Shiga Toxin/Lipopolysaccharide Activates Caspase-4 and Gasdermin D to Trigger Mitochondrial Reactive Oxygen Species Upstream of the NLRP3 Inflammasome

• DOI: 10.1016/j.celrep.2018.09.071
• Publication Date: 2018-11-06T11:53:49Z
• Authors: Jaye M. Platnich; Hyunjae Chung; Arthur Lau; Christina F. Sandall; Adom Bondzi-Simpson; Huey-Miin Chen; Takanori Komada; Aaron C. Trotman-...; Jeremy R. Brandelli; Justin Chun; Paul L. Beck; Dana J. Philpott; Stephen E. Girardin; May Ho; Roger P. Johnson; Justin A. MacDonald; Glen D. Armstrong; Daniel A. Muruve
• Keywords: Mitochondrial ROS

The non-canonical caspase-4 and canonical NLRP3 inflammasomes are both activated by intracellular lipopolysaccharide (LPS), but the crosstalk between these two pathways remains unclear. Shiga toxin 2 (Stx2)/LPS complex, from pathogenic enterohemorrhagic Escherichia coli, activates caspase-4, gasdermin D (GSDMD), inflammasome in human THP-1 macrophages, not mouse macrophages that lack Stx receptor CD77. Stx2/LPS-mediated IL-1β secretion pyroptosis dependent on mitochondrial reactive oxygen species (ROS) downstream of cleaved GSDMD, which is enriched at mitochondria. Blockade activation ROS generation as well GSDMD deficiency significantly reduces Stx2/LPS-induced production pyroptosis. plays a significant role amplifying cleavage pyroptosis, with reduction responses NLRP3-deficient cells. Together, data show Stx2/LPS complex upstream to promote cytokine maturation