Desmosterol suppresses inflammasome activation and protects against atherosclerosis
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PROVIDER: PRJNA723043 | ENA |
REPOSITORIES: ENA
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Project description:Desmosterol suppresses inflammasome activation and protects against atherosclerosis II
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Project description:Cholesterol biosynthetic intermediates such as lanosterol and desmosterol are emergent immune regulators of macrophages in response to inflammatory stimuli or lipid overloading, respectively. However, the participation of these sterols in regulating macrophage functions in the physiological context of atherosclerosis, an inflammatory disease driven by the accumulation of cholesterol-laden macrophages in the artery wall, has remained elusive. Here we report that desmosterol, the most abundant cholesterol biosynthetic intermediate in human coronary artery lesions, plays an essential role during atherogenesis, serving as a key molecule integrating cholesterol homeostasis and immune responses in macrophages. Depletion of desmosterol in myeloid cells by overexpression of 3β-hydroxysterol Δ24-reductase (DHCR24), the enzyme that catalyzes conversion of desmosterol to cholesterol, promotes the progression of atherosclerosis. Single cell transcriptomics in isolated CD45+CD11b+ cells from atherosclerotic plaques demonstrate that depletion of desmosterol increases interferon (IFN) responses and attenuates the expression of anti-inflammatory macrophage markers. Lipidomic and transcriptomic analysis of in vivo macrophage foam cells demonstrate that desmosterol is a major endogenous liver X receptor (LXR) ligand involved in LXR/RXR activation and thus, macrophage foam cell formation. Decreased desmosterol accumulation in mitochondria promotes macrophage mito-ROS production and NLRP3-dependent inflammasome activation. Deficiency of NLRP3 or ASC rescues the increased inflammasome activity and atherogenesis observed in desmosterol-depleted macrophages. Altogether, these findings underscore the critical function of desmosterol in the atherosclerotic plaque to dampen inflammation, by integrating with macrophage cholesterol metabolism and inflammatory activation, and protecting from disease progression.
2021-12-31 | GSE172374 | GEO
Project description:Cholesterol biosynthetic intermediates such as lanosterol and desmosterol are emergent immune regulators of macrophages in response to inflammatory stimuli or lipid overloading, respectively. However, the participation of these sterols in regulating macrophage functions in the physiological context of atherosclerosis, an inflammatory disease driven by the accumulation of cholesterol-laden macrophages in the artery wall, has remained elusive. Here we report that desmosterol, the most abundant cholesterol biosynthetic intermediate in human coronary artery lesions, plays an essential role during atherogenesis, serving as a key molecule integrating cholesterol homeostasis and immune responses in macrophages. Depletion of desmosterol in myeloid cells by overexpression of 3β-hydroxysterol Δ24-reductase (DHCR24), the enzyme that catalyzes conversion of desmosterol to cholesterol, promotes the progression of atherosclerosis. Single cell transcriptomics in isolated CD45+CD11b+ cells from atherosclerotic plaques demonstrate that depletion of desmosterol increases interferon (IFN) responses and attenuates the expression of anti-inflammatory macrophage markers. Lipidomic and transcriptomic analysis of in vivo macrophage foam cells demonstrate that desmosterol is a major endogenous liver X receptor (LXR) ligand involved in LXR/RXR activation and thus, macrophage foam cell formation. Decreased desmosterol accumulation in mitochondria promotes macrophage mito-ROS production and NLRP3-dependent inflammasome activation. Deficiency of NLRP3 or ASC rescues the increased inflammasome activity and atherogenesis observed in desmosterol-depleted macrophages. Altogether, these findings underscore the critical function of desmosterol in the atherosclerotic plaque to dampen inflammation, by integrating with macrophage cholesterol metabolism and inflammatory activation, and protecting from disease progression.
2021-12-01 | GSE175312 | GEO
Project description:Dynamic metabolism of endothelial triglycerides protects against atherosclerosis
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Project description:Dynamic metabolism of endothelial triglycerides protects against atherosclerosis
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Project description: Not available
| S-EPMC8617522 | biostudies-literature
Project description:Inflammation plays a crucial role in the progression of atherosclerosis. Junctional adhesion molecule-like protein (JAML), a type-I transmembrane glycoprotein, activates downstream signaling pathways. However, the precise role of macrophage-derived JAML in inflammation and atherosclerosis remains unclear. This study aimed to generate mice with macrophage-specific deletion or overexpression of JAML, with the focus of assessing its impact on macrophage function and elucidating its regulatory mechanism in atherosclerosis. High-throughput data screening was employed to investigate JAML expression in atherosclerosis, and macrophage-specific JAML-knockout and transgenic mice models were utilized to examine the effects of JAML on atherosclerosis. Furthermore, the role of JAML was assessed using Oil Red O staining, RNA-sequencing analysis, and co-immunoprecipitation techniques. Increased JAML expression was observed in macrophages from both mice and patients with atherosclerosis. Macrophage-specific JAML deletion attenuated atherosclerosis and inflammation, whereas macrophage-specific JAML overexpression exacerbated these conditions. Mechanistically, JAML deletion inhibited lipopolysaccharide (LPS) or ox-LDL-induced inflammation by decreasing nuclear translocation of pyruvate kinase M2 (PKM2) and PKM2/p65 complex formation, which consequently suppressed the nuclear factor kappa B (NF-κB) pathway and NLRP3 inflammasome activation. Taken together, these findings demonstrate that macrophage-expressed JAML facilitates the progression of atherosclerosis by activating the NF-κB pathway and NLRP3 inflammasome through nuclear migration and phosphorylation of PKM2. Notably, our study revealed a novel mechanism for the regulation of NLRP3 inflammasome activation in atherosclerosis. Therefore, targeting JAML may be an effective treatment strategy for atherosclerosis, a condition characterized by chronic inflammation.
2025-02-17 | GSE287332 | GEO
Project description:Vascular Smooth Muscle Cell-derived KIF13B Protects Against Atherosclerosis: Evidence from Humans and Mice
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Project description:Intestinal stem cells (ISCs) are essential for sustaining epithelial renewal and barrier integrity, yet their role in orchestrating defense against enteric pathogens remains unclear. Here, we identify a stem cell–intrinsic immune mechanism whereby Lgr5⁺ ISCs detect intracellular Salmonella enterica and activate an inflammasome-dependent differentiation program. Using fluorescent-labeled Salmonella enterica, single-cell transcriptomics, fate mapping, organoid models, and genetic perturbations, we show that invaded ISCs undergo rapid reprogramming toward antimicrobial peptide-enriched Paneth cells via ASC (Pycard)-mediated inflammasome signaling. This fate switch enhances epithelial antimicrobial capacity and restricts pathogen persistence in the crypt. The response is Salmonella-specific and conserved in human intestinal organoids. Moreover, the invasion-associated transcriptional signature is enriched in ISCs from Crohn’s disease patients. Our findings reveal that ISCs act as active sensors of bacterial invasion and initiate epithelial remodeling through inflammasome signaling, highlighting stem cell plasticity as a frontline innate immune strategy.
2026-04-05 | PXD075756 | Pride
Project description:Stress granule and inflammasome assembly determine contrasting fates of stressed cells. FAM69C is a brain-enriched kinase associated with neurodegenerative diseases, but its biological functions are still largely unknown. Here we show that FAM69C plays an important role in the regulation of stress responses through promoting stress granule assembly and suppressing inflammasome activation. In response to ATP, a common inflammasome activator, mouse primary microglia, and BV-2 cells form stress granules. FAM69C deficiency hastens inflammasome activation in mouse microglia, which is accompanied by inhibited stress granule assembly. FAM69C promotes the assembly of stress granules and halts protein translation under stress. Aged Fam69c knockout mice show increased neuroinflammation and ASC specks formation. We further find that FAM69C physically phosphorylates eIF2α and promotes stress granule assembly. Our data reveal that FAM69C promotes stress granule assembly under stress and suppresses inflammasome formation in microglia, suggesting that FAM69C may be a potential therapeutic target for neurodegenerative diseases.
2022-10-05 | GSE214646 | GEO