The Role of NLRP3 in Shiga toxin Induced Inflammation

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2018-01-08
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Abstract
Enterohemorrhagic Escherichia coli (EHEC) is a pathogen that causes severe colitis. Shiga toxins (Stx) are a major virulence factor for EHEC and Stx-induced inflammation and cell death play a critical role in the development of EHEC-related disease. Therefore, the goal of this project was to examine the mechanisms by which Stx activates proinflammatory cytokine IL-1β and cell death in human macrophages. Stx induced ROS-dependent IL-1β secretion and pyroptosis in human THP-1 macrophages but not murine macrophages that lacked the Stx receptor CD77. Stx triggered the assembly of NLRP3, ASC and caspase-1 containing inflammasomes and genetic deletion of NLRP3 abolished Stx-induced IL-1β maturation and pyroptosis. Stx preferentially induced expression the endoplasmic reticulum stress receptor IRE1α. Pharmacological inhibition of IRE1α significantly reduced Stx-induced mitochondrial ROS production, IL-1β, and pyroptosis. These data suggest that Stx activate the IRE1α arm of the ER stress pathway upstream of mitochondrial ROS to trigger the NLRP3 inflammasome.
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Bondzi-Simpson, N. A. (2018). The Role of NLRP3 in Shiga toxin Induced Inflammation (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/5472