Shiga Toxins Activate the NLRP3 Inflammasome Pathway To Promote Both Production of the Proinflammatory Cytokine Interleukin-1 and Apoptotic Cell Death. Academic Article uri icon

abstract

  • Shiga toxin (Stx)-mediated immune responses, including the production of the proinflammatory cytokines tumor necrosis- (TNF-) and interleukin-1 (IL-1), may exacerbate vascular damage and accelerate lethality. However, the immune signaling pathway activated in response to Stx is not well understood. Here, we demonstrate that enzymatically active Stx, which leads to ribotoxic stress, triggers NLRP3 inflammasome-dependent caspase-1 activation and IL-1 secretion in differentiated macrophage-like THP-1 (D-THP-1) cells. The treatment of cells with a chemical inhibitor of glycosphingolipid biosynthesis, which suppresses the expression of the Stx receptor globotriaosylceramide and subsequent endocytosis of the toxin, substantially blocked activation of the NLRP3 inflammasome and processing of caspase-1 and IL-1. Processing and release of both caspase-1 and IL-1 were significantly reduced or abolished in Stx-intoxicated D-THP-1 cells in which the expression of NLRP3 or ASC was stably knocked down. Furthermore, Stx mediated the activation of caspases involved in apoptosis in an NLRP3- or ASC-dependent manner. In Stx-intoxicated cells, the NLRP3 inflammasome triggered the activation of caspase-8/3, leading to the initiation of apoptosis, in addition to caspase-1-dependent pyroptotic cell death. Taken together, these results suggest that Stxs trigger the NLRP3 inflammasome pathway to release proinflammatory IL-1 as well as to promote apoptotic cell death.

published proceedings

  • Infect Immun

altmetric score

  • 3.85

author list (cited authors)

  • Lee, M., Kwon, H., Lee, E., Kim, D., Park, J., Tesh, V. L., Oh, T., & Kim, M. H.

citation count

  • 45

complete list of authors

  • Lee, Moo-Seung||Kwon, Haenaem||Lee, Eun-Young||Kim, Dong-Jae||Park, Jong-Hwan||Tesh, Vernon L||Oh, Tae-Kwang||Kim, Myung Hee

editor list (cited editors)

  • McCormick, B. A.

publication date

  • January 2016