Ovarian leptin signalling regulates NLRP3 inflammasome activation and macrophage infiltration in a cell specific manner
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ABSTRACT:
PROVIDER: PRJNA989233 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25076661.fastq.gz | Fastqsanger.gz | |||
| SRR25076662.fastq.gz | Fastqsanger.gz | |||
| SRR25076663.fastq.gz | Fastqsanger.gz | |||
| SRR25076664.fastq.gz | Fastqsanger.gz | |||
| SRR25076665.fastq.gz | Fastqsanger.gz |
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Project description:Background: Obesity is associated with increased ovarian inflammation and the establishment of local leptin resistance. We presently investigated the role of leptin signalling on Nod-Like Receptor Protein 3 (NLPR3) inflammasome and macrophage prevalence in the pathophysiology of ovarian failure of obese mice. Methods: We collected ovaries from: (i) diet induced obese (DIO) mice fed chow diet (CD) or high-fat diet (HFD) for 4 or 16 weeks (wk); (ii) mice lacking the long-isoform of leptin receptor (ObRb; db/db); (iii) mice lacking leptin (ob/ob); and (iv) pharmacologically hyperleptinemic (LEPT) mice for protein and mRNA expression analysis. Next, granulosa cells (GCs) from antral follicles isolated from db/db and ob/ob mice were subjected to transcriptome analysis. Results: We observed no changes in the mRNA and protein levels of NLRP3 inflammasome components in the ovaries of db/db mice, as well as in markers of M1 and M2 macrophage infiltration. This contrasted with the downregulation of NLRP3 inflammasome components and M1 markers in ob/ob -/- and 16 wk HFD mice. Transcriptional analysis revealed opposing profiles between genetic models, with genes associated with steroid metabolism and prostaglandin action in db/db mice and genes controlling extracellular matrix in ob/ob mice being downregulated, despite both processes being crucial for follicular development and ovulation. Conclusions: Leptin signalling regulated NLRP3 inflammasome activation and expression of M1 markers in ovaries of obese mice, in an ObRb-dependent and -independent manner. Absence of changes in the expression of leptin signalling and proinflammatory mediators in GCs from db/db and ob/ob mice was associated with impaired folliculogenesis.
2024-04-10 | GSE236196 | GEO
Project description:Inflammasome, activated by pathogen-derived and host-derived danger signals, constitutes a multimolecular signaling complex that serves as a platform for caspase-1 (CASP1) activation and interleukin-1beta (IL1B) maturation. The activation of NLRP3 inflammasome requires two-step signals. The first “priming” signal (Signal 1) enhances gene expression of inflammasome components. The second “activation” signal (Signal 2) promotes the assembly of inflammasome components. Deregulated activation of NLRP3 inflammasome contributes to the pathological processes of Alzheimer’s disease (AD) and multiple sclerosis (MS). However, at present, the precise mechanism regulating NLRP3 inflammasome activation and deactivation remains largely unknown. By genome-wide gene expression profiling, we studied the molecular network of NLRP3 inflammasome activation-responsive genes in a human monocyte cell line THP-1 sequentially given two-step signals. We identified the set of 83 NLRP3 inflammasome activation-responsive genes. Among them, we found the NR4A nuclear receptor family NR4A1, NR4A2, and NR4A3, the EGR family EGR1, EGR2, and EGR3, the IkappaB family NFKBIZ, NFKBID, and NFKBIA as a key group of the genes that possibly constitute a negative feedback loop for shutting down inflammation following NLRP3 inflammasome activation. By molecular network analysis, we identified a complex network of NLRP3 inflammasome activation-responsive genes involved in cellular development and death, and immune and inflammatory responses, where transcription factors AP-1, NR4A, and EGR serve as a hub. Thus, NLRP3 inflammasome activation-responsive genes constitute the molecular network composed of a set of negative feedback regulators for prompt resolution of inflammation. To load the Signal 1 (S1), THP-1 cells were incubated for 3 hours in the culture medium with or without inclusion of 0.2 microgram/ml lipopolysaccharide (LPS). To load the Signal 2 (S2), they were incubated further for 2 hours in the culture medium with inclusion of 10 microM nigericin sodium salt dissolved in ethanol or the equal v/v% concentration of ethanol (vehicle), followed by processing for microarray analysis on Human Gene 1.0 ST Array (Affymetrix).
2014-07-01 | E-GEOD-58959 | biostudies-arrayexpress
Project description:Obesity leads to ovarian dysfunction and the establishment of local leptin resistance. The aim of our study was to characterise levels of Nod-Like Receptor Protein 3 (NLRP3) inflammasome activation during obesity progression in the mouse ovaries and liver and test the putative role of leptin on its regulation. C57BL/6J mice were treated with equine chorionic gonadotropin (eCG) or human chorionic gonadotropin (hCG) for oestrous cycle synchronisation and ovaries collection. In diet-induced obesity (DIO) model, mice were fed chow diet (CD) or high fat diet (HFD) for 4 or 16 weeks (wk), whereas in hyperleptinemic model (LEPT), mice were injected with leptin for 16 days (16L) or saline (16C) and in the genetic obese leptin-deficient ob/ob (+/? and -/-) animals were fed CD for 4wk. Either ovaries and liver were collected, as well as cumulus cells (CCs) after superovulation from DIO and LEPT. In DIO protocol, protein expression of NLRP3 inflammasome components was increased in 4wk HFD, but decreased in 16wk HFD. Moreover LEPT and ob/ob models revealed NLRP3 and IL-1 upregulation in 16L and downregulation in ob/ob. Transcriptome analysis of CC showed common genes between LEPT and 4wk HFD modulating NLRP3 inflammasome. Moreover analysis in the liver showed upregulation of NLRP3 protein only after 16wk HFD, but also the downregulation of NLRP3 protein in ob/ob-/-. We showed the link between leptin signalling and NLRP3 inflammasome activation in the ovary throughout obesity progression in mice, elucidating the molecular mechanisms underpinning ovarian failure in maternal obesity.
2021-11-01 | GSE180300 | GEO
Project description:The NLRP3 inflammasome is a multi-protein complex that triggers the activation of the inflammatory protein caspase-1 and the maturation of the cytokine IL-1 in response to microbes and other danger signals in host cells. Here, we sought a deeper understanding of how the NLRP3 inflammasome is regulated. We found that inflammasome activation induced the Src family kinase Lyn to phosphorylate NLRP3 at Tyr918, and that this phosphorylation of NLRP3 correlated with a subsequent increase in its ubiquitination, which facilitated its proteasome-mediated degradation. NLRP3 tyrosine phosphorylation and ubiquitination was abrogated in Lyn-deficient macrophages, which produced increased amounts of IL-1. Furthermore, mice lacking Lyn were highly susceptible to LPS-induced septic shock in an NLRP3-dependent manner. Our data demonstrate that Lyn-mediated tyrosine phosphorylation of NLRP3 is a prerequisite for its ubiquitination, thus dampening NLRP3 inflammasome activity.
2022-05-19 | PXD028582 | Pride
Project description:Aging is the major risk factor for cardiovascular and many other chronic diseases. During this natural process, many alterations occur in the organism which are associated with progressive impairment of several metabolic pathways related to body composition, insulin resistance, mitochondrial and autophagy dysfunction and inflammation. Recently, the role of NLRP3 inflammasome has been studied in cardiovascular diseases showing its implication in the pathological progression of atherosclerosis, heart failure, and hypertension. However, the role of the NLRP3 inflammasome in cardiac aging has been less well studied. Herein, we investigate the molecular mechanisms by which NLRP3 inhibition may attenuate cardiac aging. Ablation of NLRP3 inflammasome increased lifespan and protected mice from age-related increased insulin sensitivity, reduced IGF-1 and leptin/adiponectin ratio levels, and reduced cardiac damage with protection of the prolongation of age–dependent PR interval, which is associated with atrial fibrillation by cardiovascular aging. Furthermore, old NLRP3 KO mice showed an inhibition of PI3K/AKT/mTOR pathway and autophagy improvement compared with old wild type mice and preserved Nampt-mediated NAD+ levels with increased SIRT1 protein expression. These findings suggest that suppression of NLRP3 prevented many age-associated changes in the heart and preserved cardiac function of aged mice.
2019-10-01 | GSE124483 | GEO
Project description:This experiment was performed to analyze the contribution of NLRP3 inflammasome activation to age-related changes in hippocampal RNA. The hypothesis was that decreased inflammasome activation would reduce hippocampal inflammation. Results indicate that inflammasome knockout animals are protected from age-related changes in hippocampal gene expression Gene expression profiles of young (1 month) and old (21-23 month) wild type, CIAS -/- and ASC -/- mouse hippocampal tissue were compared. Total mRNA was extracted using Trizol.
2013-09-05 | E-GEOD-43034 | biostudies-arrayexpress
Project description:The NLRP3 inflammasome is dysregulated in autoinflammatory disorders caused by inherited mutations and contributes to the pathogenesis of several chronic inflammatory diseases. In this study, we discovered that disulfiram, a safe FDA-approved drug, specifically inhibits the NLRP3 inflammasome, but not the NLRC4 or AIM2 inflammasomes. Disulfiram suppresses caspase-1 activation, ASC speck formation, and pyroptosis induced by several stimuli that activate NLRP3. Mechanistically, NLRP3 is palmitoylated at cysteine 126, a modification required for its localization to the trans-Golgi network and inflammasome activation which was inhibited by disulfiram. Administration of disulfiram to animals inhibited the NLRP3, but not the NLRC4 inflammasome in vivo. Our study uncovers a mechanism by which disulfiram targets NLRP3 and provides a rationale for using a safe FDA-approved drug for the treatment of NLRP3-associated inflammatory diseases.
2024-07-25 | PXD054126 | Pride
Project description:The immune system may respond to engineered nanomaterials (ENM) through inflammatory reactions. The NLRP3 inflammasome responds to a wide range of ENM, and its activation is associated with various inflammatory diseases. The objective of the study was to compare the effects of gold ENM of different shapes on NLRP3 inflammasome activation and related signalling pathways. Differentiated THP-1 cells (wildtype, ASC- or NLRP3-deficient), were exposed to PEGylated gold nanorods, nanostars, and nanospheres. Exposed cells were subjected to gene expression analysis. Nanorods, but not nanostars or nanospheres, showed NLRP3 inflammasome activation. ASC- or NLRP3-deficient cells did not show this effect. Gold nanorod-induced NLRP3 inflammasome activation was accompanied by downregulated sterol/cholesterol biosynthesis, oxidative phosphorylation, and purinergic receptor signalling. In conclusion, the shape and surface chemistry of gold nanoparticles determine NLRP3 inflammasome activation.
2023-05-29 | GSE233641 | GEO
Project description:The NLRP3 inflammasome is linked to sterile and pathogen-dependent inflammation, and its dysregulation underlies many chronic diseases. Mitochondria have been implicated as regulators of NLRP3 inflammasome through multiple mechanisms including generation of mitochondrial ROS. Here we report that mitochondrial electron transport chain (ETC) complexes I, II, III and V inhibitors all prevent NLRP3 inflammasome activation. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI1) or Ciona intestinalis alternative oxidase (AOX), which can respectively complement the functional loss of mitochondrial complex I or III, without generation of ROS, rescued NLRP3 inflammasome activation in the absence of endogenous mitochondrial complex I or complex III function. Metabolomics revealed phosphocreatine (PCr), which can sustain ATP levels, as a common metabolite that is diminished by mitochondrial ETC inhibitors. PCr depletion decreased ATP levels and NLRP3 inflammasome activation. Thus, mitochondrial ETC sustains NLRP3 inflammasome activation through PCr-dependent generation of ATP but a ROS independent mechanism.
2022-03-09 | GSE197606 | GEO
Project description:Aberrant NLRP3 inflammasome activation is linked to many inflammatory diseases, driving the search for therapeutics inhibiting this pathway. NEK7 is proposed to mediate NLRP3 inflammasome assembly and activation by bridging adjacent NLRP3 subunits. Hence, reduction of NEK7 protein may block NLRP3 activation. We identified NK7-902, a potent and selective CRBN glue degrader of NEK7. NK7-902 degraded NEK7 in human immune cells and whole blood. However, full NEK7 degradation completely blocked NLRP3-dependent IL-1β release in vitro only in certain donors and experimental conditions. Unlike most CRBN glue degraders, NK7-902 effectively degraded NEK7 in murine cells and inhibited IL-1β release in mouse in vivo. By contrast, oral administration of NK7-902 in cynomolgus monkey caused long-lasting NEK7 degradation but only transiently blocked IL-1β in blood. These findings suggest NEK7 contributes to but is not absolutely required for NLRP3 activation in monkeys and humans.
2025-06-18 | PXD057229 | Pride