IL-1 Receptor Type Research Articles

High mobility group box 1 and a network of other biomolecules influence fatigue in patients with Crohn’s disease

BackgroundFatigue is common in patients with chronic inflammatory and autoimmune diseases, often with a severe impact on the patient’s daily life. From a biological point of view, fatigue can be regarded as an element of the sickness behavior response, a coordinated set of responses induced by pathogens to enhance survival during an infection and immunological danger. The mechanisms are not fully understood but involve activation of the innate immune system, with pro-inflammatory cytokines, in particular interleukin (IL)-1β, acting on cerebral neurons. These mechanisms are also active during chronic inflammatory conditions. High mobility group box 1 (HMGB1) protein has interleukin-1 like properties and is a strong inducer of innate immune responses. Its role in generation of fatigue is not clarified. Emerging evidence indicates that also other biomolecules may influence sickness behavior. We aimed to elucidate how HMGB1 influences fatigue in patients with Crohn’s disease, and how the protein interacts with other candidate biomarkers of fatigue.MethodsIn 56 patients with newly diagnosed Crohn’s disease, fatigue was evaluated using three different fatigue instruments: the fatigue visual analog scale (fVAS), Fatigue Severity Scale (FSS), and the vitality subscale of Medical Outcomes Study Short-Form Health Survey (SF-36vs). The biochemical markers IL-1 receptor antagonist (RA), soluble IL-1 receptor type 2 (sIL-RII), heat shock protein 90 alpha (HSP90α), HMGB1, anti-fully reduced (fr)HMGB1 antibodies (abs), hemopexin (HPX), and pigment epithelium-derived factor (PEDF) were measured in plasma. Multivariable regression and principal component analyses (PCA) were applied.ResultsMultivariable regression analyses revealed significant contributions to fatigue severity for HMGB1 in the FSS model, HSP90α in the fVAS model and IL-1RA in the SF-36vs model. Depression and pain scores contributed to all three models. In PCA, two components described 53.3% of the variation. The “inflammation and cellular stress dimension” was dominated by IL-1RA, sIL-1RII, HSP90α, HPX, and PEDF scores, where the “HMGB1 dimension” was dominated by HMGB1, anti-frHMGB1 abs, and fVAS scores.ConclusionThis study supports the hypothesis that HMGB1 and a network of other biomolecules influence fatigue severity in chronic inflammatory conditions. The well-known association with depression and pain is also acknowledged.

Identification of an IL-1 receptor mutation driving autoinflammation directs IL-1-targeted drug design

The interleukin 1 (IL-1) pathway signals through IL-1 receptor type1 (IL-1R1) and emerges as a central mediator for systemic inflammation. Aberrant IL-1 signaling leads to a range of autoinflammatory diseases. Here, we identified a de novo missense variant in IL-1R1 (p.Lys131Glu) in a patient with chronic recurrent multifocal osteomyelitis (CRMO). Patient PBMCs showed strong inflammatory signatures, particularly in monocytes and neutrophils. The p.Lys131Glu substitution affected a critical positively charged amino acid, which disrupted the binding of the antagonist ligand, IL-1Ra, but not IL-1α or IL-1β. This resulted in unopposed IL-1 signaling. Mice with a homologous mutation exhibited similar hyperinflammation and greater susceptibility to collagen antibody-induced arthritis, accompanied with pathological osteoclastogenesis. Leveraging the biology of the mutation, we designed an IL-1 therapeutic, which traps IL-1β and IL-1α, but not IL-1Ra. Collectively, this work provides molecular insights and a potential drug for improved potency and specificity in treating IL-1-driven diseases.

An in vitro model of drug-resistant seizures for selecting clinically effective antiseizure medications in Febrile Infection-Related Epilepsy Syndrome.

FIRES is a rare epileptic encephalopathy induced by acute unremitting seizures that occur suddenly in healthy children or young adults after a febrile illness in the preceding 2 weeks. This condition results in high mortality, neurological disability, and drug-resistant epilepsy. The development of new therapeutics is hampered by the lack of validated experimental models. Our goal was to address this unmet need by providing a simple tool for rapid throughput screening of new therapies that target pathological inflammatory mechanisms in FIRES. The model was not intended to mimic the etiopathogenesis of FIRES which is still unknown, but to reproduce salient features of its clinical presentation such as the age, the cytokine storm and the refractoriness of epileptic activity to antiseizure medications (ASMs). We refined an in vitro model of mouse hippocampal/temporal cortex acute slices where drug-resistant epileptic activity is induced by zero Mg2+/100 μM 4-aminopirydine. Clinical evidence suggests that acute unremitting seizures in FIRES are promoted by neuroinflammation triggered in the brain by the preceding infection. We mimicked this inflammatory component by exposing slices for 30 min to 10 μg/ml lipopolysaccharide (LPS). LPS induced a sustained neuroinflammatory response, as shown by increased mRNA levels of IL-1β, CXCL1 (IL-8), TNF, and increased IL-1β/IL-1Ra ratio. Epileptiform activity was exacerbated by neuroinflammation, also displaying increased resistance to maximal therapeutic concentrations of midazolam (100 μM), phenytoin (50 μM), sodium valproate (800 μM), and phenobarbital (100 μM). Treatment of LPS-exposed slices with two immunomodulatory drugs, a mouse anti-IL-6 receptor antibody (100 μM) corresponding to tocilizumab in humans, or anakinra (1.3 μM) which blocks the IL-1 receptor type 1, delayed the onset of epileptiform events and strongly reduced the ASM-resistant epileptiform activity evoked by neuroinflammation. These drugs were shown to reduce ASM-refractory seizures in FIRES patients. The neuroinflammatory component and the pharmacological responsiveness of epileptiform events provide a proof-of-concept validation of this in vitro model for the rapid selection of new treatments for acute ASM-refractory seizures in FIRES.

Systemic proinflammatory−profibrotic response in aortic stenosis patients with diabetes and its relationship with myocardial remodeling and clinical outcome

BackgroundPrevious studies have mainly focused more on how diabetes affects the valve than the myocardium in aortic stenosis (AS). In the pressure-overloaded heart, myocardial fibrosis is an important driver of the progression from compensated hypertrophy to heart failure. Using comprehensive noninvasive imaging and plasma proteomics, we investigated whether and how diabetes aggravates the remodeling of the myocardium and its relation with prognosis in AS patients.MethodsSevere AS patients were enrolled in two prospective cohorts for imaging and biomarker analysis. The imaging cohort (n = 253) underwent echocardiography and cardiac magnetic resonance, and the biomarker cohort (n = 100) blood sampling with multiplex proximity extension assay for 92 proteomic biomarkers. The composite outcome of hospitalization for heart failure admissions and death was assessed in the imaging cohort.ResultsDiabetic patients were older (70.4 ± 6.8 versus 66.7 ± 10.1 years) with more advanced ventricular diastolic dysfunction and increased replacement and diffuse interstitial fibrosis (late gadolinium enhancement % 0.3 [0.0–1.6] versus 0.0 [0.0–0.5], p = 0.009; extracellular volume fraction % 27.9 [25.7–30.1] versus 26.7 [24.9–28.5], p = 0.025) in the imaging cohort. Plasma proteomics analysis of the biomarker cohort revealed that 9 proteins (E-selectin, interleukin-1 receptor type 1, interleukin-1 receptor type 2, galectin-4, intercellular adhesion molecule 2, integrin beta-2, galectin-3, growth differentiation factor 15, and cathepsin D) were significantly elevated and that pathways related to inflammatory response and extracellular matrix components were enriched in diabetic AS patients. During follow-up (median 6.3 years), there were 53 unexpected heart failure admissions or death in the imaging cohort. Diabetes was a significant predictor of heart failure and death, independent of clinical covariates and aortic valve replacement (HR 1.88, 95% CI 1.06−3.31, p = 0.030).ConclusionsPlasma proteomic analyses indicate that diabetes potentiates the systemic proinflammatory−profibrotic milieu in AS patients. These systemic biological changes underlie the increase of myocardial fibrosis, diastolic dysfunction, and worse clinical outcomes in severe AS patients with concomitant diabetes.

Molecular and functional characterization of chicken interleukin 1 receptor 2 (chIL-1R2)

Interleukin-1 receptor type 2 (IL1R2) is a decoy receptor for exogenous IL-1. However, its functional role in chicken immunity is poorly understood. Herein, chicken IL-1R2 (chIL-1R2) was identified and functionally characterized in vivo and in vitro. The chIL-1R2 coding sequence includes 1,236 nucleotides encoding 412 amino acids, is highly conserved, and has a close relationship with its mammalian counterpart. Its extracellular region has three Ig-like domains but no TIR domain for intracellular signaling. Using ELISA, the recombinant chIL-1R2 protein was demonstrated to specifically bind to the chicken IL-1β. ChIL-1R2 mRNA expression was shown to be higher in the spleen, lung, kidney, small intestine, and liver. The expression of chIL-1R2 and chIL-1R1 was significantly upregulated in DF-1 cells treated with poly (I:C), but significantly downregulated in the presence of NF-κB, JNK, and MEK inhibitors, indicating that the NF-κB, JNK, and MEK signaling pathways are required for the transcriptional regulation of chIL-1R1 and chIL-1R2 expression. It is worth noting that while the p30 MAPK pathway was required for chIL-1R1 expression, it was not required for chIL-1R2 expression. Furthermore, chIL-1R2 expression increased as early as day 1, and then significantly decreased until day 3, while chIL-1R1 was dramatically upregulated in four organs of chickens infected with the highly pathogenic avian influenza virus (HPAIV). These findings indicate that chIL-1R1 and chIL-1R2 may play a crucial in innate and adaptive immune responses toward HPAIV infection. In summary the present study showed that chIL-1R2 binds to chIL-1β antibody. ChIL-1R2 expression can be induced by a viral infection, and may be regulated through NF-κB/JNK/MEK-mediated signaling pathways.

Proteomics, dietary intake, and changes in cardiometabolic health within a behavioral weight-loss intervention: A pilot study.

Identifying associations among circulating proteins, dietary intakes, and clinically relevant indicators of cardiometabolic health during weight loss may elucidate biologically relevant pathways affected by diet, allowing for an incorporation of precision nutrition approaches when designing future interventions. This study hypothesized that plasma proteins would be associated with diet and cardiometabolic health indicators within a behavioral weight-loss intervention. This secondary data analysis included participants (n= 20, mean [SD], age: 40.1 [9.5] years, BMI: 34.2[4.0] kg/m2 ) who completed a 1-year behavioral weight-loss intervention. Cardiovascular disease-related plasma proteins, diet, and cardiometabolic health indicators were evaluated at baseline and 3 months. Associations were determined via linear regression and integrated networks created using Visualization Of LineAr Regression Elements (VOLARE). A total of 16 plasma proteins were associated with ≥1 diet or health indicator at baseline (p< 0.001); changes in 42 proteins were associated with changes in diet or health indicators from baseline to 3 months (p< 0.005). Baseline tumor necrosis factor receptor superfamily member 10C (TNFRSF10C) was associated with intakes of dark green vegetables (r= -0.712), and fatty acid-binding protein 4 (FABP4) was associated with intakes of unsweetened coffee (r= -0.689). Changes in refined-grain intakes were associated with changes in scavenger receptor cysteine-rich type 1 protein M130 (CD163; r= 0.725), interleukin-1 receptor type 1 (IL1R-T1; r= 0.624), insulin (r= 0.656), and triglycerides (r= 0.648). Circulating cardiovascular disease-related proteins were associated with diet and cardiometabolic health indicators prior to and in response to weight loss.

Association of Soluble IL-1 Receptor Type 2 with Recovery of Left Ventricular Function and Clinical Outcomes in Acute Myocardial Infarction.

The role of soluble interleukin-1 receptor type 2 (sIL-1R2) in acute myocardial infarction (AMI) remains undocumented. In the present study, we aimed to evaluate the possible associations of sIL-1R2 with left ventricular (LV) function, remodeling and future clinical events in the setting of AMI. Circulating sIL-1R2 levels were quantified after percutaneous coronary intervention (PCI) on day 1 of hospital admission for 204 AMI patients, and upon enrollment of 204 healthy controls. Echocardiography was conducted in the acute phase and at 12-month follow-up. Adverse clinical events were registered after 12 months. Circulating sIL-1R2 levels were significantly higher in AMI patients than in healthy controls (medians respectively 6652.81 pg/mL, 3799.13 pg/mL, p 0.0001). AMI patients with sIL-1R2 levels less than the median had a larger proportion of worsened LV ejection fraction [a decrease in LV ejection fraction (LVEF) of more than 10% units] and reduced LVEF (a final LVEF 50%). After multivariate adjustment, sIL-1R2 levels less than the median were associated with an increased risk of worsened LVEF [odds ratio (OR): 3.7, 95% confidence interval (CI): 1.6-8.5, p = 0.002] and reduced LVEF at 12 months (OR: 2.1, 95% CI: 1.1-4.3, p = 0.035). Moreover, low sIL-1R2 levels were associated with an increased risk of having an adverse clinical event during the first 12 months after AMI [hazard ratio (HR): 2.5, 95% CI: 1.0-6.1, p = 0.039]. Low levels of circulating sIL-1R2 were associated with impaired recovery of LV function and adverse clinical outcomes in AMI patients. These findings might contribute to understanding the important role of sIL-1R2 in postinfarction inflammation.

Systemic proinflammatory-profibrotic response in aortic stenosis patients with diabetes and its relationship with myocardial remodeling and clinical outcome

Abstract Background It is unclear whether and how diabetes mellitus may aggravate myocardial fibrosis and remodeling in the pressure-overloaded heart. We investigated the impact of diabetes on the prognosis of aortic stenosis (AS) patients and its underlying mechanisms using comprehensive noninvasive imaging studies and plasma proteomics. Methods Severe AS patients undergoing both echocardiography and cardiovascular magnetic resonance (CMR) (n=253 of which 66 had diabetes) comprised the imaging cohort. The degree of replacement and diffuse interstitial fibrosis by late gadolinium enhancement (LGE) and extracellular volume fraction (ECV) was quantified using CMR. Plasma samples were analyzed with the multiplex proximity extension assay for 92 proteomic biomarkers in a separate biomarker cohort of severe AS patients (n=100 of which 27 had diabetes). Results In the imaging cohort, diabetic patients were older (70.4±6.8 vs. 66.7±10.1 years) and had a higher prevalence of ischemic heart disease (28.8% vs. 9.1%), with more advanced ventricular diastolic dysfunction. On CMR, diabetic patients had increased replacement and diffuse interstitial fibrosis (LGE% 0.3 [0.0–1.6] versus 0.0 [0.0–0.5], p=0.009; ECV% 27.9 [25.7–30.1] versus 26.7 [24.9–28.5], p=0.025) (Figure 1). Plasma proteomics analysis of the biomarker cohort revealed that 9 proteins (E-selectin, interleukin-1 receptor type 1, interleukin-1 receptor type 2, galectin-4, intercellular adhesion molecule 2, integrin beta-2, galectin-3, growth differentiation factor 15, and cathepsin D) are significantly elevated in diabetic AS patients (Figure 2). Pathway over-representation analyses of the plasma proteomics with Gene Ontology terms indicated that pathways related to inflammatory response and extracellular matrix components were enriched, suggesting that diabetes is associated with systemic effects that evoke proinflammatory and profibrotic response to the pressure-overloaded myocardium. During follow-up (median 6.3 years [IQR 5.2–7.2]) of the imaging cohort, 232 patients received aortic valve replacement (AVR) with 53 unexpected heart failure admissions or death. Diabetes was a significant predictor of heart failure and death, independent of clinical covariates and AVR (hazard ratio 1.88, 95% confidence interval 1.06–3.31, p=0.030). Conclusion Plasma proteomic analyses indicate that diabetes potentiates the systemic proinflammatory and profibrotic milieu in AS patients. These systemic biological changes underlie the increase of myocardial fibrosis, diastolic dysfunction, and worse clinical outcomes in severe AS patients with concomitant diabetes. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): National Research Foundation of Korea

Immunologic aspects of migraine: A review of literature.

Migraine headaches are highly prevalent, affecting 15% of the population. However, despite many studies to determine this disease's mechanism and efficient management, its pathophysiology has not been fully elucidated. There are suggested hypotheses about the possible mediating role of mast cells, immunoglobulin E, histamine, and cytokines in this disease. A higher incidence of this disease in allergic and asthma patients, reported by several studies, indicates the possible role of brain mast cells located around the brain vessels in this disease. The mast cells are more specifically within the dura and can affect the trigeminal nerve and cervical or sphenopalatine ganglion, triggering the secretion of substances that cause migraine. Neuropeptides such as calcitonin gene-related peptide (CGRP), neurokinin-A, neurotensin (NT), pituitary adenylate-cyclase-activating peptide (PACAP), and substance P (SP) trigger mast cells, and in response, they secrete pro-inflammatory and vasodilatory molecules such as interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) as a selective result of corticotropin-releasing hormone (CRH) secretion. This stress hormone contributes to migraine or intensifies it. Blocking these pathways using immunologic agents such as CGRP antibody, anti-CGRP receptor antibody, and interleukin-1 beta (IL-1β)/interleukin 1 receptor type 1 (IL-1R1) axis-related agents may be promising as potential prophylactic migraine treatments. This review is going to summarize the immunological aspects of migraine.

Mechanisms by which dupilumab normalizes eicosanoid metabolism and restores aspirin-tolerance in AERD: A hypothesis

Aspirin-exacerbated respiratory disease (AERD) is associated with overproduction of proinflammatory cysteinyl leukotrienes (CysLTs), defective generation of anti-inflammatory prostaglandin E2 (PGE2), and reduced expression of the EP2 receptor for PGE2. Reduced PGE2 synthesis results from the downregulation of inducible COX-2. Because PGE2 signaling via EP2 inhibits the 5-lipoxygenase/leukotriene C4 synthase-dependent pathway, the deficient levels of both PGE2 and EP2 likely contribute to the excessive baseline production of cysteinyl leukotrienes in patients with AERD compared with in patients with aspirin-tolerant asthma. The COX-2 pathway is regulated by an autocrine metabolic loop involving IL-1β, IL-1 receptor type I, EP2, COX-2, membrane-bound PGE2 prostaglandin E2 synthase-1, and PGE2. Previous studies reported that this metabolic loop is dysregulated in patients with AERD. When the downexpressed EP2 receptor is normalized, the entire loop returns to its normal function. Cotreatment of airway cells from healthy subjects with IL-4 and IFN-γ induces alterations in the metabolic loop similar to those seen in patients with AERD. In these patients, IL-4, which is produced in excess in airways of patients with AERD, likely contributes to the alteration of normal functioning of the autocrine metabolic loop involving IL-1β, IL-1 receptor type I, EP2, COX-2, membrane-bound PGE2 prostaglandin E2 synthase-1, and PGE2. We hypothesized that by blocking IL-4 action, dupilumab normalizes EP2 expression and restores the normal functioning of the COX-2 pathway autocrine metabolic loop, thereby normalizing the synthesis of PGE2 and restoring aspirin tolerance.

Hepatic interleukin-1 receptor type 1 signalling regulates insulin sensitivity in the early phases of nonalcoholic fatty liver disease.

BackgroundNonalcoholic fatty liver disease (NAFLD) is associated with hepatic as well as systemic insulin resistance even in the absence of type 2 diabetes. The extent and pathways through which hepatic inflammation modulates insulin sensitivity in NAFLD are only partially understood. We explored the contribution of hepatic interleukin (IL)‐1 signalling in a novel conditional knockout mouse model and expand the knowledge on this signalling pathway with regard to its liver‐specific functions.MethodsA high‐fat, high‐carbohydrate diet (HFD) over 12 weeks was used in male hepatocyte‐specific IL‐1 receptor type 1 (IL‐1R1) knockout mice (Il1r1 Hep−/–) and wild‐type (WT) littermates.ResultsBoth genotypes developed an obese phenotype and accompanying macrovesicular hepatic steatosis. In contrast to WT mice, microvesicular steatosis and ballooning injury was less pronounced in HFD‐fed Il1r1 Hep−/– mice, and alanine aminotransferase remained in the normal range. This was paralleled by the suppression of injurious and proinflammatory hepatic c‐Jun N‐terminal kinases and extracellular signal‐regulated kinases signalling, stable peroxisome proliferator activated receptor gamma coactivator‐1alpha and farnesoid X receptor‐alpha expression and preservation of mitochondrial function. Strikingly, despite HFD‐feeding Il1r1 Hep−/– mice remained highly insulin sensitive as indicated by lower insulin levels, homeostatic model assessment for insulin resistance, higher glucose tolerance, more stable hepatic insulin signalling cascade, and less adipose tissue inflammation compared to the WT.ConclusionsThe current data highlights that hepatocyte IL‐1R1 contributes to hepatic and extrahepatic insulin resistance. Future liver‐directed therapies in NAFLD could have effects on insulin sensitivity when improving hepatic inflammation and IL‐1R1 signalling.

Over-expression of IL1R2 in PBMCs of Patients with Coronary Artery Disease and Its Clinical Significance.

Background:IL-1 has been widely explored and played a role in regulating inflammatory and immune responses to various disorders. Nevertheless, the role of interleukin-1 receptor type II, a protein-coding gene of interleukin-1 in coronary artery disease patients with peripheral blood mononuclear cells, persists to be undetermined.Methods:Our study discovered the IL-1 receptor type II expression through gene expression omnibus (GEO) public repository based on bioinformatics tools and further validation was carried out between coronary artery disease patients and healthy participants using peripheral blood mononuclear cells samples in Second Hospital of Tianjin Medical University. A total of 180 participants, comprising 90 cases of coronary artery disease and 90 samples of healthy control were retrospectively evaluated and the correlation of IL-1 receptor type II was observed between serum levels of oxidized low-density lipoprotein and SYNTAX score. Furthermore, the clinical significance of IL-1 receptor type II was evaluated in peripheral blood mononuclear cells of coronary artery disease patients by the receiver operating curve using the area under the curve.Results:IL-1 receptor type II was markedly overexpressed in peripheral blood mononuclear cells and severe patients with coronary artery disease compared to the healthy control participants. Meanwhile, a positive correlation of IL-1 receptor type II expression was significantly observed between SYNTAX score and oxidized low-density lipoprotein of coronary artery disease patients. Further, the receiver operating curve achieved a significantly higher area under the curve of 0.813 in coronary artery disease patients with peripheral blood mononuclear cells. Thus, IL-1 receptor type II expressions were not only directly correlated with peripheral blood mononuclear cells but also showed potential significance in coronary artery disease patients.Conclusion:IL-1 receptor type II might be involved in the immune/inflammatory responses of coronary artery disease accompanied by other cytokine receptor genes.

Uncovering Streptomyces-Derived Compounds as Cosmeceuticals for the Development of Improved Skin Photoprotection Products: An In Silico Approach to Explore Multi-Targeted Agents

The search for novel photoprotective substances has become a challenge in cosmeceutical research. Streptomyces-derived compounds can serve as a promising source of photoprotective agents to formulate skin photoprotection products, such as sunscreens. This study aimed to identify specialized metabolites with the potential to modulate UV-induced cellular damage in the skin by identifying potential multi-target-directed ligands. Using a combination of ligand- and target-based virtual screening approaches, a public compound library comprising 6524 Streptomyces-derived specialized metabolites was studied for their photoprotective capability. The compounds were initially filtered by safety features and then examined for their ability to interact with key targets in the photodamage pathway by molecular docking. A set of 50 commercially available UV filters was used as the benchmark. The protein–ligand stability of selected Streptomyces-derived compounds was also studied by molecular dynamics (MD) simulations. From the compound library, 1981 compounds were found to meet the safety criteria for topically applied products, such as low skin permeability and low or non-toxicity-alerting substructures. A total of 34 compounds had promising binding scores against crucial targets involved in UV-induced photodamage, such as serotonin-receptor subtype 5-HT2A, platelet-activating factor receptor, IL-1 receptor type 1, epidermal growth factor receptor, and cyclooxygenase-2. Among these compounds, aspergilazine A and phaeochromycin F showed the highest ranked interactions with four of the five targets and triggered complex stabilization over time. Additionally, the predicted UV-absorbing profiles also suggest a UV-filtering effect. Streptomyces is an encouraging biological source of compounds for developing topical products. After in silico protein–ligand interactions, binding mode and stabilization of aspergilazine A and phaeochromycin F led to the discovery of potential candidates as photodamage multi-target inhibitors. Therefore, they can be further explored for the formulation of skin photoprotection products.

Anti-inflammatory effects of hydrophobic constituents in the extract of the root cortex of Paeonia suffruticosa

Background: The root cortex of Paeonia suffruticosa Andrews (Paeoniaceae), which is also called moutan bark, is known as Botanpi in Japan. This crude drug has been used in several Kampo formulas, such as Daiobotanpito, to treat menstrual disturbance and constipation by improving blood stasis and suppressing inflammation. However, the anti-inflammatory effect has not been well studied.Objective: To clarify the anti-inflammatory effects of moutan bark, we isolated its constituents and investigated their activity.Methods: Moutan bark was extracted and successively fractionated with ethyl acetate (EtOAc) and n-butanol. The constituents were analyzed using HPLC. The production of nitric oxide (NO), an inflammatory mediator, was measured in interleukin (IL)-1β-treated rat hepatocytes to identify active fractions or constituents.Results: The EtOAc-soluble fraction of moutan bark extract significantly inhibited NO production. Three hydrophobic constituents were isolated from this fraction and identified as paeonol (1), 1,2,3,4,6-pentagalloyl-β-D-glucose (β-PGG; 2), and methyl gallate (3). Paeonol and paeoniflorin (4) were abundantly present in the EtOAc-soluble fraction and n-butanol-soluble fraction, respectively. The hydrophobic constituents suppressed NO production without exerting cytotoxicity and reduced the protein and mRNA levels of inducible nitric oxide synthase in IL-1β-treated hepatocytes; β-PGG showed the highest potency. Furthermore, β-PGG, methyl gallate, and paeonol decreased the mRNA levels of tumor necrosis factor α and IL-1 receptor type 1, which are involved in inflammation.Conclusion: These results suggest that hydrophobic constituents of moutan bark, such as β-PGG, methyl gallate, and paeonol, are involved in the anti-inflammatory effects of moutan bark.Keywords: Galloylglucose, tannin, nitric oxide, Kampo medicine, cytokine.

IL-1-dependent enteric gliosis guides intestinal inflammation and dysmotility and modulates macrophage function

Muscularis Externa Macrophages (ME-Macs) and enteric glial cells (EGCs) are closely associated cell types in the bowel wall, and important interactions are thought to occur between them during intestinal inflammation. They are involved in developing postoperative ileus (POI), an acute, surgery-induced inflammatory disorder triggered by IL-1 receptor type I (IL1R1)-signaling. In this study, we demonstrate that IL1R1-signaling in murine and human EGCs induces a reactive state, named enteric gliosis, characterized by a strong induction of distinct chemokines, cytokines, and the colony-stimulating factors 1 and 3. Ribosomal tagging revealed enteric gliosis as an early part of POI pathogenesis, and mice with an EGC-restricted IL1R1-deficiency failed to develop postoperative enteric gliosis, showed diminished immune cell infiltration, and were protected from POI. Furthermore, the IL1R1-deficiency in EGCs altered the surgery-induced glial activation state and reduced phagocytosis in macrophages, as well as their migration and accumulation around enteric ganglia. In patients, bowel surgery also induced IL-1-signaling, key molecules of enteric gliosis, and macrophage activation. Together, our data show that IL1R1-signaling triggers enteric gliosis, which results in ME-Mac activation and the development of POI. Intervention in this pathway might be a useful prophylactic strategy in preventing such motility disorders and gut inflammation.

IL1R2 promotes tumor progression via JAK2/STAT3 pathway in human clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is known as the most aggressive subtype of genitourinary cancers. The lack of effective therapies has prompted us to further explore the complex network of genes involved in ccRCC tumor progression and metastasis and to seek new biomarkers and therapeutic strategies to improve clinical outcomes. Interleukin-1 receptor type 2 (IL1R2), a decoy receptor of IL-1, is found to be differentially expressed in various tumors types recently. However, the role of IL1R2 in ccRCC has not been documented. Herein, we found that the expression of IL1R2 in ccRCC tissues was significantly increased as the tumor’s Furman pathological grade was elevated. Compared to lower IL1R2 expression, ccRCC patients with high IL1R2 expression had a significantly worse OS rate. IL1R2 could serve as an independent prognostic predictor for ccRCC patients. Depletion of IL1R2 could inhibit cell proliferation, migration, invasion, and cell cycle arrest at the G1 phase, while overexpression of IL1R2 could reverse this effect. Moreover, depletion of IL1R2 led to changes and enrichment of several signaling pathways, as shown by RNA sequencing. We subsequently verified that Janus kinase 2 / signal transducer and activator of transcription 3 (JAK2/STAT3) pathway was involved in the IL1R2 mediated regulation of cellular functions of ccRCC cells and these functions were acted by the intracellular domain of IL1R2, not the extracellular domain. Our findings suggested that IL1R2 could serve as a potential therapeutic target for ccRCC progression and metastasis via its regulation of the JAK2/STAT3 signaling pathway.

Tubular IL-1β Induces Salt Sensitivity in Diabetes by Activating Renal Macrophages.

Chronic renal inflammation has been widely recognized as a major promoter of several forms of high blood pressure including salt-sensitive hypertension. In diabetes, IL (interleukin)-6 induces salt sensitivity through a dysregulation of the epithelial sodium channel. However, the origin of this inflammatory process and the molecular events that culminates with an abnormal regulation of epithelial sodium channel and salt sensitivity in diabetes are largely unknown. Both in vitro and in vivo approaches were used to investigate the molecular and cellular contributors to the renal inflammation associated with diabetic kidney disease and how these inflammatory components interact to develop salt sensitivity in db/db mice. Thirty-four-week-old db/db mice display significantly higher levels of IL-1β in renal tubules compared with nondiabetic db/+ mice. Specific suppression of IL-1β in renal tubules prevented salt sensitivity in db/db mice. A primary culture of renal tubular epithelial cells from wild-type mice releases significant levels of IL-1β when exposed to a high glucose environment. Coculture of tubular epithelial cells and bone marrow-derived macrophages revealed that tubular epithelial cell-derived IL-1β promotes the polarization of macrophages towards a proinflammatory phenotype resulting in IL-6 secretion. To evaluate whether macrophages are the cellular target of IL-1β in vivo, diabetic db/db mice were transplanted with the bone marrow of IL-1R1 (IL-1 receptor type 1) knockout mice. db/db mice harboring an IL-1 receptor type 1 knockout bone marrow remained salt resistant, display lower renal inflammation and lower expression and activity of epithelial sodium channel compared with db/db transplanted with a wild-type bone marrow. Renal tubular epithelial cell-derived IL-1β polarizes renal macrophages towards a proinflammatory phenotype that promotes salt sensitivity through the accumulation of renal IL-6. When tubular IL-1β synthesis is suppressed or in db/db mice in which immune cells lack the IL-1R1, macrophage polarization is blunted resulting in no salt-sensitive hypertension.

Extricating human tumour immune alterations from tissue inflammation

Immunotherapies have achieved remarkable successes in the treatment of cancer, but major challenges remain1,2. An inherent weakness of current treatment approaches is that therapeutically targeted pathways are not restricted to tumours, but are also found in other tissue microenvironments, complicating treatment3,4. Despite great efforts to define inflammatory processes in the tumour microenvironment, the understanding of tumour-unique immune alterations is limited by a knowledge gap regarding the immune cell populations in inflamed human tissues. Here, in an effort to identify such tumour-enriched immune alterations, we used complementary single-cell analysis approaches to interrogate the immune infiltrate in human head and neck squamous cell carcinomas and site-matched non-malignant, inflamed tissues. Our analysis revealed a large overlap in the composition and phenotype of immune cells in tumour and inflamed tissues. Computational analysis identified tumour-enriched immune cell interactions, one of which yields a large population of regulatory T (Treg) cells that is highly enriched in the tumour and uniquely identified among all haematopoietically-derived cells in blood and tissue by co-expression of ICOS and IL-1 receptor type 1 (IL1R1). We provide evidence that these intratumoural IL1R1+ Treg cells had responded to antigen recently and demonstrate that they are clonally expanded with superior suppressive function compared with IL1R1− Treg cells. In addition to identifying extensive immunological congruence between inflamed tissues and tumours as well as tumour-specific changes with direct disease relevance, our work also provides a blueprint for extricating disease-specific changes from general inflammation-associated patterns.

Activation and Function of NLRP3 Inflammasome in Bone and Joint-Related Diseases.

Inflammation is a pivotal response to a variety of stimuli, and inflammatory molecules such as cytokines have central roles in the pathogenesis of various diseases, including bone and joint diseases. Proinflammatory cytokines are mainly produced by immune cells and mediate inflammatory and innate immune responses. Additionally, proinflammatory cytokines accelerate bone resorption and cartilage destruction, resulting in the destruction of bone and joint tissues. Thus, proinflammatory cytokines are involved in regulating the pathogenesis of bone and joint diseases. Interleukin (IL)-1 is a representative inflammatory cytokine that strongly promotes bone and cartilage destruction, and elucidating the regulation of IL-1 will advance our understanding of the onset and progression of bone and joint diseases. IL-1 has two isoforms, IL-1α and IL-1β. Both isoforms signal through the same IL-1 receptor type 1, but the activation mechanisms are completely different. In particular, IL-1β is tightly regulated by protein complexes termed inflammasomes. Recent research using innovative technologies has led to a series of discoveries about inflammasomes. This review highlights the current understanding of the activation and function of the NLRP3 (NOD-like receptor family, pyrin domain-containing 3) inflammasome in bone and joint diseases.

Phytoconstituents of Red Grape Seeds Extract as Inflammatory Modulator in Adjuvant Arthritic Rats: Role Of IL-1 and its Receptor Blocking

This study focused on investigating the phytochemical composition of the total extract and the ethyl acetate fraction of red grape (Vitis vinifera L.) seeds as well as evaluating the total extract as anti-arthritis agents in rats compering with the new treating agent; interleukin-1 receptor antagonist (IL-1RA) and the classical anti-inflammatory drug; indomethacin. HPLC and LC-ESI-MS analysis was applied for identification and quantification the flavonoid and phenolic compounds. Arthritis was induced by using complete Freund’s adjuvant (CFA). The percentages of edema as well as the arthritis index were evaluated on the 7th, 14th, 21th and 28th day post CFA-induction. The evaluation was done by measuring serum interleukin-1 beta (IL-1β), IL-1 receptor type I gene expression, oxidative stress markers, intracellular adhesion molecule-1 (ICAM-1), caspase-3 (cas-3), c-reactive protein (CRP), prostaglandin E2 (PGE2), total protein content, DNA fragmentation, chromosomal aberration and cytogenic damage. The histopathological features of the ankle joint were analyzed. Stilbenes, phenolic acids, and anthocyanins were the major identified classes in the ethyl acetate fraction, while flavan-3-ol, oligomeric and polymeric procyanidins, flavonoid glucosides and phenolic acids were the main categories in the total extract. Three major proanthocyanidin compounds; gallic-4-O-β-glucopyranoside, catechin 3,5-di-O-gallate and catechin 3-O-gallate were identified in the ethyl acetate fraction. Treatment with seeds extract and IL-1RA improved the selected parameters by variable degrees. IL-1 RA showed a pronounced treating effect. In conclusion, Vitis vinifera seeds extract and IL-1RA are considered as promising anti-arthritis agents. More studies are required to conduct Vitis vinifera seeds extract and IL-1RA in pharmacological and clinical applications.