Anti-inflammatory properties of low dose epirubicin on human macrophages
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE136758 | GEO | 2020/01/17
REPOSITORIES: GEO
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Project description:Anti-inflammatory properties of low dose epirubicin on human macrophages
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Project description:The repair of injured enthesis remains a challenging clinical issue in sports medicine due to dysregulated inflammation and limited regenerative capability. Nevertheless, the mechanisms through which this dysregulated inflammation deteriorates the regenerative niche of enthesis remain unclear. Here, we found that Nlrp3 inflammasomes were activated in macrophages after enthesis injury and subsequently suppressed the regeneration. Nlrp3 inflammasomes generated a proinflammatory niche through an imbalance between the pro-inflammatory factor IL-1β and anti-inflammatory factors including IL-10 and IL-13. Mechanistically, IL-1β was identified as an inhibitory inflammation signaling in proinflammatory niche, reducing the differentiation and migration of stem cells. Moreover, the P2rx7 receptors were verified as an activation signal for Nlrp3 inflammasome post-injury, and conditional knockout of P2rx7 receptors on myeloid cells promoted enthesis regeneration. Together, these results illustrate that Nlrp3 inflammasome generates a proinflammatory niche to suppress enthesis regeneration, and demonstrate that the P2rx7/Nlrp3 inflammasome axis and IL-1β are promising niche-directed regenerative therapeutic targets for enthesis injury treatment.
2024-07-01 | GSE256128 | GEO
Project description:NLRP3 inflammasome assembles in response to stress or danger signals and leads to unconventional secretion of proinflammatory IL-1. FADD is an NLRP3 inflammasome component. Here we found that classical NLRP3 inflammasome activation in human monocytes/macrophages induced FADD secretion, which required potassium efflux, functional NLRP3 sensor, ASC adaptor and caspase-1 scaffold molecule. FADD is a leaderless protein unconventionally secreted through plasma membrane-derived microvesicles. Blood-derived monocytes from rheumatoid arthritis (RA) patients secreted more FADD following NLRP3 inflammasome activation than those from healthy donors, and we found increased levels of FADD in the sera (ESPOIR cohort) and synovial fluids from RA patients. Levels of synovial FADD correlated with the inflammatory status of the joint. These data reveal that FADD secretion occurs during inflammatory disease in vivo.
2019-02-28 | PXD008168 | Pride
Project description:The innate immune system recognizes nucleic acids as a signature of microbial infection and initiates host-protective responses, including the production of type I IFN and proinflammatory cytokines. Z-DNA binding protein 1 (ZBP1, also known as DLM-1 or DAI) was previously identified as a dsDNA binding protein, triggering DNA-mediated activation of innate immune responses. However, mice or cells lacking ZBP1 produce normal levels of type I IFN in response to dsDNA. Therefore, the classification of ZBP1 as a true DNA sensor remains to be resolved. Here, we report that the single stranded RNA virus, influenza A virus (IAV) is a trigger of the cytosolic sensor ZBP1. Sensing of IAV infection by ZBP1 engages a novel NLRP3 inflammasome pathway that is not defined by the conventions of the canonical and non-canonical NLRP3 inflammasome pathways. Surprisingly, IAV-induced cell death was not prevented by the absence of the NLRP3 inflammasome. Instead, we identified parallel contributions from pyroptosis, necroptosis and apoptosis in the execution of ZBP1-dependent cell death, mediated by the kinase RIPK3. Overall, the ability of ZBP1 to sense IAV infection signifies a point of divergence for IAV-induced programmed cell death pathways and inflammasome activation. We used microarrays to explore the gene expression profiles differentially expressed in influenza-infected bone marrow derived macrophages (BMDM) isolated from Ifnar1-/- and wild-type mice.
2016-08-11 | E-GEOD-77611 | biostudies-arrayexpress
Project description:Inflammasomes are multi-protein complexes that control the production of pro-inflammatory cytokines such as IL-1beta. Inflammasomes play an important role in the control of immunity to tumors and infections, and also in autoimmune diseases, but the mechanisms controlling the activation of human inflammasomes are largely unknown. We found that human activated CD4+CD45RO+ memory T-cells specifically suppress P2X7R-mediated NLRP3 inflammasome activation, without affecting P2X7R-independent NLRP3 or NLRP1 inflammasome activation. The concomitant increase in pro-IL-1β production induced by activated memory T-cells concealed this effect. Priming with IFNβ decreased pro-IL-1β production in addition to NLRP3 inflammasome inhibition and thus unmasked the inhibitory effect on NLRP3 inflammasome activation. IFNβ did not suppress NLRP3 inflammasome activation by acting directly on monocytes. The inhibition of pro-IL-1β production and suppression of NLRP3 inflammasome activation by IFNβ-primed human CD4+CD45RO+ memory T-cells is partly mediated by soluble FasL and is associated with down-regulated P2X7R mRNA expression and reduced response to ATP in monocytes. CD4+CD45RO+ memory T-cells from multiple sclerosis (MS) patients showed a reduced ability to suppress NLRP3 inflammasome activation, however their suppressive ability was recovered following in vivo treatment with IFNβ. Thus, our data demonstrate that human P2X7R-mediated NLRP3 inflammasome activation is regulated by activated CD4+CD45RO+ memory T cells, and provide new information on the mechanisms mediating the therapeutic effects of IFNβ in MS. Memory T-cells were cultured in the presence of monocytes with and without Interferon-beta, resorted and expression profile was determined
2012-12-01 | E-GEOD-35601 | biostudies-arrayexpress
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:Macrophage-inducible C-type lectin (Mincle) dependent sensing of pathogens trig-gers proinflammatory immune responses in professional phagocytes that contribute to protect the host against pathogen invasion. Here, we examined whether overex-pression of Mincle designed to improve early pathogen sensing by professional phagocytes would improve lung protective immunity against Streptococcus pneu-moniae in mice. Proteomic profiling of alveolar macrophages (AM) of Mincle trans-genic (tg) mice stimulated with the Mincle-specific pneumococcal ligand glucosyl-diacylglycerol (Glc-DAG) revealed increased Nlrp3 inflammasome activation and downstream IL-1 cytokine release that was not observed in Glc-DAG stimulated Mincle KO or Nlrp3 KO macrophages. Along this line, Mincle tg mice also responded with a stronger Nlrp3 expression and early proinflammatory cytokine release after challenge with S. pneumoniae, ultimately leading to fatal pneumonia in the Mincle tg mice. Importantly, Nlrp3 inhibitor treatment of Mincle tg mice significantly mitigated the observed hyperinflammatory response to pneumococcal challenge. Together, we show that overexpression of the pattern recognition receptor Mincle triggers in-creased Glc-DAG dependent Nlrp3 inflammasome activation in professional phago-cytes leading to fatal pneumococcal pneumonia in mice, which is amenable to Nlrp3 inhibitor treatment. These data show that ectopic expression of Mincle receptor con-fers increased susceptibility rather than resistance to S. pneumoniae in mice, thus highlighting the importance of an inducible Mincle receptor expression in response to microbial challenge.
2020-10-05 | PXD018752 | Pride
Project description:The cellular stress response plays a vital role in regulating homeostasis by modulating cell survival and death. Stress granules (referred to as SGs) are cytoplasmic compartments that allow cells to survive various stressors. Defects in SG assembly and disassembly have been found to play important roles in neurodegenerative diseases, antiviral responses and cancer1–5. Inflammasomes are multi-protein heteromeric complexes that sense intracellular pathogen- and damage-associated molecular patterns and assemble into cytosolic compartments called ASC specks to facilitate caspase-1 (CASP1) activation. This activation of inflammasomes induces secretion of the leaderless proinflammatory cytokines IL-1β and IL-18 and also drives cell fate towards pyroptosis, a form of programmed inflammatory cell death that plays major role in health and disease6–12. Cellular stress sensing can trigger both SGs and inflammasomes; however, they drive contrasting cell fate decisions during stress conditions. Crosstalk between SGs and inflammasomes to decide cell fate has not been well studied. Here we show that the induction of SGs specifically inhibits NLRP3 inflammasome activation, ASC speck formation and pyroptosis. The SG protein DDX3X interacts with NLRP3 to drive inflammasome activation in the absence of SGs. Assembly of SGs leads to the sequestration of DDX3X to inhibit NLRP3 inflammasome function. SGs and the NLRP3 inflammasome compete for DDX3X molecules to coordinate the activation of innate responses and subsequent cell fate decisions under stress conditions. Induction of SGs or loss of DDX3X in the myeloid compartment leads to decreased production of inflammasome-dependent cytokines in vivo. Our findings suggest that macrophages utilize DDX3X availability to interpret stress signals and choose between pro-survival SGs and pyroptotic ASC specks. Together, our data show the role of DDX3X in driving NLRP3 inflammasome and SG assembly, informing a new rheostat-like mechanistic paradigm for regulating live or die cell fate decisions under stress conditions.
2019-10-03 | PXD014828 | Pride
Project description:Streptococcus (S.) pneumoniae is the most frequently isolated causative pathogen community-acquired pneumonia, a leading cause of mortality worldwide. We investigated the role of the inflammasome sensor NLRP3 and the inflammasome adapter ASC during S. pneumoniae pneumonia. Detailed analysis of the early inflammatory response in the lung by whole genome transcriptional profiling, we identified several mediators that were differentially expressed between Nlrp3-/- and Asc-/ - mice. WT, Nlrp3- and Asc-deficient mice were intranasally inocculated with Streptococcus pneumoniae D39 and ATCC6303 both at high and low dose. Lung homogenates were harvested and gene expression profiling was performed.
2014-11-27 | E-GEOD-42464 | biostudies-arrayexpress
Project description:The activation of the NLRP3 inflammasome is spatiotemporally orchestrated by various organelles, but the precise roles of lysosomes are still unclear. Here we show the vital role of the Ragulator complex, a lysosomal protein, in NLRP3 inflammasome activation. Deficiency of Lamtor1, an essential component of the Ragulator complex, abrogated NLRP3 inflammasome activation in murine macrophage and human monocytic cells. Myeloid-specific Lamtor1-deficient mice showed remarkable attenuation of the severity of NLRP3-associated inflammatory diseases, including LPS-induced sepsis, alum-induced peritonitis, and monosodium urate (MSU)-induced arthritis. Mechanistically, Lamtor1 interacted with histone deacetylase 6 (HDAC6) during NLRP3 inflammasome activation, and this interaction augmented the interaction between the Ragulator complex and NLRP3. Lack of HDAC6 attenuated the interaction between Lamtor1 and NLRP3, resulting in insufficient NLRP3 inflammasome activation. Furthermore, DL-all-rac-α-tocopherol inhibited Lamtor1–HDAC6 interaction, resulting in diminished NLRP3 inflammasome activation. DL-all-rac-α-tocopherol alleviated acute gouty arthritis and MSU-induced peritonitis. Our results provide insight into the role of lysosomes in providing a platform for the activation of NLRP3 inflammasomes by the Ragulator complex.
2022-11-29 | PXD033497 | Pride