ABSTRACT
Cardiovascular complications pose a significant burden in type 2 diabetes mellitus (T2DM), driven by the intricate interplay of chronic hyperglycemia, insulin resistance, and lipid metabolism disturbances. Myocardial ischemia/reperfusion (MI/R) injury during cardiopulmonary bypass (CPB) exacerbates cardiac vulnerability. This study aims to probe the role of Caspase-1-dependent pyroptosis in global ischemia/reperfusion injury among T2DM rats undergoing CPB, elucidating the mechanisms underlying heightened myocardial injury in T2DM. This study established a rat model of T2DM and compared Mean arterial pressure (MAP), heart rate (HR), and hematocrit (Hct) between T2DM and normal rats. Myocardial cell morphology, infarction area, mitochondrial ROS and caspase-1 levels, NLRP3, pro-caspase-1, caspase-1 p10, GSDMD expressions, plasma CK-MB, cTnI, IL-1ß, and IL-18 levels were assessed after reperfusion in both T2DM and normal rats. The role of Caspase-1-dependent pyroptosis in myocardial ischemia/reperfusion injury during CPB in T2DM rats was examined using the caspase-1 inhibitor VX-765 and the ROS scavenger NAC. T2DM rats demonstrated impaired glucose tolerance but stable hemodynamics during CPB, while showing heightened vulnerability to MI/R injury. This was marked by substantial lipid deposition, disrupted myocardial fibers, and intensified cellular apoptosis. The activation of caspase-1-mediated pyroptosis and increased reactive oxygen species (ROS) production further contributed to tissue damage and the ensuing inflammatory response. Notably, myocardial injury was mitigated by inhibiting caspase-1 through VX-765, which also attenuated the inflammatory cascade. Likewise, NAC treatment reduced oxidative stress and partially suppressed ROS-mediated caspase-1 activation, resulting in diminished myocardial injury. This study proved that Caspase-1-dependent pyroptosis significantly contributes to the inflammation and injury stemming from global MI/R in T2DM rats under CPB, which correlate with the surplus ROS generated by oxidative stress during reperfusion.
Subject(s)
Cardiopulmonary Bypass , Caspase 1 , Diabetes Mellitus, Type 2 , Myocardial Reperfusion Injury , Pyroptosis , Reactive Oxygen Species , Animals , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/etiology , Myocardial Reperfusion Injury/pathology , Cardiopulmonary Bypass/adverse effects , Caspase 1/metabolism , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/complications , Rats , Male , Reactive Oxygen Species/metabolism , para-Aminobenzoates/pharmacology , Rats, Sprague-Dawley , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/complications , Interleukin-18/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , DipeptidesABSTRACT
Systemic autoinflammatory diseases (SAIDs) arise from dysregulated innate immune system activity, which leads to systemic inflammation. These disorders, encompassing a diverse array of genetic defects classified as inborn errors of immunity, are significant diagnostic challenges due to their genetic heterogeneity and varied clinical presentations. Although recent advances in genetic sequencing have facilitated pathogenic gene discovery, approximately 40% of SAIDs patients lack molecular diagnoses. SAIDs have distinct clinical phenotypes, and targeted therapeutic approaches are needed. This review aims to underscore the complexity and clinical significance of SAIDs, focusing on prototypical disorders grouped according to their pathophysiology as follows: (i) inflammasomopathies, characterized by excessive activation of inflammasomes, which induces notable IL-1ß release; (ii) relopathies, which are monogenic disorders characterized by dysregulation within the NF-κB signaling pathway; (iii) IL-18/IL-36 signaling pathway defect-induced SAIDs, autoinflammatory conditions defined by a dysregulated balance of IL-18/IL-36 cytokine signaling, leading to uncontrolled inflammation and tissue damage, mainly in the skin; (iv) type I interferonopathies, a diverse group of disorders characterized by uncontrolled production of type I interferons (IFNs), notably interferon α, ß, and ε; (v) anti-inflammatory signaling pathway impairment-induced SAIDs, a spectrum of conditions characterized by IL-10 and TGFß anti-inflammatory pathway disruption; and (vi) miscellaneous and polygenic SAIDs. The latter group includes VEXAS syndrome, chronic recurrent multifocal osteomyelitis/chronic nonbacterial osteomyelitis, Schnitzler syndrome, and Still's disease, among others, illustrating the heterogeneity of SAIDs and the difficulty in creating a comprehensive classification. Therapeutic strategies involving targeted agents, such as JAK inhibitors, IL-1 blockers, and TNF inhibitors, are tailored to the specific disease phenotypes.
Subject(s)
Hereditary Autoinflammatory Diseases , Humans , Hereditary Autoinflammatory Diseases/genetics , Hereditary Autoinflammatory Diseases/drug therapy , Hereditary Autoinflammatory Diseases/diagnosis , Inflammasomes/genetics , Inflammation/genetics , Signal Transduction , Interleukin-18/genetics , Interleukin-1beta/genetics , Interleukin-1beta/antagonists & inhibitors , NF-kappa B , Anemia, Dyserythropoietic, Congenital/genetics , Anemia, Dyserythropoietic, Congenital/therapy , Anemia, Dyserythropoietic, Congenital/diagnosis , Schnitzler Syndrome/genetics , Schnitzler Syndrome/drug therapy , Schnitzler Syndrome/diagnosis , Osteomyelitis/genetics , Osteomyelitis/drug therapy , Osteomyelitis/immunology , Mevalonate Kinase Deficiency/genetics , Mevalonate Kinase Deficiency/drug therapy , Mevalonate Kinase Deficiency/diagnosis , Immunologic Deficiency SyndromesABSTRACT
Globally, hepatitis C virus (HCV) and coronavirus disease 2019 (COVID-19) are the most common causes of death due to the lack of early predictive and diagnostic tools. Therefore, research for a new biomarker is crucial. Inflammatory biomarkers are critical central players in the pathogenesis of viral infections. IL-18, produced by macrophages in early viral infections, triggers inflammatory biomarkers and interferon production, crucial for viral host defense. Finding out IL-18 function can help understand COVID-19 pathophysiology and predict disease prognosis. Histamine and its receptors regulate allergic lung responses, with H1 receptor inhibition potentially reducing inflammation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. angiotensin-converting enzyme 2 (ACE-2) receptors on cholangiocytes suggest liver involvement in SARS-CoV-2 infection. The current study presents the potential impact of circulating acetylcholine, histamine, IL-18, and interferon-Alpha as diagnostic tools in HCV, COVID-19, and dual HCV-COVID-19 pathogenesis. The current study was a prospective cross-section conducted on 188 participants classified into the following four groups: Group 1 COVID-19 (n = 47), Group 2 HCV (n = 47), and Group 3 HCV-COVID-19 patients (n = 47), besides the healthy control Group 4 (n = 47). The levels of acetylcholine, histamine, IL-18, and interferon-alpha were assayed using the ELISA method. Liver and kidney functions within all groups showed a marked alteration compared to the healthy control group. Our statistical analysis found that individuals with dual infection with HCV-COVID-19 had high ferritin levels compared to other biomarkers while those with COVID-19 infection had high levels of D-Dimer. The histamine, acetylcholine, and IL-18 biomarkers in both COVID-19 and dual HCV-COVID-19 groups have shown discriminatory power, making them potential diagnostic tests for infection. These three biomarkers showed satisfactory performance in identifying HCV infection. The IFN-Alpha test performed well in the HCV-COVID-19 group and was fair in the COVID-19 group, but it had little discriminative value in the HCV group. Moreover, our findings highlighted the pivotal role of acetylcholine, histamine, IL-18, and interferon-Alpha in HCV, COVID-19, and dual HCV-COVID-19 infection. Circulating levels of acetylcholine, histamine, IL-18, and interferon-Alpha can be potential early indicators for HCV, COVID-19, and dual HCV-COVID-19 infection. We acknowledge that further large multicenter experimental studies are needed to further investigate the role biomarkers play in influencing the likelihood of infection to confirm and extend our observations and to better understand and ultimately prevent or treat these diseases.
Subject(s)
Acetylcholine , Biomarkers , COVID-19 , Histamine , Interferon-alpha , Interleukin-18 , Humans , Interleukin-18/blood , COVID-19/diagnosis , Biomarkers/blood , Histamine/blood , Male , Female , Middle Aged , Interferon-alpha/blood , Prospective Studies , Hepatitis C/diagnosis , Adult , Cross-Sectional Studies , SARS-CoV-2 , Hepacivirus , Aged , Coinfection/diagnosis , Coinfection/virologyABSTRACT
Cytokine Storm is a complex and heterogeneous state of life-threatening systemic inflammation and immunopathology. Autoinflammation is a mechanistic category of immune dysregulation wherein immunopathology originates due to poor regulation of innate immunity. The growing family of monogenic Systemic Autoinflammatory Diseases (SAIDs) has been a wellspring for pathogenic insights and proof-of-principle targeted therapeutic interventions. There is surprisingly little overlap between SAID and Cytokine Storm Syndromes, and there is a great deal to be inferred from those SAID that do, and do not, consistently lead to Cytokine Storm. This chapter will summarize how illustrations of the autoinflammatory paradigm have advanced the understanding of human inflammation, including the role of autoinflammation in familial HLH. Next, it will draw from monogenic SAID, both those with strong associations with cytokine storm and those without, to illustrate how the cytokine IL-18 links innate immune dysregulation and cytokine storm.
Subject(s)
Cytokine Release Syndrome , Immunity, Innate , Humans , Cytokine Release Syndrome/immunology , Interleukin-18/immunology , Interleukin-18/genetics , Inflammation/immunology , Hereditary Autoinflammatory Diseases/immunology , Hereditary Autoinflammatory Diseases/genetics , Animals , Cytokines/immunology , Cytokines/metabolismABSTRACT
Interleukin-1 is a prototypic proinflammatory cytokine that is elevated in cytokine storm syndromes (CSSs), such as secondary hemophagocytic lymphohistiocytosis (sHLH) and macrophage activation syndrome (MAS). IL-1 has many pleotropic and redundant roles in both innate and adaptive immune responses. Blockade of IL-1 with recombinant human interleukin-1 receptor antagonist has shown efficacy in treating CSS. Recently, an IL-1 family member, IL-18, has been demonstrated to be contributory to CSS in autoinflammatory conditions, such as in inflammasomopathies (e.g., NLRC4 mutations). Anecdotally, recombinant IL-18 binding protein can be of benefit in treating IL-18-driven CSS. Lastly, another IL-1 family member, IL-33, has been postulated to contribute to CSS in an animal model of disease. Targeting of IL-1 and related cytokines holds promise in treating a variety of CSS.
Subject(s)
Cytokine Release Syndrome , Interleukin-1 , Humans , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/drug therapy , Interleukin-1/antagonists & inhibitors , Interleukin-1/immunology , Interleukin-1/genetics , Interleukin-1/metabolism , Animals , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Interleukin 1 Receptor Antagonist Protein/genetics , Calcium-Binding Proteins/genetics , Interleukin-18/genetics , Interleukin-18/immunology , Macrophage Activation Syndrome/immunology , Macrophage Activation Syndrome/drug therapy , Macrophage Activation Syndrome/genetics , Lymphohistiocytosis, Hemophagocytic/immunology , Lymphohistiocytosis, Hemophagocytic/genetics , Lymphohistiocytosis, Hemophagocytic/drug therapy , CARD Signaling Adaptor ProteinsABSTRACT
OBJECTIVE: To investigate the changes and clinical significance of NOD like receptor protein 3 (NLRP3) inflammasomes and related factors in patients with spinal fractures complicated with acute spinal cord injury (SCI). METHODS: Eighty-six spinal fracture patients complicated with acute SCI admitted to hospital from June 2019 to March 2022 were selected as SCI group, There were 48 males and 38 females, with an average age of (43.48±6.58) years old. And 100 healthy volunteers who underwent physical examination during the same time were selected as control group, including 56 males patients and 44 females patients, with an average age of (45.13±6.43) years old. Peripheral blood mononuclear cell (PBMC) were collected, and the mRNA expressions of NLRP3 and Caspase-1 were detected. Serum was collected and the levels of interleukin (IL)- 1ß, IL-18 were detected. According to Frankel's grade, the SCI group was divided into complete injury patients and incomplete injury patients, and according to the Japanese Orthopedic Society (JOA) grade, the SCI group was divided into good prognosis group and poor prognosis group. The difference of NLRP3, Caspase-1, IL-1ß, IL-18 among groups were compared, the influencing factors for poor prognosis in SCI patients was analyzed by Logistic regression. RESULTS: The mRNA expression levels of NLRP3 (1.41±0.33) and Caspase-1 (1.44±0.35) in PBMC and the levels of IL-1ß(45.34±13.22) pg·ml-1, IL-18(40.95±8.77) pg·ml-1 in serum of SCI group were higher than those of the control group[(1.00±0.19), (1.00±0.16), (16.58±4.24) pg·ml-1, (12.57±3.68) pg·ml-1] (P<0.05). The mRNA expression levels of NLRP3(1.63±0.34) and Caspase-1 (1.67±0.27) in PBMC and the levels of IL-1ß(51.09±11.10) pg·ml-1, IL-18 (47.65±7.93) pg·ml-1 in serum of patients with complete injury in the SCI group were higher than those of patients with incomplete injury [(1.31±0.27), (1.34±0.33), (42.85±13.36) pg·ml-1, (38.05±7.48) pg·ml-1](P<0.05). The mRNA expression levels of NLRP3 (1.66±0.31) and Caspase-1 (1.72±0.31)in PBMC and the levels of IL-1ß(51.21±11.31) pg·ml-1, IL-18 (45.70±7.25) pg·ml-1 in serum, the proportion of complete injury(21 patients), and the proportion of spinal cord edema or bleeding of patients(15 patients) with poor prognosis in the SCI group were higher than those of patients with good prognosis[(1.28±0.26), (1.37±0.36), (42.79±13.25) pg·ml-1ã(38.90±8.63) pg·ml-1, 5ã20 cases](P<0.05). Complete injury and the mRNA expression of NLRP3 in PBMC were the influencing factors for poor prognosis in the SCI group (P<0.05). CONCLUSION: The activation of NLRP3 inflammasomes in patients with spinal fractures complicated with acute SCI is associated with worsening injury and poor prognosis, and NLRP3 expression can serve as a marker for evaluating prognosis.
Subject(s)
Caspase 1 , Inflammasomes , Interleukin-18 , Interleukin-1beta , NLR Family, Pyrin Domain-Containing 3 Protein , Spinal Cord Injuries , Spinal Fractures , Humans , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Male , Female , Spinal Cord Injuries/complications , Spinal Cord Injuries/blood , Adult , Middle Aged , Interleukin-18/blood , Interleukin-1beta/blood , Interleukin-1beta/genetics , Caspase 1/blood , Spinal Fractures/blood , Spinal Fractures/complications , Leukocytes, Mononuclear/metabolism , Prognosis , Clinical RelevanceABSTRACT
Atopic dermatitis and psoriasis are prevalent inflammatory skin conditions that significantly impact the quality of life of patients, with diverse treatment options available. Despite advances in understanding their underlying mechanisms, recent research highlights the significance of interleukins IL-18 and IL-37, in Th1, Th2, and Th17 inflammatory responses, closely associated with the pathogenesis of psoriasis and atopic dermatitis. Hence, IL-18 and IL-37 could potentially become therapeutic targets. This narrative review synthesizes knowledge on these interleukins, their roles in atopic dermatitis and psoriasis, and emerging treatment strategies. Findings of a literature search up to 30 May 2024, underscore a research gap in IL-37-targeted therapies. Conversely, IL-18-focused treatments have demonstrated promise in adult-onset Still's Disease, warranting further exploration for their potential efficacy in psoriasis and atopic dermatitis.
Subject(s)
Dermatitis, Atopic , Interleukin-18 , Interleukin-1 , Psoriasis , Humans , Dermatitis, Atopic/immunology , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/etiology , Dermatitis, Atopic/metabolism , Psoriasis/drug therapy , Psoriasis/immunology , Psoriasis/metabolism , Interleukin-18/metabolism , Interleukin-1/metabolism , Interleukin-1/antagonists & inhibitors , Animals , Molecular Targeted TherapyABSTRACT
Objective: This study aimed to evaluate the role of absent in melanoma 2 (AIM2) inflammasome-mediated pyroptosis in the pathogenesis of acute gouty arthritis (AGA) and asymptomatic hyperuricemia(AHU). Methods: A cohort of 30 AGA patients, 30 AHU individuals, and 30 healthy controls (HC) was assembled. Demographic and biochemical data, along with blood samples, were collected. Serum double-stranded DNA (dsDNA) levels were quantified using a fluorescent assay. Transcriptomic and proteomic analysis of AIM2, Caspase-1, GSDMD, IL-1ß, and IL-18 in peripheral blood mononuclear cells was performed using qRT-PCR and Western blot. Enzyme-linked immunosorbent assay (ELISA) was employed to measure serum IL-1ß and IL-18. Spearman correlation analysis was utilized to assess relationships between variables. Results: Both AGA and AHU groups demonstrated elevated metabolic indicators and serum levels of dsDNA, IL-1ß, and IL-18 compared to the HC group. AGA patients exhibited higher inflammatory markers than the AHU group. In the AGA group, there was a significant increase in the mRNA and protein levels of AIM2, Caspase-1, GSDMD, IL-1ß, and IL-18 (P<0.05 to P<0.001). The AHU group showed higher AIM2, Caspase-1, GSDMD, and IL-18 mRNA levels than the HC group (P<0.001 to P<0.01), with a non-significant increase in AIM2, GSDMD, and IL-1ß proteins (P>0.05). In contrast, Caspase-1 and IL-18 proteins were significantly higher in the AHU group (P<0.05). Notable correlations were observed between AIM2 protein expression and levels of Caspase-1 and GSDMD in both AGA and AHU groups. In the AGA group, AIM2 protein correlated with IL-1ß, but not in the AHU group. The AIM2 protein in the AHU group was positively associated with IL-18, with no such correlation in the AGA group. Conclusion: AIM2 inflammasome may play a role in the inflammatory processes of AGA and AHU and that its activation may be related to the pyroptosis pathway.
Subject(s)
Arthritis, Gouty , DNA-Binding Proteins , Hyperuricemia , Inflammasomes , Pyroptosis , Humans , Male , Inflammasomes/metabolism , Arthritis, Gouty/immunology , Arthritis, Gouty/blood , Arthritis, Gouty/metabolism , Middle Aged , Hyperuricemia/blood , Hyperuricemia/immunology , Female , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Adult , Interleukin-18/blood , Aged , Case-Control Studies , Biomarkers/blood , Caspase 1/metabolismABSTRACT
Autoimmune skin disease is a kind of heterogeneous disease with complicated pathogenesis. Many factors such as genetic, infectious, environmental and even psychological factors may interact together to trigger a synergistic effect for the development of abnormal innate and adaptive immune responses. Although the exact mechanisms remain unclear, recent evidence suggests that pyroptosis plays a pivotal role in the development of autoimmune skin disease. The feature of pyroptosis is the first formation of pores in cellular membranes, then cell rupture and the release of intracellular substances and pro-inflammatory cytokines, such as interleukin-1 beta (IL-1ß) and IL-18. This hyperactive inflammatory programmed cell death damages the homeostasis of the immune system and advances autoimmunity. This review briefly summarises the molecular regulatory mechanisms of pyrin domain-containing protein 3 (NLRP3) inflammasome and gasdermin family, as well as the molecular mechanisms of pyroptosis, highlights the latest progress of pyroptosis in autoimmune skin disease, including systemic lupus erythematosus, psoriasis, atopic dermatitis and systemic scleroderma and attempts to identify its potential advantages as a therapeutic target or prognostic biomarker for these diseases.
Subject(s)
Autoimmune Diseases , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Pyroptosis , Humans , Autoimmune Diseases/immunology , Autoimmune Diseases/metabolism , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Skin Diseases/immunology , Animals , Phosphate-Binding Proteins/metabolism , Interleukin-1beta/metabolism , Scleroderma, Systemic/immunology , Lupus Erythematosus, Systemic/immunology , Intracellular Signaling Peptides and Proteins/metabolism , Psoriasis/immunology , Psoriasis/metabolism , Autoimmunity , Interleukin-18/metabolism , Dermatitis, Atopic/immunologyABSTRACT
Introduction: Interleukin-18 (IL-18), a pro-inflammatory cytokine belonging to the IL-1 Family, is a key mediator ofautoinflammatory diseases associated with the development of macrophage activation syndrome (MAS).High levels of IL-18 correlate with MAS and COVID-19 severity and mortality, particularly in COVID-19patients with MAS. As an inflammation inducer, IL-18 binds its receptor IL-1 Receptor 5 (IL-1R5), leadingto the recruitment of the co-receptor, IL-1 Receptor 7 (IL-1R7). This heterotrimeric complex subsequentlyinitiates downstream signaling, resulting in local and systemic inflammation. Methods: We reported earlier the development of a novel humanized monoclonal anti-human IL-1R7 antibody whichspecifically blocks the activity of human IL-18 and its inflammatory signaling in human cell and wholeblood cultures. In the current study, we further explored the strategy of blocking IL-1R7 inhyperinflammation in vivo using animal models. Results: We first identified an anti-mouse IL-1R7 antibody that significantly suppressed mouse IL-18 andlipopolysaccharide (LPS)-induced IFNg production in mouse splenocyte and peritoneal cell cultures. Whenapplied in vivo, the antibody reduced Propionibacterium acnes and LPS-induced liver injury and protectedmice from tissue and systemic hyperinflammation. Importantly, anti-IL-1R7 significantly inhibited plasma,liver cell and spleen cell IFNg production. Also, anti-IL-1R7 downregulated plasma TNFa, IL-6, IL-1b,MIP-2 production and the production of the liver enzyme ALT. In parallel, anti-IL-1R7 suppressed LPSinducedinflammatory cell infiltration in lungs and inhibited the subsequent IFNg production andinflammation in mice when assessed using an acute lung injury model. Discussion: Altogether, our data suggest that blocking IL-1R7 represents a potential therapeutic strategy to specificallymodulate IL-18-mediated hyperinflammation, warranting further investigation of its clinical application intreating IL-18-mediated diseases, including MAS and COVID-19.
Subject(s)
Inflammation , Lipopolysaccharides , Animals , Mice , Lipopolysaccharides/immunology , Inflammation/immunology , Humans , Interleukin-18/metabolism , Interleukin-18/immunology , Disease Models, Animal , COVID-19/immunology , Mice, Inbred C57BL , Macrophage Activation Syndrome/immunology , SARS-CoV-2/immunologyABSTRACT
Chagas disease is caused by the intracellular protozoan parasite Trypanosoma cruzi. This disease affects mainly rural areas in Central and South America, where the insect vector is endemic. However, this disease has become a world health problem since migration has spread it to other continents. It is a complex disease with many reservoirs and vectors and high genetic variability. One of the host proteins involved in the pathogenesis is SLAMF1. This immune receptor acts during the infection of macrophages controlling parasite replication and thus affecting survival in mice but in a parasite strain-dependent manner. Therefore, we studied the role of SLAMF1 by quantitative proteomics in a macrophage in vitro infection and the different responses between Y and VFRA strains of Trypanosoma cruzi. We detected different significant up- or downregulated proteins involved in immune regulation processes, which are SLAMF1 and/or strain-dependent. Furthermore, independently of SLAMF1, this parasite induces different responses in macrophages to counteract the infection and kill the parasite, such as type I and II IFN responses, NLRP3 inflammasome activation, IL-18 production, TLR7 and TLR9 activation specifically with the Y strain, and IL-11 signaling specifically with the VFRA strain. These results have opened new research fields to elucidate the concrete role of SLAMF1 and discover new potential therapeutic approaches for Chagas disease.
Subject(s)
Chagas Disease , Macrophages , Proteomics , Trypanosoma cruzi , Trypanosoma cruzi/metabolism , Animals , Mice , Macrophages/metabolism , Macrophages/parasitology , Macrophages/immunology , Proteomics/methods , Chagas Disease/parasitology , Chagas Disease/metabolism , Chagas Disease/immunology , Antigens, CD/metabolism , Toll-Like Receptor 7/metabolism , Toll-Like Receptor 9/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Interleukin-18/metabolism , Receptors, Cell Surface/metabolism , Inflammasomes/metabolism , Signaling Lymphocytic Activation Molecule Family Member 1 , Membrane GlycoproteinsABSTRACT
OBJECTIVE: We assessed the levels of Interleukin-10 (IL-10), Interleukin-12 (IL-12), and Interleukin-18 (IL-18) in the gingival crevicular fluid (GCF) of subjects with advanced periodontitis (SIII-SIV) compared to healthy controls and evaluated their correlations with clinical measurements. METHODS: This cross-sectional study involved subjects (n = 60) diagnosed with stage III grade B-C (n = 13) to stage IV grade C (n = 17) periodontitis, and periodontally healthy controls (n = 30). Clinical periodontal measurements involved full-mouth. The concentrations of IL-10, IL-12, and IL-18 were determined using enzyme-linked immunosorbent assay (ELISA). RESULTS: There were no significant differences in IL-12 level and IL-18/IL-10 ratio between the healthy and periodontitis groups (p = 0.413, p = 0.636, respectively). The IL-10 and IL-18 levels were significantly higher in the periodontitis group than in controls (p < 0.001, p < 0.001, respectively). Significant associations were observed between the periodontitis and IL-10 and IL-18 levels (OR = 1.46, %95 CI 1.19-1.795; OR = 1.13, %95 CI 1.059-1.207, respectively) (p < 0.001, p < 0.001, respectively). CONCLUSIONS: There was a correlation between pocket depth and the presence of IL-18 and a strong association between periodontitis and a high level of IL-18. However, there were no direct correlations among the three biomarkers and IL-18/IL-10 ratio, indicating that their roles in periodontal health are complex and multidimensional. CLINICAL RELEVANCE: Understanding the cytokine dynamics in GCF provides valuable insights into their potential clinical implications for periodontal disease diagnosis, risk assessment, and tailored therapeutic interventions.
Subject(s)
Enzyme-Linked Immunosorbent Assay , Gingival Crevicular Fluid , Interleukin-10 , Interleukin-18 , Humans , Cross-Sectional Studies , Male , Female , Gingival Crevicular Fluid/chemistry , Interleukin-10/metabolism , Interleukin-18/metabolism , Middle Aged , Adult , Interleukin-12/metabolism , Case-Control Studies , Periodontal Index , Periodontitis , BiomarkersABSTRACT
Bronchopulmonary dysplasia (BPD) is a common serious complication of premature babies. No effective means control it. Hyperoxia damage is one of the important mechanisms of BPD. The reaserach confirmed pyroptosis existed in BPD. Dexmedetomidine is a new, high-specific α2 receptor agonist. Previous research foundation found that dexmedetomidine has a protective effect on BPD. To investigate how dexmedetomidine improves hyperoxic lung injury in neonatal mice by regulating pyroptosis. Neonatal rats were randomly divided into four groups: normal control group, hyperoxic injury group, air plus dexmedetomidine group, and hyperoxia plus dexmedetomidine group. After seven days the lungs of rats in each group were extracted, and the wet-to-dry weight ratio of the lung was measured. The lung injury in rats was observed using hematoxylin-eosin staining. Additionally, the expression and localization of nucleotide-binding oligomerization domain-like receptor thermal protein domain associated protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), and gasdermin D (GSDMD) proteins were examined in the lungs of rats using immunofluorescence staining. The mRNA levels of NLRP3, ASC, caspase-1, and interleukin 18 (IL-18) in the lungs of rats were determined using real-time PCR. Moreover, the protein levels of NLRP3, ASC, caspase-1/cleaved caspase-1, interleukin 1beta (IL-1ß), IL-18, and tunor necrosis factor alpha (TNF-α) were detected in lungs of rats using Western blot. The extent of mitochondrial damage in lung tissues of each group was observed by transmission electron microscopy. The lung tissue injury of the neonatal rats was significantly improved in the hyperoxia plus dexmedetomidine group compared to the hyperoxic injury group. Furthermore, the expressions of pyroptosis-related proteins such as NLRP3, ASC, cleaved-caspase-1, and GSDMD were significantly decreased, along with the expressions of inflammatory factors in lung tissues. By inhibiting the NLRP3/caspase-1/GSDMD pyroptosis pathway, dexmedetomidine reduces the activation and release of inflammatory factors and provides a protective effect against hyperoxic lung injury in neonatal mice.
Subject(s)
Animals, Newborn , Dexmedetomidine , Hyperoxia , Lung Injury , Lung , NLR Family, Pyrin Domain-Containing 3 Protein , Pyroptosis , Rats, Sprague-Dawley , Animals , Dexmedetomidine/pharmacology , Dexmedetomidine/therapeutic use , Hyperoxia/metabolism , Hyperoxia/complications , Hyperoxia/drug therapy , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Lung/drug effects , Lung/pathology , Lung/metabolism , Pyroptosis/drug effects , Lung Injury/metabolism , Lung Injury/prevention & control , Lung Injury/pathology , Lung Injury/drug therapy , Rats , Phosphate-Binding Proteins/metabolism , CARD Signaling Adaptor Proteins/metabolism , Caspase 1/metabolism , Interleukin-18/metabolism , Adrenergic alpha-2 Receptor Agonists/pharmacology , Adrenergic alpha-2 Receptor Agonists/therapeutic use , Male , GasderminsABSTRACT
Inflammation through activation of caspase-1, seems to play a role in pulmonary hypertension induced by alveolar hypoxia. Whether alveolar hypoxia induces caspase-1-mediated inflammation and influx of leukocytes in other organs than the lungs, is not known. Our aim was to explore sites of caspase-1-related inflammation in alveolar hypoxia. Wild type (WT) mice were exposed to environmental hypoxia or room-air, and organs were analyzed. Right heart catheterization was performed after 14 days of alveolar hypoxia in WT mice and mice transplanted with WT or caspase-1-/- bone marrow. Hypoxia induced leukocyte accumulation and increased caspase-1 protein in the lungs, not in other organs. WT mice transplanted with WT or caspase-1-/- bone marrow showed no difference in pulmonary leukocyte accumulation or development of pulmonary hypertension after alveolar hypoxia. Caspase-1 and IL-18 were detected in bronchial epithelium in WT mice, and hypoxia induced IL-18 secretion from bronchial epithelial cells. IL-18 stimulation generated IL-6 mRNA in monocytes. Phosphorylated STAT3 was increased in hypoxic lungs, not in other organs. Alveolar hypoxia induces caspase-1 activation and leukocyte accumulation specific to the lungs, not in other organs. Caspase-1 activation and IL-18 secretion from bronchial epithelial cells might initiate hypoxia-induced inflammation, leading to pulmonary hypertension.
Subject(s)
Caspase 1 , Hypoxia , Inflammasomes , Interleukin-18 , Lung , Mice, Inbred C57BL , Animals , Male , Inflammasomes/metabolism , Mice , Caspase 1/metabolism , Caspase 1/genetics , Lung/metabolism , Lung/pathology , Interleukin-18/metabolism , Interleukin-18/genetics , Hypoxia/metabolism , Inflammation/metabolism , Inflammation/pathology , Pulmonary Alveoli/metabolism , Pulmonary Alveoli/pathology , STAT3 Transcription Factor/metabolism , STAT3 Transcription Factor/genetics , Mice, Knockout , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/etiology , Hypertension, Pulmonary/pathologyABSTRACT
Polycystic ovarian syndrome (PCOS) is related to pro-apoptotic and pro-inflammatory conditions generated by Endoplasmic reticulum (ER) stress. This study aimed to determine the effect of Astaxanthin (ASX), as carotenoid with potent antioxidant and anti-inflammatory properties, on serum inflammatory markers, apoptotic factors and ER stress-apoptotic genes in peripheral blood mononuclear cells (PBMCs) of women with PCOS. This randomized, double-blind clinical trial included 56 PCOS patients aged 18-40. For 8 weeks, subjects were randomly assigned to one of two groups: either 12 mg ASX (n = 28) or placebo (n = 28). Real-time PCR was used to quantify gene expression associated with ER stress-apoptosis in PCOS women's PBMCs. The levels of TNF-α, IL18, IL6 and CRP were determined by obtaining blood samples from all patients before and after the intervention using Enzyme-linked immunosorbent assay (ELISA). Also, the levels of active caspase-3 and caspase-8 were detected in the PBMC by ELISA kit. Furthermore, we evaluated the efficacy of ASX on disease symptoms. Following the 8-week intervention, ASX supplementation was able to reduce the expression of GRP78 (p = 0.051), CHOP (p = 0.008), XBP1 (p = 0.002), ATF4 (0.038), ATF6 (0.157) and DR5 (0.016) when compared to the placebo. However, this decrease was not statistically significant for ATF6 (p = 0.067) and marginally significant for GRP78 (p = 0.051). The levels of TNF-α (p = 0.009), IL-18 (p = 0.003), IL-6 (p = 0.013) and active caspase-3 (p = 0.012) were also statistically significant lower in the therapy group. However, there was no significant difference in CRP (p = 0.177) and caspase-8 (p = 0.491) levels between the treatment and control groups. In our study, ASX had no significant positive effect on BMI, hirsutism, hair loss and regularity of the menstrual cycle. It appears that ASX may benefit PCOS by changing the ER stress-apoptotic pathway and reducing serum inflammatory markers; however, additional research is required to determine this compound's potential relevance.
Subject(s)
Apoptosis , Biomarkers , Dietary Supplements , Endoplasmic Reticulum Chaperone BiP , Endoplasmic Reticulum Stress , Leukocytes, Mononuclear , Polycystic Ovary Syndrome , Xanthophylls , Humans , Female , Polycystic Ovary Syndrome/drug therapy , Polycystic Ovary Syndrome/blood , Polycystic Ovary Syndrome/genetics , Endoplasmic Reticulum Stress/drug effects , Xanthophylls/pharmacology , Xanthophylls/administration & dosage , Xanthophylls/therapeutic use , Adult , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/drug effects , Apoptosis/drug effects , Biomarkers/blood , Young Adult , Adolescent , Double-Blind Method , Gene Expression Regulation/drug effects , Tumor Necrosis Factor-alpha/blood , Interleukin-18/blood , Interleukin-18/genetics , Inflammation/blood , Inflammation/drug therapy , Inflammation/genetics , Interleukin-6/blood , Interleukin-6/genetics , Caspase 8/genetics , Caspase 8/metabolismABSTRACT
OBJECTIVE: To explore the correlations between serum levels of brain-derived neurotrophic factor (BDNF), interleukin-18 (IL-18) and hypersensitivity C-reactive protein (hs-CRP) in patients with acute cerebral infarction and vascular cognitive impairment (VCI), and to provide some clinical bases for early prevention of VCI. METHODS: A total of 160 patients with acute cerebral infarction admitted in Department of Neurology of Jincheng People' s Hospital from May 2019 to April 2020 were enrolled in this study and were devided into three groups according to whether or not combined with cognitive impairment, including no cognitive impairment group (NCI, 57 cases), vascular cognitive impairment no dementia group (VCIND, 56 cases) and vascular dementia group (VaD, 47 cases). The cognitive function of all the patients were evaluated by Montreal cognitive assessment (MoCA). The National Institute of Health stroke scale (NIHSS) was used to assess the degree of neurological deficit (mild-, moderate-, severe-neurologic deficit group). The infarct size was calculated by Pullicino' s method (small-, middle-, large-infarct group). The levels of serum BDNF and IL-18 were measured by enzyme-linked immunosorbent assay (ELISA), and serum levels of hs-CRP were measured by immunoturbidimetry during the acute phase (0-7 d), recovery period (15-30 d) and 6 months after cerebral infarction. The effects of varying degrees of neurological deficits and different size of infarction on BDNF, IL-18 and hs-CRP were observed. The levels of serum BDNF, IL-18 and hs-CRP in the patients of the three groups with acute, convalescent and six-month cerebral infarction were compared, and their correlations with VCI were analyzed. RESULTS: Serum BDNF level and MoCA scores in mild-neurologic deficit group and small-infarct group were significantly higher than those in moderate- and severe-deficit group, middle- and large-infarct group, respectively (P < 0.05). Their levels of IL-18 and hs-CRP were significantly lower than those in moderate- and severe-deficit group, middle- and large-infarct group, respectively (P < 0.05). The levels of serum BDNF in NCI group, VCIND group and VaD group during the acute phase, convalescence and 6 months after cerebral infarction were in a significant decline, and the differences during the acute phase and recovery period were statistically significant (P < 0.05). The levels of IL-18 and hs-CRP during the acute phase, recovery period and 6 months after cerebral infarction showed a significant increasing trend with significance (P < 0.05). Correlation analysis revealed that the levels of BDNF was positively correlated with MoCA scores but negatively correlated with the severity of cognitive impairment while the expression levels of IL-18 and hs-CRP were negatively correlated with MoCA scores but positively correlated with the severity of cognitive impairment. CONCLUSION: Serum BDNF, IL-18 and hs-CRP are involved in the pathological process of occurrence and development of VCI in the patients with acute cerebral infarction. BDNF has a protective effect on VCI while IL-18 and hs-CRP cause severe cognitive impairment. The levels of serum BDNFãIL-18 and hs-CRP in the patients with acute ischemic cerebral infarction are closely related to the severity of cognitive impairment and can be used as biomarkers of early diagnosis of VCI.
Subject(s)
Brain-Derived Neurotrophic Factor , C-Reactive Protein , Cerebral Infarction , Cognitive Dysfunction , Interleukin-18 , Humans , Brain-Derived Neurotrophic Factor/blood , Interleukin-18/blood , C-Reactive Protein/metabolism , C-Reactive Protein/analysis , Cerebral Infarction/blood , Male , Female , Cognitive Dysfunction/blood , Cognitive Dysfunction/etiology , Aged , Dementia, Vascular/blood , Middle Aged , Mental Status and Dementia TestsABSTRACT
OBJECTIVE: Monoclonal gammopathy of undetermined significance (MGUS) is a preneoplastic disease that often precedes multiple myeloma. The multistep evolutionary pattern of multiple myeloma is driven by genetic instability, a pro-inflammatory and immunosuppressive microenvironment, and tumor growth. Inflammation has long been recognized as a factor in both the onset and progression of cancer. PATIENTS AND METHODS: In this study, interleukin-18 plasma levels were compared in patients with multiple myeloma and monoclonal gammopathy of undetermined significance, as well as in a group of healthy controls. RESULTS: Our study shows that monoclonal gammopathy of undetermined significance patients have lower levels of interleukin-18 than healthy controls (521.657 ± 168.493 pg/ml vs. 1,266.481 ± 658.091 pg/ml for controls, p < 0.001). Thus, we discovered a significant difference in interleukin-18 levels between multiple myeloma patients and controls (418.177 ± 197.837 pg/ml; p = 0.001). CONCLUSIONS: In our work, we identified a reduction of interleukin-18 in monoclonal gammopathies. Furthermore, in this paper, we aimed to evaluate the existing literature on the potential mechanisms of action of this pro-inflammatory cytokine in the development of these diseases.
Subject(s)
Interleukin-18 , Monoclonal Gammopathy of Undetermined Significance , Multiple Myeloma , Humans , Interleukin-18/blood , Multiple Myeloma/blood , Multiple Myeloma/diagnosis , Multiple Myeloma/immunology , Monoclonal Gammopathy of Undetermined Significance/blood , Monoclonal Gammopathy of Undetermined Significance/diagnosis , Male , Female , Middle Aged , Aged , Case-Control StudiesABSTRACT
PROBLEM: Vulvovaginal candidiasis (VVC) is a common mucosal fungal infection, and Candida albicans is the main causative agent. The NLRP3 inflammasome plays an important role in VVC, but the underlying mechanism is unknown. METHOD OF STUDY: Vaginal epithelial cells were divided into three groups: control, C. albicans strain SC5314 (wild-type, WT), and WT+ Matt Cooper Compound 950 (MCC950, a specific NLRP3 inhibitor). After human vaginal epithelial cells were pretreated with 1 µmol/L MCC950 for 2 h, C. albicans (MOI = 1) was cocultured with the human vaginal epithelial cells for 12 h. The cell supernatants were collected, LDH was detected, and the IL-1ß and IL-18 levels were determined by ELISA. The expression of the pyroptosis-related proteins NLRP3, Caspase-1 p20 and GSDMD was measured by Western blotting analysis. The protein expression of the pyroptosis-related N-terminus of GSDMD (GSDMD-N) was detected by immunofluorescence. RESULTS: In this study, we showed that the WT C. albicans strain induced pyroptosis in vaginal epithelial cells, as indicated by the LDH and proinflammatory cytokine levels and the upregulated levels of the pyroptosis-related proteins NLRP3, Caspase-1 p20, and GSDMD-N. MCC950 reversed the changes in the expression of these proteins and proinflammatory cytokines in vaginal epithelial cells. CONCLUSION: C. albicans activated the NLRP3 inflammasome to induce vaginal epithelial cell pyroptosis. MCC950 inhibited the NLRP3 inflammasome, reduced vaginal epithelial cell pyroptosis, and decreased the release of inflammatory cytokines.
Subject(s)
Candida albicans , Candidiasis, Vulvovaginal , Epithelial Cells , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Pyroptosis , Vagina , Female , Humans , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Candidiasis, Vulvovaginal/immunology , Candidiasis, Vulvovaginal/microbiology , Candidiasis, Vulvovaginal/metabolism , Epithelial Cells/immunology , Epithelial Cells/metabolism , Inflammasomes/metabolism , Inflammasomes/immunology , Candida albicans/immunology , Vagina/microbiology , Vagina/immunology , Vagina/pathology , Interleukin-18/metabolism , Interleukin-1beta/metabolism , Indenes , Furans/pharmacology , Caspase 1/metabolism , Heterocyclic Compounds, 4 or More Rings/pharmacology , Phosphate-Binding Proteins/metabolism , Cells, Cultured , SulfonamidesABSTRACT
OBJECTIVE: To observe the effects of Zhoutian moxibustion on pain symptoms and serum inflammatory factors in patients with ankylosing spondylitis of cold-damp obstruction. METHODS: Eighty-four patients with ankylosing spondylitis of cold-damp obstruction were randomly divided into a Zhoutian moxibustion group (42 cases, 2 cases dropped out) and a governor vessel moxibustion group (42 cases, 2 cases dropped out, 1 case discontinued). Both groups were given oral administration of sulfasalazine enteric-coated tablets as basic treatment. The governor vessel moxibustion group was treated with moxibustion box from Dazhui (GV 14) to Yaoyangguan (GV 3), one hour per treatment; the Zhoutian moxibustion group was treated with moxibustion box from Tiantu (CV 22) to Zhongji (CV 3) in addition to the governor vessel moxibustion group, two hours per treatment. Both groups were treated once every 3 days, twice a week, for a total of 9 weeks. The pain symptom scores of the two groups were observed before treatment and at the 3rd, 6th, and 9th weeks into treatment. ELISA was used to detect the levels of serum interleukin (IL)-1ß, IL-18, and tumor necrosis factor-α (TNF-α) before and after treatment, and the clinical efficacy of the two groups was evaluated after treatment. RESULTS: Except for the joint pain scores at the 3rd week into treatment, the total scores and the each sub-item score of pain symptom in the two groups were lower than those before treatment at the 3rd, 6th, and 9th weeks into treatment (P<0.05); at the 3rd, 6th, and 9th weeks into treatment, the total scores of pain symptom and the scores of lumbar sacral pain, back pain, joint cold pain, and limited mobility in the Zhoutian moxibustion group were lower than those in the governor vessel moxibustion group (P<0.05). After treatment, the levels of serum IL-1ß, IL-18 and TNF-α in both groups were lower than those before treatment (P<0.05), and the levels of serum IL-1ß, IL-18, and TNF-α in the Zhoutian moxibustion group were lower than those in the governor vessel moxibustion group (P<0.05). The total effective rate was 90.0% (36/40) in the Zhoutian moxibustion group, which was higher than 76.9% (30/39) in the governor vessel moxibustion group (P<0.05). CONCLUSION: Zhoutian moxibustion could effectively improve various pain symptoms in patients with ankylosing spondylitis of cold-damp obstruction, and reduce the expression of inflammatory factors.
Subject(s)
Acupuncture Points , Moxibustion , Spondylitis, Ankylosing , Tumor Necrosis Factor-alpha , Humans , Male , Female , Adult , Spondylitis, Ankylosing/therapy , Spondylitis, Ankylosing/complications , Middle Aged , Young Adult , Tumor Necrosis Factor-alpha/blood , Interleukin-1beta/blood , Adolescent , Interleukin-18/blood , Pain ManagementABSTRACT
Infection with Glaesserella parasuis, the primary pathogen behind Glässer's disease, is often associated with diverse clinical symptoms, including serofibrinous polyserositis, arthritis, and meningitis. Autophagy plays a dual role in bacterial infections, exerting either antagonistic or synergistic effects depending on the nature of the pathogen. Our previous studies have demonstrated that autophagy serves as a defense mechanism, combating inflammation and invasion caused by infection of highly virulent G. parasuis. However, the precise mechanisms remain to be elucidated. Pathogens exhibit distinct interactions with inflammasomes and autophagy processes. Herein, we explored the effect of autophagy on inflammasomes during G. parasuis infection. We found that G. parasuis infection triggers NLRP3-dependent pro-CASP-1-IL-18/IL-1ß processing and maturation pathway, resulting in increased release of IL-1ß and IL-18. Inhibition of autophagy enhances NLRP3 inflammasome activity, whereas stimulation of autophagy restricts it during G. parasuis infection. Furthermore, assembled NLRP3 inflammasomes undergo ubiquitination and recruit the autophagic adaptor, p62, facilitating their sequestration into autophagosomes during G. parasuis infection. These results suggest that the induction of autophagy mitigates inflammation by eliminating overactive NLRP3 inflammasomes during G. parasuis infection. Our research uncovers a mechanism whereby G. parasuis infection initiates inflammatory responses by promoting the assembly of the NLRP3 inflammasomes and activating NLRP3-CASP-1, both of which processes are downregulated by autophagy. This suggests that pharmacological manipulation of autophagy could be a promising approach to modulate G. parasuis-induced inflammatory responses.