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Noncanonical Caspase 4/-5 Inflammasome Activation in Coronary Artery Endothelial Cells by Lipopolysaccharides Drives Extracellular Vesicle Secretion

ABSTRACT: Intestinal dysbiosis and impaired gut barrier function increase the blood bacterial lipopolysaccharide (LPS) load, referred to as endotoxemia. Endotoxemia has been implicated in cardiovascular diseases, but the underlying mechanisms are yet to be elucidated. We investigated whether intracellular LPS induces activation of the noncanonical caspase-4 and -5 inflammasome in human coronary artery endothelial cells (HCAECs) and whether this activation could mediate arterial wall inflammation. When introduced into the endothelial cell cytosol, LPS massively increased extracellular vesicle (EV)-mediated proteins secretion. The secreted proteins included biologically active kinases, transporters, transmembrane receptors, and regulators of protein synthesis. Bioinformatic analysis of the secretome data revealed increased bacterial invasion pathways, cell survival processes, and enrichment of ribosome and proteasome components upon intracellular LPS stimulation. Inhibition or depletion of the pore forming proteins Gasdermin D and MLKL reduced protein secretion. The EVs released from endothelial cells after intracellular LPS activation stimulated the expression of proinflammatory cytokines and interferon-response genes in human primary macrophages. Furthermore, intracellular LPS increased the expression of adhesion molecules and promoted monocyte attachment to HCAECs. Ultimately noncanonical inflammasome activation increased endothelial cell pyroptosis.

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ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Tuula Nyman

LAB HEAD: Tuula Nyman

PROVIDER: PXD062376 | Pride | 2026-01-14

REPOSITORIES: Pride

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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).

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Noncanonical Caspase 4/-5 Inflammasome Activation in Coronary Artery Endothelial Cells by Lipopolysaccharides Drives Extracellular Vesicle Secretion

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