IL-37b alleviates endothelial cell apoptosis and inflammation in Kawasaki disease through IL-1R8 pathway.
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ABSTRACT:
SUBMITTER: Jia C
PROVIDER: S-EPMC8174541 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectivesMelatonin has been reported to be an appropriate candidate for mitigating various cardiovascular injuries, owing to its versatility. This study aimed to explore the role of melatonin in Kawasaki disease (KD)-associated vasculitis and its underlying mechanisms.Material and methodsThe role of melatonin was evaluated in human coronary artery endothelial cells (HCAECs), peripheral blood mononuclear cells from KD patients, human THP1 cell line in vitro, and a Candida albicans water-soluble fraction (CAWS)-induced KD mouse model in vivo. Cell proliferation assay, cell apoptosis assay, cell co-culture, RNA extraction, RNA sequencing, reverse transcription quantitative PCR, enzyme-linked immunosorbent assay (ELISA), transwell assay, western blot, dual-luciferase reporter assay, and autophagic flux assay were performed to investigate the function and regulatory mechanisms of melatonin in vitro, while haematoxylin and eosin staining, Verhoeff's van Gieson staining, ELISA, and immunohistochemical analysis were performed to detect the effect of melatonin in vivo.ResultsMelatonin suppressed cell apoptosis directly reduced the expression of endothelial cell damage markers in HCAECs, and alleviated vasculitis in the CAWS-induced KD mouse model. Mechanistically, melatonin promoted autophagy by activating the melatonin/ melatonin receptor (MT)/cAMP-response element binding protein (CREB) pathway and upregulating the expression of autophagy-related gene-3, thereby suppressing cell apoptosis in an autophagy-dependent manner. Additionally, melatonin decreased the production of pro-inflammatory cytokines in macrophages and indirectly reduced the immunopathological damage of HCAECs.ConclusionsThis study revealed that melatonin protects vascular endothelial cells in KD, by suppressing cell apoptosis in an autophagy-dependent manner and reducing the immunopathological damage mediated by macrophages.
| S-EPMC9201377 | biostudies-literature
Project description:Interleukin-1 receptor family members (ILRs) and Toll-Like Receptors (TLRs) are key players in immunity and inflammation and are tightly regulated at different levels. Most cell types, including cells of the innate and adaptive immune system express ILRs and TLRs. In addition, IL-1 family members are emerging as key players in the differentiation and function of innate and adaptive lymphoid cells. IL-1R2 and IL-1R8 (also known as TIR8 or SIGIRR) are members of the ILR family acting as negative regulators of the IL-1 system. IL-1R2 binds IL-1 and the accessory protein IL-1RAcP without activating signaling and can be released as a soluble form (sIL-1R2), thus modulating IL-1 availability for the signaling receptor. IL-1R8 dampens ILR- and TLR-mediated cell activation and it is a component of the receptor recognizing human IL-37. Here, we summarize our current understanding of the structure and function of IL-1R2 and IL-1R8, focusing on their role in different pathological conditions, ranging from infectious and sterile inflammation, to autoimmunity and cancer-related inflammation. We also address the emerging evidence regarding the role of IL-1R8 as a crucial checkpoint molecule in NK cells in anti-cancer and antiviral activity and the potential therapeutic implications of IL-1R8 blockade in specific pathological contexts.
| S-EPMC5922415 | biostudies-literature
Project description:Interleukin-1 receptor family members (ILRs) and toll-like receptors (TLRs) are characterized by the presence of a conserved intracellular domain and the toll-IL-1resistance (TIR) domain and are key players in immunity and inflammation. ILR and TLR signaling is tightly regulated at different levels. All cell types of the innate immune system express ILRs and TLRs. In addition, IL-1 family members are emerging as key players in the differentiation and function of innate and adaptive lymphoid cells. IL-1R8, also known as TIR8 or SIGIRR, is a fringe member of the ILR family and acts as a negative regulator of ILR and TLR signaling, which dampens ILR- and TLR-mediated cell activation. IL-1R8 is a component of the receptor recognizing human IL-37. Here, we summarize our current understanding of the structure and function of IL-1R8, focusing on its role in different pathological conditions, ranging from infectious and sterile inflammation to autoimmunity and cancer-related inflammation.
| S-EPMC4837151 | biostudies-literature
Project description:Background: Kawasaki disease (KD) is a self-limiting illness with acute systematic vascular inflammation. It causes pathological changes in mostly medium and small-sized arteries, especially the arteria coronaria, which adds the risk of developing coronary heart disease in adults. Materials and methods: We detected the miR-223-3p expression in 30 KD patients combined with 12 normal controls using miRNA microarrays and RT-PCR. A KD mouse model was constructed using Candida albicans water insoluble substance (CAWS). We also checked the miR-223-3p's expression using qRT-PCR. The Luciferase reporting system was implemented to validate the correlation between miR-223-3p and Interleukin-6 receptor subunit beta (IL-6ST). TNF-? was used to stimulate human coronary artery endothelial cells (HCAECs), and miR-223-3p activator or inhibitor and KD serum were used to treat HCAECs. A Western blotting automatic quantitative analysis protein imprinting system was used to test the expression of signal transducer and the activator of transcription 3 (STAT3), phosphorylated-signal transducer and the activator of transcription 3 (pSTAT3) and NF-?B p65. Results: Clinical trials found that miR-223-3p expressions were markedly different (more than 2-fold) between the acute KD group and the control group. E-selectin and intercellular cell adhesion molecule-1 (ICAM-1) levels were also significantly higher (about 2-fold) in KD especially with coronary artery lesions. MiR-223-3p could alleviate vascular endothelial damage in KD mice, and IL-6 (Interleukin-6), E-selectin and ICAM-1 were simultaneously negative. The values of IL-6, E-selectin, and ICAM-1 mRNA expressions decreased, while the value of IL-6ST was increased between the agonist treated mice and KD mice. The RT-qPCR consequences displayed that miR-223-3p explored the highest expression on the third day in both the KD mice as well as the agonist group. MiR-223-3p can directly combine with IL-6ST 3' untranslatable regions (UTR) and held back the IL-6's expression. Overexpression of miR-223 down regulated IL6ST expression and decreased the expression of p-STAT3 and NF-?B p65, while the miR-223 inhibitor could reverse the above process. Conclusion: MiR-223-3p is an important regulatory factor of vascular endothelial damage in KD and could possibly become a potential target of KD treatment in the future.
| S-EPMC6667785 | biostudies-literature
Project description:Background: Interleukin 37 (IL-37), a member of IL-1 family, broadly suppresses inflammation in many pathological conditions by acting as a dual-function cytokine in that IL-37 signals via the extracellular receptor complex IL1-R5/IL-1R8, but it can also translocate to the nucleus. However, whether IL-37 exerts beneficial actions in neuroinflammatory diseases, such as multiple sclerosis, remains to be elucidated. Thus, the goals of the present study were to evaluate the therapeutic effects of IL-37 in a mouse model of multiple sclerosis, and if so, whether this is mediated via the extracellular receptor complex IL-1R5/IL-1R8. Methods: We used a murine model of MS, the experimental autoimmune encephalomyelitis (EAE). We induced EAE in three different single and double transgenic mice (hIL-37tg, IL-1R8 KO, hIL-37tg-IL-1R8 KO) and wild type littermates. We also induced EAE in C57Bl/6 mice and treated them with various forms of recombinant human IL-37 protein. Functional and histological techniques were used to assess locomotor deficits and demyelination. Luminex and flow cytometry analysis were done to assess the protein levels of pro-inflammatory cytokines and different immune cell populations, respectively. qPCRs were done to assess the expression of IL-37, IL-1R5 and IL-1R8 in the spinal cord of EAE, and in blood peripheral mononuclear cells and brain tissue samples of MS patients. Results: We demonstrate that IL-37 reduces inflammation and protects against neurological deficits and myelin loss in EAE mice by acting via IL1-R5/IL1-R8. We also reveal that administration of recombinant human IL-37 exerts therapeutic actions in EAE mice. We finally show that IL-37 transcripts are not up-regulated in peripheral blood mononuclear cells and in brain lesions of MS patients, despite the IL-1R5/IL-1R8 receptor complex is expressed. Conclusions: This study presents novel data indicating that IL-37 exerts therapeutic effects in EAE by acting through the extracellular receptor complex IL-1R5/IL-1R8, and that this protective physiological mechanism is defective in MS individuals. IL-37 may therefore represent a novel therapeutic avenue for the treatment of MS with great promising potential.
| S-EPMC7681099 | biostudies-literature
Project description:BACKGROUND It is well established that inflammation and apoptosis of renal tubular epithelial cells caused by hyperglycemia contribute to the development of diabetic nephropathy (DN). Although microRNAs (miRNAs) are known to have roles in inflammation-related disorders, the exact role of miR-34b in DN has not been defined, and the regulatory mechanism has been unclear. This study aimed to clarify the role of miR-34b in DN pathogenesis. MATERIAL AND METHODS Expression of miR-34b, IL-6R, and other key factors of inflammation, apoptosis (TNF-alpha, IL-1ß, IL-6, caspase-3) in high glucose (HG)-induced HK-2 cells were measured by real-time PCR, Western blot, and flow cytometric cell apoptosis assays. We used luciferase reporter assay to detect the target of miR-34b. Moreover, the targeting gene of miR-34b and its downstream JAK2/STAT3 signaling pathway were explored. RESULTS It was demonstrated that miR-34b overexpression inhibited apoptosis and expression levels of TNF-alpha, IL-1ß, IL-6, and caspase-3 in HG-treated HK-2 cells. We also found that IL-6R is a direct target of miR-34b, which could rescue inflammation and apoptosis in HG-treated HK-2 cells transfected with miR-34b mimic. Furthermore, we showed that overexpression of miR-34b inhibited the IL-6R/JAK2/STAT3 signaling pathway in HG-treated HK-2 cells. CONCLUSIONS Our data suggest that overexpression of miR-34b improves inflammation and ameliorates apoptosis in HG-induced HK-2 cells via the IL-6R/JAK2/STAT3 pathway, indicating that miR-34b could be a promising therapeutic target in DN.
| S-EPMC6842269 | biostudies-literature
Project description:BackgroundThe Single immunoglobin interleukin-1 (IL-1)-related receptor (Sigirr), also known as IL-1R8, has been shown to exhibit broad anti-inflammatory effects against inflammatory diseases including acute lung injury, while molecular regulation of IL-1R8/Sigirr protein stability has not been reported. This study is designed to determine whether stabilization of IL-1R8/Sigirr by a deubiquitinating enzyme (DUB) is sufficient to suppress inflammatory responses and lessen lung inflammation.MethodsA molecular signature of ubiquitination and degradation of IL-1R8/Sigirr was determined using a receptor ligation chase model. The anti-inflammatory effects on USP13 were investigated. USP13 knockout mice were evaluated for stabilization of IL-1R8/Sigirr and disease phenotype in an acute lung injury model.FindingsIL-1R8/Sigirr degradation is mediated by the ubiquitin-proteasome system, through site-specific ubiquitination. This effect was antagonized by the DUB USP13. USP13 levels correlate directly with IL-1R8/Sigirr, and both proteins were reduced in cells and tissue from mice subjected to inflammatory injury by the TLR4 agonist lipopolysaccharide (LPS). Knockdown of USP13 in cells increased IL-1R8/Sigirr poly-ubiquitination and reduced its stability, which enhanced LPS-induced TLR4 signaling and cytokine release. Likewise, USP13-deficient mice were highly susceptible to LPS or Pseudomonas aeruginosa models of inflammatory lung injury. IL-1R8/Sigirr overexpression in cells or by pulmonary viral transduction attenuated the inflammatory phenotype conferred by the USP13-/- genotype.InterpretationStabilization of IL-1R8/Sigirr by USP13 describes a novel anti-inflammatory pathway in diseases that could provide a new strategy to modulate immune activation. FUND: This study was supported by the US National Institutes of Health (R01HL131665, HL136294 to Y.Z., R01 GM115389 to J.Z.).
| S-EPMC6642080 | biostudies-literature
Project description:ObjectiveAt present, studies have confirmed that NDRG4 is specifically expressed in the heart, while its effect on the heart is still unclear. This study is to explore the effect of NDRG4 on cardiomyocyte apoptosis caused by acute myocardial infarction (AMI).MethodsTwenty SD rats were randomly divided into Sham (left anterior descent of heart without ligation) and AMI groups. In this study, coronary artery ligation was used to establish an AMI model, and the AMI model was verified by auxiliary examination and pathological examination. Besides, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting (WB) was used to detect the expression level of Bax and Bcl-2 in heart tissues, and NDRG mRNA levels in tissues were also detected. qRT-PCR technology was used to verify the transfection efficiency of NDRG4 in H9C2 cells, and the change of apoptosis level of H9C2 cells was detected by Cell Counting Kit-8 (CCK-8) assay and TUNEL staining; besides, the expression level of apoptosis-related factors was detected by WB and qRT-PCR technology. Simultaneously with the modeling of rats, we injected adenovirus (Ad) into the heart tissue and examined the structural and functional changes of the rat heart. Then, WB technology was used to detect the expression level of the JAK2/STAT3 signaling pathway.ResultsThe heart function and heart structure of rats in the MI group were dramatically worse, and the expression level of NDRG4 was also dramatically reduced. The overexpression of NDRG4 in H9C2 cells can effectively inhibit the ischemia/hypoxia- (I/H-) induced decrease in cell viability and increase in apoptosis rate and inhibit the increase in Bax/Bcl-2 ratio. Moreover, overexpression of NDRG4 in heart tissue can effectively improve the cardiac function and structural destruction caused by MI. In addition, NDRG4 can inhibit JAK2/STAT3 pathway activation.ConclusionThe expression of NDRG4 in the MI tissue of rats was suppressed, while overexpression of NDRG4 by injection of Ad can obviously protect the rat heart. Furthermore, overexpression of NDRG4 in H9C2 cells can effectively inhibit the I/H-induced decrease in cell viability and increase in apoptosis rate, and this may be related to the inhibition of the JAK2/STAT3 signaling pathway.
| S-EPMC8814718 | biostudies-literature
Project description:Protein S-nitrosylation is a reversible protein modification implicated in both physiological and pathophysiological regulation of protein function. However, the relationship between dysregulated S-nitrosylation homeostasis and diabetic vascular complications remains incompletely understood. Here, we demonstrate that basic fibroblast growth factor (bFGF) is a key regulatory link between S-nitrosylation homeostasis and inflammation, and alleviated endothelial dysfunction and angiogenic defects in diabetes. Subjecting human umbilical vein endothelial cells (HUVECs) to hyperglycemia and hyperlipidemia significantly decreased endogenous S-nitrosylated proteins, including S-nitrosylation of inhibitor kappa B kinase β (IKKβC179) and transcription factor p65 (p65C38), which was alleviated by bFGF co-treatment. Pretreatment with carboxy-PTIO (c-PTIO), a nitric oxide scavenger, abolished bFGF-mediated S-nitrosylation increase and endothelial protection. Meanwhile, nitrosylation-resistant IKKβC179S and p65C38S mutants exacerbated endothelial dysfunction in db/db mice, and in cultured HUVECs subjected to hyperglycemia and hyperlipidemia. Mechanistically, bFGF-mediated increase of S-nitrosylated IKKβ and p65 was attributed to synergistic effects of increased endothelial nitric oxide synthase (eNOS) and thioredoxin (Trx) activity. Taken together, the endothelial protective effect of bFGF under hyperglycemia and hyperlipidemia can be partially attributed to its role in suppressing inflammation via the S-nitrosylation pathway.
| S-EPMC7972985 | biostudies-literature
Project description:Hypertension increases the pressure load on the heart and is associated with a poorly understood chronic systemic inflammatory state. Interleukin 33 (IL-33) binds to membrane-bound ST2 (ST2L) and has antihypertrophic and antifibrotic effects in the myocardium. In contrast, soluble ST2 appears to act as a decoy receptor for IL-33, blocking myocardial and vascular benefits, and is a prognostic biomarker in patients with cardiovascular diseases. Here we report that a highly local intramyocardial IL-33/ST2 conversation regulates the heart's response to pressure overload. Either endothelial-specific deletion of IL33 or cardiomyocyte-specific deletion of ST2 exacerbated cardiac hypertrophy with pressure overload. Furthermore, pressure overload induced systemic circulating IL-33 as well as systemic circulating IL-13 and TGF-beta1; this was abolished by endothelial-specific deletion of IL33 but not by cardiomyocyte-specific deletion of IL33. Our study reveals that endothelial cell secretion of IL-33 is crucial for translating myocardial pressure overload into a selective systemic inflammatory response.
| S-EPMC4466705 | biostudies-other