. This review will mainly discuss the structures of GSDMD and GSDMD pores, activation pathways, GSDMD-mediated diseases, and the development of GSDMD inhibitors.


Subject(s)
COVID-19 , Pyroptosis , Humans , Gasdermins , Inflammasomes/metabolism , Intracellular Signaling Peptides and Proteins/metabolism
8.
Front Immunol ; 14: 1182454, 2023.
Article in English | MEDLINE | ID: covidwho-2326927

ABSTRACT

Introduction: The pathophysiology of the Corona Virus Disease 2019 (COVID-19) is incompletely known. A robust inflammatory response caused by viral replication is a main cause of the acute lung and multiorgan injury observed in critical patients. Inflammasomes are likely players in COVID-19 pathogenesis. The P2X7 receptor (P2X7R), a plasma membrane ATP-gated ion channel, is a main activator of the NLRP3 inflammasome, of the ensuing release of inflammatory cytokines and of cell death by pyroptosis. The P2X7R has been implicated in COVID-19-dependent hyperinflammation and in the associated multiorgan damage. Shed P2X7R (sP2X7R) and shed NLRP3 (sNLRP3) have been detected in plasma and other body fluids, especially during infection and inflammation. Methods: Blood samples from 96 patients with confirmed SARS-CoV-2 infection with various degrees of disease severity were tested at the time of diagnosis at hospital admission. Standard haematological parameters and IL-6, IL-10, IL-1ß, sP2X7R and sNLRP3 levels were measured, compared to reference values, statistically validated, and correlated to clinical outcome. Results: Most COVID-19 patients included in this study had lymphopenia, eosinopenia, neutrophilia, increased inflammatory and coagulation indexes, and augmented sNLRP3, IL-6 and IL-10 levels. Blood concentration of sP2X7R was also increased, and significantly positively correlated with lymphopenia, procalcitonin (PCT), IL-10, and alanine transaminase (ALT). Patients with increased sP2X7R levels at diagnosis also showed fever and respiratory symptoms, were more often transferred to Pneumology division, required mechanical ventilation, and had a higher likelihood to die during hospitalization. Conclusion: Blood sP2X7R was elevated in the early phases of COVID-19 and predicted an adverse clinical outcome. It is suggested that sP2X7R might be a useful marker of disease progression.


Subject(s)
COVID-19 , Lymphopenia , Humans , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Interleukin-10/metabolism , Receptors, Purinergic P2X7 , Interleukin-6/metabolism , SARS-CoV-2/metabolism , Inflammasomes/metabolism
9.
Front Immunol ; 14: 1014665, 2023.
Article in English | MEDLINE | ID: covidwho-2315123

ABSTRACT

Introduction: One of the main characteristics of COVID-19 is an exacerbated inflammatory response that results in cardiometabolic complications and dysfunction in the nervous system. Moreover, these complications may extend beyond the period of active SARS-CoV2 infection and even extend over a year. Thus, it is important to better understand the contribution of the inflammatory responses in COVID-19 patients, not just in the acute phase but also after the infection has subsided. Methods: We measured the protein levels of inflammasome signaling proteins using Simple Plex microfluidics technology in patients with an active SARS-CoV2 infection and in recovered patients to determine their potential use as biomarkers of COVID-19. We carried out statistical analyses to identify which proteins were increased in COVID-19 patients with active infection and in recovered patients. The receiver operating characteristics (ROC) were calculated for each analyte to determine their potential fit as biomarkers. Results: The inflammasome proteins caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), interleukin (IL)-1ß and IL-18 were elevated in the plasma of patients with active infection and remained elevated after the infection was resolved for approximately 2 months after. Levels of caspase-1 and ASC continued to increase long after patients had recovered from the infection. Furthermore, when measuring biomarkers of inflammation during active infection, analyses with area under the curve (AUC) values above 0.75 indicated that caspase-1, ASC, IL-1ß and IL-18 are reliable biomarkers of the inflammatory response during active COVID-19 infection. Moreover, when measuring biomarkers of inflammation after recovery from active infection, caspase-1 and ASC presented AUC values above 0.9. Discussion: These findings indicate that inflammasome signaling proteins can be used to reliably monitor the inflammatory innate immune response in COVID-19 patients.


Subject(s)
COVID-19 , Inflammasomes , Humans , Inflammasomes/metabolism , Interleukin-18/metabolism , RNA, Viral , CARD Signaling Adaptor Proteins/metabolism , SARS-CoV-2/metabolism , Caspase 1/metabolism , Inflammation/metabolism , Biomarkers
10.
Cell ; 186(10): 2144-2159.e22, 2023 05 11.
Article in English | MEDLINE | ID: covidwho-2312256

ABSTRACT

Bats are special in their ability to live long and host many emerging viruses. Our previous studies showed that bats have altered inflammasomes, which are central players in aging and infection. However, the role of inflammasome signaling in combating inflammatory diseases remains poorly understood. Here, we report bat ASC2 as a potent negative regulator of inflammasomes. Bat ASC2 is highly expressed at both the mRNA and protein levels and is highly potent in inhibiting human and mouse inflammasomes. Transgenic expression of bat ASC2 in mice reduced the severity of peritonitis induced by gout crystals and ASC particles. Bat ASC2 also dampened inflammation induced by multiple viruses and reduced mortality of influenza A virus infection. Importantly, it also suppressed SARS-CoV-2-immune-complex-induced inflammasome activation. Four key residues were identified for the gain of function of bat ASC2. Our results demonstrate that bat ASC2 is an important negative regulator of inflammasomes with therapeutic potential in inflammatory diseases.


Subject(s)
Apoptosis Regulatory Proteins , Chiroptera , Inflammasomes , Ribonucleoproteins , Virus Diseases , Animals , Humans , Mice , Apoptosis Regulatory Proteins/metabolism , Chiroptera/immunology , COVID-19 , Inflammasomes/immunology , Ribonucleoproteins/metabolism , SARS-CoV-2 , Virus Diseases/immunology , Virus Physiological Phenomena
11.
Int J Mol Sci ; 24(7)2023 Mar 28.
Article in English | MEDLINE | ID: covidwho-2306813

ABSTRACT

Neutrophils-polymorphonuclear cells (PMNs) are the cells of the initial immune response and make up the majority of leukocytes in the peripheral blood. After activation, these cells modify their functional status to meet the needs at the site of action or according to the agent causing injury. They receive signals from their surroundings and "plan" the course of the response in both temporal and spatial contexts. PMNs dispose of intracellular signaling pathways that allow them to perform a wide range of functions associated with the development of inflammatory processes. In addition to these cells, some protein complexes, known as inflammasomes, also have a special role in the development and maintenance of inflammation. These complexes participate in the proteolytic activation of key pro-inflammatory cytokines, such as IL-1ß and IL-18. In recent years, there has been significant progress in the understanding of the structure and molecular mechanisms behind the activation of inflammasomes and their participation in the pathogenesis of numerous diseases. The available reports focus primarily on macrophages and dendritic cells. According to the literature, the activation of inflammasomes in neutrophils and the associated death type-pyroptosis-is regulated in a different manner than in other cells. The present work is a review of the latest reports concerning the course of inflammasome activation and inflammatory cytokine secretion in response to pathogens in neutrophils, as well as the role of these mechanisms in the pathogenesis of selected diseases.


Subject(s)
Inflammasomes , Neutrophils , Humans , Inflammasomes/metabolism , Neutrophils/metabolism , Inflammation/metabolism , Macrophages/metabolism , Cytokines/metabolism , Interleukin-1beta/metabolism , Carrier Proteins/metabolism , Pyroptosis , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
12.
Cells ; 12(8)2023 04 19.
Article in English | MEDLINE | ID: covidwho-2295139

ABSTRACT

Inflammation and mitochondrial-dependent oxidative stress are interrelated processes implicated in multiple neuroinflammatory disorders, including Alzheimer's disease (AD) and depression. Exposure to elevated temperature (hyperthermia) is proposed as a non-pharmacological, anti-inflammatory treatment for these disorders; however, the underlying mechanisms are not fully understood. Here we asked if the inflammasome, a protein complex essential for orchestrating the inflammatory response and linked to mitochondrial stress, might be modulated by elevated temperatures. To test this, in preliminary studies, immortalized bone-marrow-derived murine macrophages (iBMM) were primed with inflammatory stimuli, exposed to a range of temperatures (37-41.5 °C), and examined for markers of inflammasome and mitochondrial activity. We found that exposure to mild heat stress (39 °C for 15 min) rapidly inhibited iBMM inflammasome activity. Furthermore, heat exposure led to decreased ASC speck formation and increased numbers of polarized mitochondria. These results suggest that mild hyperthermia inhibits inflammasome activity in the iBMM, limiting potentially harmful inflammation and mitigating mitochondrial stress. Our findings suggest an additional potential mechanism by which hyperthermia may exert its beneficial effects on inflammatory diseases.


Subject(s)
Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Animals , Mice , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Macrophages/metabolism , Inflammation/metabolism , Heat-Shock Response
14.
Nat Commun ; 14(1): 2329, 2023 04 22.
Article in English | MEDLINE | ID: covidwho-2302201

ABSTRACT

Rhinoviruses and allergens, such as house dust mite are major agents responsible for asthma exacerbations. The influence of pre-existing airway inflammation on the infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely unknown. We analyse mechanisms of response to viral infection in experimental in vivo rhinovirus infection in healthy controls and patients with asthma, and in in vitro experiments with house dust mite, rhinovirus and SARS-CoV-2 in human primary airway epithelium. Here, we show that rhinovirus infection in patients with asthma leads to an excessive RIG-I inflammasome activation, which diminishes its accessibility for type I/III interferon responses, leading to their early functional impairment, delayed resolution, prolonged viral clearance and unresolved inflammation in vitro and in vivo. Pre-exposure to house dust mite augments this phenomenon by inflammasome priming and auxiliary inhibition of early type I/III interferon responses. Prior infection with rhinovirus followed by SARS-CoV-2 infection augments RIG-I inflammasome activation and epithelial inflammation. Timely inhibition of the epithelial RIG-I inflammasome may lead to more efficient viral clearance and lower the burden of rhinovirus and SARS-CoV-2 infections.


Subject(s)
Antiviral Restriction Factors , Asthma , COVID-19 , DEAD Box Protein 58 , Inflammasomes , Rhinovirus , Humans , Antiviral Restriction Factors/genetics , Antiviral Restriction Factors/metabolism , Asthma/genetics , Asthma/immunology , COVID-19/genetics , COVID-19/immunology , DEAD Box Protein 58/metabolism , Enterovirus Infections/genetics , Enterovirus Infections/immunology , Inflammasomes/genetics , Inflammasomes/metabolism , Inflammation , Interferon Type I , Picornaviridae Infections/genetics , Picornaviridae Infections/immunology , Rhinovirus/metabolism , Rhinovirus/pathogenicity , SARS-CoV-2
15.
Phytomedicine ; 114: 154753, 2023 Jun.
Article in English | MEDLINE | ID: covidwho-2302077

ABSTRACT

BACKGROUND: Dehydroandrographolide (Deh) from Andrographis paniculata (Burm.f.) Wall has strong anti-inflammatory and antioxidant activities. PURPOSE: To explore the role of Deh in acute lung injury (ALI) of coronavirus disease 19 (COVID-19) and its inflammatory molecular mechanism. METHODS: Liposaccharide (LPS) was injected into a C57BL/6 mouse model of ALI, and LPS + adenosine triphosphate (ATP) was used to stimulate BMDMs in an in vitro model of ALI. RESULTS: In an in vivo and in vitro model of ALI, Deh considerably reduced inflammation and oxidative stress by inhibiting NLRP3-mediated pyroptosis and attenuated mitochondrial damage to suppress NLRP3-mediated pyroptosis through the suppression of ROS production by inhibiting the Akt/Nrf2 pathway. Deh inhibited the interaction between Akt at T308 and PDPK1 at S549 to promote Akt protein phosphorylation. Deh directly targeted PDPK1 protein and accelerated PDPK1 ubiquitination. 91-GLY, 111-LYS, 126-TYR, 162-ALA, 205-ASP and 223-ASP may be the reason for the interaction between PDPK1 and Deh. CONCLUSION: Deh from Andrographis paniculata (Burm.f.) Wall presented NLRP3-mediated pyroptosis in a model of ALI through ROS-induced mitochondrial damage through inhibition of the Akt/Nrf2 pathway by PDPK1 ubiquitination. Therefore, it can be concluded that Deh may be a potential therapeutic drug for the treatment of ALI in COVID-19 or other respiratory diseases.


Subject(s)
Acute Lung Injury , COVID-19 , Mice , Animals , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Andrographis paniculata , Proto-Oncogene Proteins c-akt/metabolism , Reactive Oxygen Species/metabolism , Medicine, Chinese Traditional , Pyroptosis , Lipopolysaccharides/pharmacology , NF-E2-Related Factor 2 , Mice, Inbred C57BL , Acute Lung Injury/chemically induced , Inflammasomes
16.
Egypt J Immunol ; 30(2): 99-108, 2023 Apr.
Article in English | MEDLINE | ID: covidwho-2290471

ABSTRACT

There are conflicting data regarding the relationship between coronavirus disease 2019 (COVID-19) severity and Caspase-1 (Casp-1), interleukin-1ß (IL-1ß), and IL-18. Our study sought to quantify the levels of IL-18, IL-1ß, and Casp-1 as indicators for inflammasome activation in COVID-19 patients at Assiut University Hospitals and to correlate their levels with parameters of disease severity in COVID-19 patients. Serum levels of Casp-1, IL-1ß and IL-18 were measured in 63 COVID-19 patients and 26 normal controls by an enzyme linked immunosorbent assay (ELISA). Also, arterial blood gas analysis and laboratory parameters including hemoglobin, platelets, lymphocyte count, liver function test, kidney function test, C-reactive protein (CRP), D-dimer, ferritin and LDH were estimated. Serum levels of Casp-1, IL-1ß and IL-18 were significantly higher in the COVID-19 group as compared to controls (p= 0.04, p=0.001 and p=0.03, respectively). Although the three markers were higher in the severe group, yet only IL-1ß showed a significant difference as compared to the non-severe group (p=0.04). IL-18 had significant positive correlations with CRP and ferritin (p = 0.04 and p = 0.02, respectively). IL-1ß was positively correlated with alanine aminotransferase. Casp-1 had significant positive correlations with CRP and lactate dehydrogenase (p=0.045 and p=0.001, respectively). Patients showed weak positive correlations between serum level of Casp-1 and each of IL-1ß and IL-18. Also, a strong positive correlation was found between IL-1ß and IL-18 (p < 0.0001). In conclusion, inflammasome activation was a hallmark in COVID-19 patients. The markers of activation were positively correlated with many parameters of inflammation, may suggest their important roles in the pathophysiology of the disease and its progression. IL-1ß was the only marker to be correlated with disease severity and therefore may be suggested as a potential marker for identifying severe COVID-19 patients.


Subject(s)
COVID-19 , Humans , Inflammasomes/metabolism , Interleukin-18 , Egypt , C-Reactive Protein , Patient Acuity , Biomarkers
17.
Front Cell Infect Microbiol ; 13: 1139998, 2023.
Article in English | MEDLINE | ID: covidwho-2301324

ABSTRACT

Background: The coronavirus disease 2019 (COVID-19) has been spreading astonishingly and caused catastrophic losses worldwide. The high mortality of severe COVID-19 patients is an serious problem that needs to be solved urgently. However, the biomarkers and fundamental pathological mechanisms of severe COVID-19 are poorly understood. The aims of this study was to explore key genes related to inflammasome in severe COVID-19 and their potential molecular mechanisms using random forest and artificial neural network modeling. Methods: Differentially expressed genes (DEGs) in severe COVID-19 were screened from GSE151764 and GSE183533 via comprehensive transcriptome Meta-analysis. Protein-protein interaction (PPI) networks and functional analyses were conducted to identify molecular mechanisms related to DEGs or DEGs associated with inflammasome (IADEGs), respectively. Five the most important IADEGs in severe COVID-19 were explored using random forest. Then, we put these five IADEGs into an artificial neural network to construct a novel diagnostic model for severe COVID-19 and verified its diagnostic efficacy in GSE205099. Results: Using combining P value < 0.05, we obtained 192 DEGs, 40 of which are IADEGs. The GO enrichment analysis results indicated that 192 DEGs were mainly involved in T cell activation, MHC protein complex and immune receptor activity. The KEGG enrichment analysis results indicated that 192 GEGs were mainly involved in Th17 cell differentiation, IL-17 signaling pathway, mTOR signaling pathway and NOD-like receptor signaling pathway. In addition, the top GO terms of 40 IADEGs were involved in T cell activation, immune response-activating signal transduction, external side of plasma membrane and phosphatase binding. The KEGG enrichment analysis results indicated that IADEGs were mainly involved in FoxO signaling pathway, Toll-like receptor, JAK-STAT signaling pathway and Apoptosis. Then, five important IADEGs (AXL, MKI67, CDKN3, BCL2 and PTGS2) for severe COVID-19 were screened by random forest analysis. By building an artificial neural network model, we found that the AUC values of 5 important IADEGs were 0.972 and 0.844 in the train group (GSE151764 and GSE183533) and test group (GSE205099), respectively. Conclusion: The five genes related to inflammasome, including AXL, MKI67, CDKN3, BCL2 and PTGS2, are important for severe COVID-19 patients, and these molecules are related to the activation of NLRP3 inflammasome. Furthermore, AXL, MKI67, CDKN3, BCL2 and PTGS2 as a marker combination could be used as potential markers to identify severe COVID-19 patients.


Subject(s)
COVID-19 , Inflammasomes , Humans , Inflammasomes/genetics , Cyclooxygenase 2 , Random Forest , Gene Expression Profiling/methods , Computational Biology/methods , Proto-Oncogene Proteins c-bcl-2
18.
J Biochem ; 171(4): 367-377, 2022 Mar 31.
Article in English | MEDLINE | ID: covidwho-2288636

ABSTRACT

Glutathione (GSH) is the most abundant non-protein thiol (-SH) in mammalian cells. Its synthesis and metabolism serve to maintain cellular reduction-oxidation (redox) homeostasis, which is important for multiple cellular processes including proliferation, differentiation and death. An accumulating body of evidence suggests that the essential roles of GSH extended far beyond its oxidant and electrophile scavenger activities and regulatory role in the lifespan of cells. Recent findings revealed that altered GSH levels are closely associated with a wide range of pathologies including bacterial and viral infections, neurodegenerative diseases and autoimmune disorders, all of which are also characterized by aberrant activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome. As a result of these findings, GSH was assigned a central role in influencing the activation of the NLRP3 inflammasome. To expand on our recent advances in understanding this process, we discuss here the emerging roles of GSH in activation of the NLRP3 inflammasome, and the therapeutic potential of GSH in its associated pathologies.


Subject(s)
Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Animals , Glutathione/metabolism , Inflammasomes/metabolism , Mammals , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Oxidation-Reduction
19.
Arterioscler Thromb Vasc Biol ; 42(9): 1103-1112, 2022 09.
Article in English | MEDLINE | ID: covidwho-2285811

ABSTRACT

The activating interplay of thrombosis and inflammation (thromboinflammation) has been established as a major underlying pathway, driving not only cardiovascular disease but also autoimmune disease and most recently, COVID-19. Throughout the years, innate immune cells have emerged as important modulators of this process. As the most abundant white blood cell in humans, neutrophils are well-positioned to propel thromboinflammation. This includes their ability to trigger an organized cell death pathway with the release of decondensed chromatin structures called neutrophil extracellular traps. Decorated with histones and cytoplasmic and granular proteins, neutrophil extracellular traps exert cytotoxic, immunogenic, and prothrombotic effects accelerating disease progression. Distinct steps leading to extracellular DNA release (NETosis) require the activities of PAD4 (protein arginine deiminase 4) catalyzing citrullination of histones and are supported by neutrophil inflammasome. By linking the immunologic function of neutrophils with the procoagulant and proinflammatory activities of monocytes and platelets, PAD4 activity holds important implications for understanding the processes that fuel thromboinflammation. We will also discuss mechanisms whereby vascular occlusion in thromboinflammation depends on the interaction of neutrophil extracellular traps with ultra-large VWF (von Willebrand Factor) and speculate on the importance of PAD4 in neutrophil inflammasome assembly and neutrophil extracellular traps in thromboinflammatory diseases including atherosclerosis and COVID-19.


Subject(s)
Atherosclerosis , COVID-19 , Extracellular Traps , Thrombosis , Atherosclerosis/metabolism , Extracellular Traps/metabolism , Histones/metabolism , Humans , Inflammasomes/metabolism , Inflammation/metabolism , Neutrophils/metabolism , Thromboinflammation , Thrombosis/etiology , Thrombosis/metabolism , von Willebrand Factor/metabolism
20.
J Interferon Cytokine Res ; 42(8): 406-420, 2022 08.
Article in English | MEDLINE | ID: covidwho-2282941

ABSTRACT

The coronavirus 2019 disease (COVID-19) pandemic has caused massive morbidity and mortality worldwide. In severe cases, it is mainly associated with acute pneumonia, cytokine storm, and multi-organ dysfunction. Inflammasomes play a primary role in various pathological processes such as infection, injury, and cancer. However, their role in COVID-19-related complications has not been explored. In addition, the role of underlying medical conditions on COVID-19 disease severity remains unclear. Therefore, this review expounds on the mechanisms of inflammasomes following COVID-19 infection and provides recent evidence on the potential double-edged sword effect of inflammasomes during COVID-19 pathogenesis. The assembly and activation of inflammasomes are critical for inducing effective antiviral immune responses and disease resolution. However, uncontrolled activation of inflammasomes causes excessive production of proinflammatory cytokines (cytokine storm), increased risk of acute respiratory distress syndrome, and death. Therefore, discoveries in the role of the inflammasome in mediating organ injury are key to identifying therapeutic targets and treatment modifications to prevent or reduce COVID-19-related complications.


Subject(s)
COVID-19 , Cytokine Release Syndrome , Cytokines , Humans , Inflammasomes , SARS-CoV-2
SELECTION OF CITATIONS
SEARCH DETAIL