Abstract
The present study aimed at exploring the mechanisms by which NOD‐like receptor protein 3 (Nlrp3) inflammasomes are activated to result in endothelial dysfunction and coronary arteritis induced by Lactobacillus casei (L. casei) cell wall fragments (LCWE). Endothelial dysfunction and vascular lesion were observed during coronary arteritis in mice treated with LCWE, as shown by media thickening, increases in vascular cell adhesion protein 1 (VCAM‐1) expression, and enhanced adhesion of inflammatory cells to the endothelium including macrophages, neutrophils and T cells. Accompanied with these changes, the inflammasome activation was also shown in the coronary arterial endothelium of these mice, which was characterized by a marked increase in caspase‐1 activity and interleukin‐1β (IL‐1β) production. In isolated cultured endothelial cells (ECs), 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, dexamethasome, and C2‐ceramide. However, blockade of two activating pathways of Nlrp3 inflammasomes by glibenclamide, a potassium channel blocker or N‐Acetyl‐L‐cysteine (NAC), an oxygen free radical scavenger or antioxidant had no effects on LCWE‐induced inflammsome activation. It was also found that LCWE increased EC lysosomal membrane permeability and triggered a release of lysosomal cathepsin B into the cytosol and that silencing of cathepsin B blocked LCWE‐induced Nlrp3 inflammasome formation and activation in ECs. It is concluded that LCWE activate endothelial Nlrp3 inflammasomes through enhanced lysosomal membrane permeabilization and consequent release of lysosomal cathepsin B in ECs. This activation of endothelial Nlrp3 inflammasomes during LCWE stimulation contributes to the development of coronary arteritis.Grant Funding Source: Supported by NIH grants HL057244, HL091464 and HL075316
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