title: Endothelial Nlrp3 inflammasome activation associated with lysosomal destabilization during coronary arteritis.
abstract: Inflammasomes play a critical role in the development of vascular diseases. However, the molecular mechanisms activating the inflammasome in endothelial cells and the relevance of this inflammasome activation is far from clear. Here, we investigated the mechanisms by which an Nlrp3 inflammasome is activated to result in endothelial dysfunction during coronary arteritis by Lactobacillus casei (L. casei) cell wall fragments (LCWE) in a mouse model for Kawasaki disease. Endothelial dysfunction associated with increased vascular cell adhesion protein 1 (VCAM-1) expression and endothelial-leukocyte adhesion was observed during coronary arteritis in mice treated with LCWE. Accompanied with these changes, the inflammasome activation was also shown in coronary arterial endothelium, which was characterized by a marked increase in caspase-1 activity and IL-1β production. In cultured endothelial cells, LCWE induced Nlrp3 inflammasome formation, caspase-1 activation and IL-1β production, which were blocked by Nlrp3 gene silencing or lysosome membrane stabilizing agents such as colchicine, dexamethasone, and ceramide. However, a potassium channel blocker glibenclamide or an oxygen free radical scavenger N-acetyl-l-cysteine had no effects on LCWE-induced inflammasome activation. LCWE also increased endothelial cell lysosomal membrane permeability and triggered lysosomal cathepsin B release into cytosol. Silencing cathepsin B blocked LCWE-induced Nlrp3 inflammasome formation and activation in endothelial cells. In vivo, treatment of mice with cathepsin B inhibitor also abolished LCWE-induced inflammasome activation in coronary arterial endothelium. It is concluded that LCWE enhanced lysosomal membrane permeabilization and consequent release of lysosomal cathepsin B, resulting in activation of the endothelial Nlrp3 inflammasome, which may contribute to the development of coronary arteritis.
authors.affiliation: Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Krishna M
authors.initials: KM
authors.lastname: Boini
authors.affiliation: Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Ashley L
authors.initials: AL
authors.lastname: Pitzer
authors.affiliation: Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
authors.affiliation: Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA. Electronic address: yzhang3@vcu.edu.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA. Electronic address: pli@vcu.edu.
authors.forename: Pin-Lan
authors.initials: PL
authors.lastname: Li
mesh_terms: D000818:Animals; D001167:Arteritis / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism*; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism; D002473:Cell Wall / Q000737:chemistry; D003331:Coronary Vessels / Q000378:metabolism* / Q000473:pathology*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016166:Free Radical Scavengers / Q000378:metabolism; D020868:Gene Silencing / Q000187:drug effects; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology; D007780:Lacticaseibacillus casei; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D026902:Potassium Channel Blockers / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D016166:Free Radical Scavengers; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D026902:Potassium Channel Blockers; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; D002401:Cathepsin B
keywords: Cathepsin B; Endothelium; LCWE; Lysosomal membrane permeabilization; Nlrp3 inflammasome