Several interleukin-1 (IL-1) family members, including IL-1β and IL-18, require processing by inflammasome-associated caspases to unleash their activities. Here, we unveil, by cryoelectron microscopy ...(cryo-EM), two major conformations of the complex between caspase-1 and pro-IL-18. One conformation is similar to the complex of caspase-4 and pro-IL-18, with interactions at both the active site and an exosite (closed conformation), and the other only contains interactions at the active site (open conformation). Thus, pro-IL-18 recruitment and processing by caspase-1 is less dependent on the exosite than the active site, unlike caspase-4. Structure determination by nuclear magnetic resonance uncovers a compact fold of apo pro-IL-18, which is similar to caspase-1-bound pro-IL-18 but distinct from cleaved IL-18. Binding sites for IL-18 receptor and IL-18 binding protein are only formed upon conformational changes after pro-IL-18 cleavage. These studies show how pro-IL-18 is selected as a caspase-1 substrate, and why cleavage is necessary for its inflammatory activity.
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•Cryo-EM structure reveals two major conformations of the caspase-1/pro-IL-18 complex•Caspase-1 cleavage of pro-IL-18 depends less on the exosite interaction than caspase-4•NMR structure of apo pro-IL-18 is similar to that of caspase-1-bound pro-IL-18•The receptor-binding site of IL-18 is built by conformational changes upon cleavage
The inflammatory activity of IL-1 family cytokines is unleashed by caspase cleavage, but the underlying molecular mechanisms are unclear. Here, using cryo-EM and NMR techniques, Dong et al. reveal the conformational steps in the pathway for recognition and cleavage of pro-IL-18 by caspase-1 and suggest diverse ways with which inflammatory caspases process their substrates.
Interleukin 18 (IL-18) is a pleiotropic cytokine involved in the regulation of innate and acquired immune response. In the milieu of IL-12 or IL-15, IL-18 is a potent inducer of IFN-gamma in natural ...killer (NK) cells and CD4 T helper (Th) 1 lymphocytes. However, IL-18 also modulates Th2 and Th17 cell responses, as well as the activity of CD8 cytotoxic cells and neutrophils, in a host microenvironment-dependent manner. It is produced by various hematopoietic and nonhematopoietic cells, including dendritic cells and macrophages. In an organism, bioactivity of the cytokine depends on the intensity of IL-18 production, the level of its natural inhibitory protein - IL-18BP (IL-18 binding protein) and the surface expression of IL-18 receptors (IL-18R) on the responding cells. This review summarizes the biology of the IL-18/IL-18BP/IL-18R system and its role in the host defense against infections. The prospects for IL-18 application in immunotherapeutic or prophylactic interventions in infectious and non-infectious diseases are discussed.
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•Inflammatory biomarkers sampled in a convalescence phase were increased in young patients with a first myocardial infarction.•IL-6 was the most important predictor of long-term ...cardiovascular events.•IL-18 was the most important predictor of long-term hospitalization of myocardial infarction.•IL-6 is a potential treatment target for the residual inflammatory risk in secondary prevention.
Studies on predictive value of circulating inflammatory biomarkers after myocardial infarction (MI) have often been limited by blood sampling only in an acute setting and short follow-up time. We aimed to compare the long-term predictive value of nine inflammatory biomarkers, known to be involved in atherosclerosis, in young patients investigated three months after a first-time MI.
Nine biomarkers (high-sensitivity C-reactive protein, interleukin (IL)-6, IL-18, monocyte chemoattractant protein-1, matrix metalloproteinase (MMP)-1, MMP-3, MMP-9, serum amyloid A and tumor necrosis factor-alfa) were sampled in 382 young (<60 years) patients and in age and sex-matched controls, three months after a first-time MI between 1996 and 2000. Swedish national patient registers were used to determine cardiovascular (CV) outcomes during 20 years of follow-up.
In cases, random forest models identified IL-6 as the most important predictor of the primary composite endpoint of death, heart failure (HF) or MI hospitalization, and the separate endpoints death and HF hospitalization. IL-18 was the most important predictor of MI hospitalization. In a Cox regression, the highest tertile of IL-6 was associated with the composite endpoint (HR (95% CI) 1.91 (1.31–2.79)), death (2.38 (1.42–3.98)) and HF hospitalization (2.70 (1.32–5.50)), when adjusting for age, sex and CV risk factors. The highest tertile of IL-18 was associated with MI hospitalization (2.31 (1.08–4.91)) when severity of coronary atherosclerosis was added to the same type of model.
When nine inflammatory markers involved in atherosclerosis were analyzed three months after the acute event in young MI patients, IL-6 and IL-18 were the most important biomarkers to predict long-term CV outcomes during 20 years of follow-up.
Excess IL-18 and graded defects in cytotoxicity are fundamental susceptibility factors for HLH and MAS. In mice, neither excess IL-18 (18tg mice) nor perforin-deficiency individually cause ...immunopathology without inflammatory challenge. However, 18tg mice lacking perforin (18tg; Prf1-/-) develop spontaneous lethal hyperinflammation, while subclinical MAS was found in 18tg;Prf1+/- mice. HLH and MAS patients demonstrate CD8 T-cell activation in tissue & peripheral blood. We sought to understand how IL-18 and cytotoxic impairment may interact in driving spontaneous hyperinflammation.
We examined mice bearing single- and dual-susceptibility factors for “clinical” features of hyperinflammation, cytokine levels, and flow cytometric, transcriptional, functional, and TCR-seq phenotypes.
Flow cytometric analysis of dual susceptibility mice showed spontaneous expansion of CD8 T-cells (and not CD4 T- or NK-cells), which expressed the IL-18 receptor and multiple inhibitory receptors (PD-1, Lag-3, CD39), yet overproduced IFNg. Such “hyperinflammatory CD8 T-cells” were present in reticuloendothelial organs (spleen, bone marrow, and liver) but not lymph nodes, peripheral blood, or thymus. Transcriptional analysis demonstrated hyperactivated CD8 T cells showed features of both terminal effector function and exhaustion when compared to well-described datasets. This analysis also revealed a strong signature for recent antigen activation. Bulk
CD8 TCR sequencing showed dramatic oligoclonal hyper-expansion of TCR sequences from dual susceptibility mice with no significant clonal overlap between biologic replicate samples. In vitro, TCR stimulation was necessary for IL-18 to promote IFNg production and restimulation-induced cell death (RICD), whereas perforin-deficiency prevented RICD. Broad-spectrum antibiotics did not rescue spontaneous hyperinflammation in dual-susceptibility mice, suggesting T-cell responses were not directed at commensal bacteria. Attempts to circumvent CD8 T-cell activation, using inducible CD8 T-cell-specific deletion of Il18r1 or by promoting allelic exclusion by fixing the T-cell receptor, showed breakthrough expansion of hyperactivated CD8 T-cells.
Thus, IL-18 and cytotoxicity drive progressive, post-thymic, oligoclonal CD8 T-cell expansion that may underly life-threatening immunopathology in HLH and MAS. Expansion of hyperactivated CD8T cells in reticuloendothelial organs aligns with sites of hemophagocytosis. These data together implicate HLH/MAS susceptibility factors interact with TCR stimulation, whether by infectious triggers or as-yet undetermined self antigens, to drive potentially-targetable mechanisms of T-cell activation. Display omitted Supporting figures.
Background
Since dysregulation of total Interleukin (IL)-18 and IL-18 binding protein (IL-18BP) may participate in systemic lupus erythematosus (SLE) and contribute to the occurrence of ...non-autoimmune epilepsy, the aim of the current work is to investigate whether the interaction between IL-18 and IL-18BP plays any role in neuropsychiatric systemic lupus erythematosus related seizures.
Methods
Data from 137 SLE patients and 30 healthy controls (HC) were consecutively collected from 2020 to 2021. Serum levels of total IL-18 and IL-18BP for all patients and HC were measured by ELISA test. Free IL-18 was calculated based on the law of mass action.
Results
Among the 137 SLE patients, 103 had active disease and were classified into NPSLE (n = 50) and Non-NPSLE (n = 53) groups. Among the NPSLE patients, 16 had seizure disorders. Serum free IL-18 levels were increased in NPSLE (277.6 150.9–428.8pg/mL) and were correlated with disease activity (r = 0.268, p = 0.002). Moreover, serum free IL-18 levels in NPSLE patients with seizure disorders (350.9 237.9–455.9pg/mL) were significantly higher than the levels in those with other neuropsychiatric symptoms (237.7 124.6–428.8 pg/mL).
Conclusions
The expression of free IL-18 was increased in neuropsychiatric systemic lupus erythematosus(NPSLE), especially in NPSLE related seizures. Also, serum levels of free IL-18 were significantly increased in active SLE patients. In this regard, free IL-18 may be involved in the pathogenesis of NPSLE related seizures and associated with disease activity.
Interleukin-1 (IL-1) family cytokines are key signaling molecules in both the innate and adaptive immune systems, mediating inflammation in response to a wide range of stimuli. The basic mechanism of ...signal initiation is a stepwise process in which an agonist cytokine binds its cognate receptor. Together, this cytokine-receptor complex recruits an often-common secondary receptor. Intracellularly, the Toll/IL-1 Receptor (TIR) domains of the two receptors are brought into close proximity, initiating an NF-κB signal transduction cascade. Due to the potent inflammatory response invoked by IL-1 family cytokines, several physiological mechanisms exist to inhibit IL-1 family signaling, including antagonist cytokines and decoy receptors. The numerous cytokines and receptors in the IL-1 superfamily are further classified into four subfamilies, dependent on their distinct cognate receptors-the IL-1, IL-33, and IL-36 subfamilies share IL-1RAcP as their secondary receptor, while IL-18 subfamily utilizes a distinct secondary receptor. Here, we describe how structural biology has informed our understanding of IL-1 family cytokine signaling, with a particular focus on molecular mechanisms of signaling complex formation and antagonism at the atomic level, as well as how these findings have advanced therapeutics to treat some chronic inflammatory diseases that are the result of dysregulated IL-1 signaling.
The IL-1 family of cytokines currently comprises of seven ligands with pro-inflammatory activity (IL-1α and IL-1β, IL-18, IL-33, IL-36α, IL-36β, IL-36γ) as well as two ligands with anti-inflammatory ...activity (IL-37, IL-38). These cytokines are known to play a key role in modulating both the innate and adaptive immunes response, with dysregulation linked to a variety of autoimmune and inflammatory diseases. Given the increasing appreciation of the link between inflammation and cancer, the role of several members of this family in the pathogenesis of cancer has been extensively investigated. In this review, we highlight both the pro- and anti-tumorigenic effects identified for almost all members of this family, and explore potential underlying mechanisms accounting for these divergent effects. Such dual functions need to be carefully assessed when developing therapeutic intervention strategies targeting these cytokines in cancer.
Idiopathic pulmonary fibrosis (IPF) is a fatal parenchymal lung disease with limited effective therapies. Interleukin (IL)-18 belongs to a rather large IL-1 gene family and is a proinflammatory ...cytokine, which acts in both acquired and innate immunity. We have previously reported that IL-18 play an important role in lipopolysaccharide-induced acute lung injury in mice. Persistent inflammation often drives fibrotic progression in the bleomycin (BLM) injury model. However, the role of IL-18 in pulmonary fibrosis (PF) is still unknown. IL-18 binding protein (IL-18BP) is able to neutralize IL-18 biological activity and has a protective effect against renal fibrosis. The aim of this study was to investigate the effects of IL-18BP on BLM-induced PF. In the present study, we found that IL-18 was upregulated in lungs of BLM-injured mice. Neutralization of IL-18 by IL-18BP improved the survival rate and ameliorated BLM-induced PF in mice, which was associated with attenuated pathological changes, reduced collagen deposition, and decreased content of transforming growth factor-β1 (TGF-β1). We further demonstrated that IL-18BP treatment suppressed the BLM-induced epithelial mesenchymal transition (EMT), characterized by decreased α-smooth muscle actin (α-SMA) and increased E-cadherin (E-cad) in vivo. In addition, we provided in vitro evidence demonstrating that IL-18 promoted EMT through upregulation of Snail-1 in A549 cells. In conclusion, our findings raise the possibility that the increase of IL-18 is involved in the development of BLM-induced PF through modulating EMT in a Snail-1-dependent manner. IL-18BP may be a worthwhile candidate option for PF therapy.
•IL-18 expression is increased in BLM-induced pulmonary fibrosis mice.•Neutralization of IL-18 by IL-18BP ameliorates pulmonary fibrosis via inhibition of EMT.•IL-18 promotes EMT in a Snial-1-dependent manner in A549 cells.
A cross-sectional, analytical study conducted over a period of 6 months from April to September 2021 after the approval of REC on 50 patients with confirmed positive of COVID-19 by SARS-CoV-2 nucleic ...acid RT-PCR recruited from Isolation departments and intensive care units (ICUs), Beni-Suef University hospital. The goal of this study was to assess the serum level of (IL-18) as a biomarker of COVID-19 disease progression. All participants underwent complete blood count (CBC), C- reactive protein (CRP), fibrinogen, D-dimer and liver enzymes and measurement of serum IL- 18 level. All patients had been followed until hospital discharge or death. Forty-two patients (84%) recovered and discharged from the hospital while eight cases (16%) died due to different etiologies: 2 patients due to suppurative lung infection, another 2 because of multi organ failure, 2 patients owing to respiratory failure and alveolar damage, and the last 2 patients with cardiac comorbidity after ischemic heart disease and hypertension. There were a significant higher level of CRP, D-dimer, ferritin, and IL-18 among died as compared with recovered COVID-19 patients. Platelets count was significantly higher among recovered as compared with died COVID-19 patients. Correlation test showed a significant positive strong linear relationship between CRP level and IL-18, D-dimer level, and IL-18, and between ferritin level and IL-18. High values of IL-18 in patients’ serum helped to assess the poor prognosis which was statistically significant with 81.5% sensitivity and 57.5% specificity at a cutoff point level ≥ 230.75. Elevated serum levels of IL-18 were associated with fatal outcome in the COVID-19 infected patients and showed strong correlation with other inflammatory markers.
Inflammasomes are multiprotein complexes that can sense danger signals and activate caspase-1 to mediate pro-inflammatory cytokines release and pyroptotic cell death. There are two main canonical and ...non-canonical signaling pathways that trigger inflammasome activation. Inflammasomes are expressed and assembled in parenchymal and nonparenchymal cells in response to liver injury in the liver. Additionally, the hepatocytes, biliary epithelial cells (cholangiocytes), hepatic stellate cells (HSCs), hepatic macrophages, and liver sinusoidal endothelial cells (LSECs) contribute to liver fibrosis
different mechanisms. However, the underlying mechanism of the inflammasome and pyroptosis in these liver cells in liver fibrosis remains elusive. This review summarizes the activation and function of inflammasome complexes and then discusses the association between inflammasomes, pyroptosis, and liver fibrosis. Unlike other similar reviewers, we will focus on the effect of inflammasome activation and pyroptosis in the various liver cells during the development of liver fibrosis. We will also highlight the latest progress of pharmacological intervention in inflammasome-mediated liver fibrosis.
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