Interleukin-1 (IL-1) is the prototypical inflammatory cytokine: two distinct ligands (IL-1α and IL-1β) bind the IL-1 type 1 receptor (IL-1R1) and induce a myriad of secondary inflammatory mediators, ...including prostaglandins, cytokines, and chemokines. IL-1α is constitutively present in endothelial and epithelial cells, whereas IL-1β is inducible in myeloid cells and released following cleavage by caspase-1. Over the past 30 years, IL-1-mediated inflammation has been established in a broad spectrum of diseases, ranging from rare autoinflammatory diseases to common conditions such as gout and rheumatoid arthritis (RA), type 2 diabetes, atherosclerosis, and acute myocardial infarction. Blocking IL-1 entered the clinical arena with anakinra, the recombinant form of the naturally occurring IL-1 receptor antagonist (IL-1Ra); IL-1Ra prevents the binding of IL-1α as well as IL-1β to IL-1R1. Quenching IL-1-mediated inflammation prevents the detrimental consequences of tissue damage and organ dysfunction. Although anakinra is presently approved for the treatment of RA and cryopyrin-associated periodic syndromes, off-label use of anakinra far exceeds its approved indications. Dosing of 100 mg of anakinra subcutaneously provides clinically evident benefits within days and for some diseases, anakinra has been used daily for over 12 years. Compared to other biologics, anakinra has an unparalleled record of safety: opportunistic infections, particularly
, are rare even in populations at risk for reactivation of latent infections. Because of this excellent safety profile and relative short duration of action, anakinra can also be used as a diagnostic tool for undefined diseases mediated by IL-1. Although anakinra is presently in clinical trials to treat cancer, this review focuses on anakinra treatment of acute as well as chronic inflammatory diseases.
Role of the Inflammasome in Liver Disease de Carvalho Ribeiro, Marcelle; Szabo, Gyongyi
Annual review of pathology,
01/2022, Letnik:
17, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The involvement of inflammasomes in the proinflammatory response observed in chronic liver diseases, such as alcohol-associated liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD), is ...widely recognized. Although there are different types of inflammasomes, most studies to date have given attention to NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3) in the pathogenesis of ALD, NAFLD nonalcoholic steatohepatitis, and fibrosis. Canonical inflammasomes are intracellular multiprotein complexes that are assembled after the sensing of danger signals and activate caspase-1, which matures interleukin (IL)-1β, IL-18, and IL-37 and also induces a form of cell death called pyroptosis. Noncanonical inflammasomes activate caspase-11 to induce pyroptosis. We discuss the different types of inflammasomes involved in liver diseases with a focus on (
a
) signals and mechanisms of inflammasome activation, (
b
) the role of different types of inflammasomes and their products in the pathogenesis of liver diseases, and (
c
) potential therapeutic strategies targeting components of the inflammasomes or cytokines produced upon inflammasome activation.
The Role of NLRP3 Inflammasome in Pericarditis Mauro, Adolfo G.; Bonaventura, Aldo; Vecchié, Alessandra ...
JACC. Basic to translational science,
February 2021, 2021-02-00, Letnik:
6, Številka:
2
Journal Article
Recenzirano
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•Acute pericarditis is characterized by an intense inflammatory response involving the pericardium. Although mostly benign in its clinical course, 30% of patients may experience ...complications (recurrence, treatment failure, cardiac tamponade).•The pathogenesis of pericarditis is poorly understood. The scarcity of animal models might justify the limited understanding of this syndrome and the lack of targeted therapies.•Acute pericarditis is believed to represent a stereotypical response to an acute injury of the pericardium. The NLRP3 inflammasome, through its main product, IL-1β, could play a central role in the clinical manifestations.•A mouse model of acute pericarditis was developed through the intrapericardial injection of zymosan A, leading to the classical features of the inflamed pericardium: pericardial effusion, pericardial thickening, and increased expression of the NLRP3 inflammasome. By inhibiting the NLRP3 inflammasome or IL-1β, the pericardial effusion and thickening and the NLRP3 inflammasome expression were greatly reduced compared with vehicle.•Treatment with IL-1 trap, neutralizing both IL-1β and IL-1α, produced a powerful effect on pericardial inflammation in the experimental pericarditis model.
Human samples of patients with chronic pericarditis and appropriate control subjects were stained for the inflammasome components. A mouse model of pericarditis was developed through the intrapericardial injection of zymosan A. Different inflammasome blockers were tested in the mouse model. Patients with pericarditis presented an intensification of the inflammasome activation compared with control subjects. The experimental model showed the pathological features of pericarditis. Among inflammasome blockers, NLRP3 inflammasome inhibitor, anakinra, and interleukin-1 trap were found to significantly improve pericardial alterations. Colchicine partially improved the pericardial inflammation. An intense activation of the inflammasome in pericarditis was demonstrated both in humans and in mice.
Interleukin-1β (IL-1β)-mediated inflammation suppresses antitumor immunity, leading to the generation of a tumor-permissive environment, tumor growth, and progression. Here, we demonstrate that ...nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation in melanoma is linked to IL-1β production, inflammation, and immunosuppression. Analysis of cancer genome datasets (TCGA and GTEx) revealed greater NLRP3 and IL-1β expression in cutaneous melanoma samples (
= 469) compared to normal skin (
= 324), with a highly significant correlation between NLRP3 and IL-1β (
< 0.0001). We show the formation of the NLRP3 inflammasome in biopsies of metastatic melanoma using fluorescent resonance energy transfer analysis for NLRP3 and apoptosis-associated speck-like protein containing a CARD. In vivo, tumor-associated NLRP3/IL-1 signaling induced expansion of myeloid-derived suppressor cells (MDSCs), leading to reduced natural killer and CD8
T cell activity concomitant with an increased presence of regulatory T (Treg) cells in the primary tumors. Either genetic or pharmacological inhibition of tumor-derived NLRP3 by dapansutrile (OLT1177) was sufficient to reduce MDSCs expansion and to enhance antitumor immunity, resulting in reduced tumor growth. Additionally, we observed that the combination of NLRP3 inhibition and anti-PD-1 treatment significantly increased the antitumor efficacy of the monotherapy by limiting MDSC-mediated T cell suppression and tumor progression. These data show that NLRP3 activation in melanoma cells is a protumor mechanism, which induces MDSCs expansion and immune evasion. We conclude that inhibition of NLRP3 can augment the efficacy of anti-PD-1 therapy.
The present study examined whether serum biomarkers can predict the prognosis of childhood epilepsy, including seizure frequency, electroencephalographic (EEG) changes, and cognitive impairment. We ...measured serum concentrations of high mobility group protein B1 (HMGB1), interleukin-1β (IL-1β), S100 calcium-binding protein B (S-100B), glial fibrillary acidic protein (GFAP), and α1-antichymotrypsin (AACT) in 180 children with new-onset epilepsy and 40 healthy children. Cognitive evaluations were performed 18 months after the initial seizure episodes at diagnosis (ie, baseline visit). The relationship between serum biomarkers and epilepsy prognosis was investigated using Pearson correlation coefficients, logistic regression analyses, and receiver operating characteristic curves. Sixty-seven patients had generalized tonic-clonic seizures, 92 had focal motor seizures, and 21 had epileptic spasms. Serum concentrations of HMGB1, IL-1β, S-100B, and GFAP were significantly higher in the epilepsy group within 24 hours of a seizure episode than in the control group. Furthermore, HMGB1 and IL-1β were significant predictors of epilepsy prognosis. Receiver operating characteristic curve analysis revealed that HMGB1 could more accurately predict seizure frequency than IL-1β; when the serum concentration of HMGB1 was >9.625 ng/mL, there was 80.6% sensitivity and 92.5% specificity for predicting seizure frequency reduction. In conclusion, HMGB1 and IL-1β have a predictive value for epilepsy prognosis in children.
The coronavirus disease-19 pandemic (COVID-19), which appeared in China in December 2019 and rapidly spread throughout the world, has forced clinicians and scientists to take up extraordinary ...challenges. This unprecedented situation led to the inception of numerous fundamental research protocols and many clinical trials. It quickly became apparent that although COVID-19, in the vast majority of cases, was a benign disease, it could also develop a severe form with sometimes fatal outcomes. Cytokines are central to the pathophysiology of COVID-19; while some of them are beneficial (type-I interferon, interleukin-7), others appear detrimental (interleukin-1β, -6, and TNF-α) particularly in the context of the so-called cytokine storm. Yet another characteristic of the disease has emerged: concomitant immunodeficiency, notably involving impaired type-I interferon response, and lymphopenia. This review provides an overview of current knowledge on COVID-19 immunopathology. We discuss the defective type-I IFN response, the theoretical role of IL-7 to restore lymphocyte repertoire, as well as we mention the two patterns observed in severe COVID-19 (i.e. interleukin-1β-driven macrophage activation syndrome vs. interleukin-6-driven immune dysregulation). Next, reviewing current evidence drawn from clinical trials, we examine a number of cytokine and anti-cytokine therapies, including interleukin-1, -6, and TNF inhibitors, as well as less targeted therapies, such as corticosteroids, chloroquine, or JAK inhibitors.
•COVID-19 induces both impairment and hyperactivation of the immune system.•Early viral clearance by type-I IFN is a key to preventing further viral replication, T cell exhaustion, and cytokine storm.•Timely administration of treatments may reduce viral load and avoid hyperinflammation.
The Krebs cycle-derived metabolite itaconate is highly upregulated in inflammatory macrophages and exerts immunomodulatory effects through cysteine modifications on target proteins. The NLRP3 ...inflammasome, which cleaves IL-1β, IL-18, and gasdermin D, must be tightly regulated to avoid excessive inflammation. Here we provide evidence that itaconate modifies NLRP3 and inhibits inflammasome activation. Itaconate and its derivative, 4-octyl itaconate (4-OI), inhibited NLRP3 inflammasome activation, but not AIM2 or NLRC4. Conversely, NLRP3 activation was increased in itaconate-depleted Irg1−/− macrophages. 4-OI inhibited the interaction between NLRP3 and NEK7, a key step in the activation process, and “dicarboxypropylated” C548 on NLRP3. Furthermore, 4-OI inhibited NLRP3-dependent IL-1β release from PBMCs isolated from cryopyrin-associated periodic syndrome (CAPS) patients, and reduced inflammation in an in vivo model of urate-induced peritonitis. Our results identify itaconate as an endogenous metabolic regulator of the NLRP3 inflammasome and describe a process that may be exploited therapeutically to alleviate inflammation in NLRP3-driven disorders.
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•Itaconate and its derivative 4-OI (which generates itaconate) block NLRP3 activation•Itaconate-depleted Irg1−/− BMDMs exhibit increased NLRP3 inflammasome activation•4-OI “dicarboxypropylates” C548 on NLRP3 and blocks the NLRP3-NEK7 interaction•4-OI reduces peritonitis in vivo and blocks IL-1β release from CAPS patient PBMCs
Hooftman et al. reveal a role for the Krebs cycle-derived metabolite itaconate in regulating the NLRP3 inflammasome. Itaconate specifically blocks NLRP3 inflammasome activation by reducing the NLRP3-NEK7 interaction, likely due to modification of C548 on NLRP3. Furthermore, itaconate inhibits IL-1β release from cells isolated from patients with the NLRP3-mediated disease CAPS.
PurposeCD40 is an upstream inducer of inflammation in the diabetic retina. CD40 is upregulated in retinal endothelial cells in diabetes. The purpose of this study was to determine whether expression ...of CD40 in endothelial cells is sufficient to promote inflammatory responses in the retina of diabetic mice. MethodsTransgenic mice with CD40 expression restricted to endothelial cells (Trg-CD40 EC), transgenic control mice (Trg-Ctr), B6, and CD40-/- mice were made diabetic using streptozotocin. Leukostasis was assessed using FITC-conjugated ConA. Pro-inflammatory molecule expression was examined by real-time PCR, immunohistochemistry, ELISA, or flow cytometry. Release of ATP was assessed by ATP bioluminescence. ResultsDiabetic B6 and Trg-CD40 EC mice exhibited increased retinal mRNA levels of ICAM-1, higher ICAM-1 expression in endothelial cells, and increased leukostasis. These responses were not detected in diabetic mice that lacked CD40 (CD40-/- and Trg-Ctr). Diabetic B6 but not Trg-CD40 EC mice upregulated TNF-α, IL-1β, and NOS2 mRNA levels. CD40 stimulation in retinal endothelial cells upregulated ICAM-1 but not TNF-α, IL-1β, or NOS2. CD40 ligation did not trigger ATP release by retinal endothelial cells or pro-inflammatory cytokine production in bystander myeloid cells. In contrast to diabetic B6 mice, diabetic Trg-CD40 EC mice did not upregulate P2X7 mRNA levels in the retina. ConclusionsEndothelial cell CD40 promotes ICAM-1 upregulation and leukostasis. In contrast, endothelial cell CD40 does not lead to pro-inflammatory cytokine and NOS2 upregulation likely because it does not activate purinergic-mediated pro-inflammatory molecule expression by myeloid cells or induce expression of these pro-inflammatory molecules in endothelial cells.
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