title: Effect of enterohaemorrhagic Escherichia coli O157:H7-specific enterohaemolysin on interleukin-1β production differs between human and mouse macrophages due to the different sensitivity of NLRP3 activation.
abstract: Enterohaemorrhagic Escherichia coli (EHEC) O157:H7 infection in humans can cause acute haemorrhagic colitis and severe haemolytic uraemic syndrome. The role of enterohaemolysin (Ehx) in the pathogenesis of O157:H7-mediated disease in humans remains undefined. Recent studies have revealed the importance of the inflammatory response in O157:H7 pathogenesis in humans. We previously reported that Ehx markedly induced interleukin-1β (IL-1β) production in human macrophages. Here, we investigated the disparity in Ehx-induced IL-1β production between human and mouse macrophages and explored the underlying mechanism regarding the activation of NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasomes. In contrast to the effects on human differentiated THP-1 cells and peripheral blood mononuclear cells, Ehx exerted no effect on IL-1β production in mouse macrophages and splenocytes because of a disparity in pro-IL-1β cleavage into mature IL-1β upon caspase-1 activation. Additionally, Ehx significantly contributed to O157:H7-induced ATP release from THP-1 cells, which was not detected in mouse macrophages. Confocal microscopy demonstrated that Ehx was a key inducer of cathepsin B release in THP-1 cells but not in mouse IC-21 cells upon O157:H7 challenge. Inhibitor experiments indicated that O157:H7-induced IL-1β production was largely dependent upon caspase-1 activation and partially dependent upon ATP signalling and cathepsin B release, which were both involved in NLRP3 activation. Moreover, inhibition of K(+) efflux drastically diminished O157:H7-induced IL-1β production and cytotoxicity. The findings in this study may shed light on whether and how the Ehx contributes to the development of haemolytic uraemic syndrome in human O157:H7 infection.
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Communicable Disease Control and Prevention, Chinese Centre for Disease Control and Prevention, Beijing, China; Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
authors.forename: Yu-Li
authors.initials: YL
authors.lastname: Cheng
authors.forename: Li-Qiong
authors.initials: LQ
authors.lastname: Song
authors.forename: Yuan-Ming
authors.initials: YM
authors.lastname: Huang
authors.forename: Yan-Wen
authors.initials: YW
authors.lastname: Xiong
authors.forename: Xiao-Ai
authors.initials: XA
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Sun
authors.forename: Xin-Ping
authors.initials: XP
authors.lastname: Zhu
authors.forename: Guang-Xun
authors.initials: GX
authors.lastname: Meng
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Xu
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Ren
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000276:immunology*; D020170:Caspase 1 / Q000276:immunology; D002401:Cathepsin B / Q000276:immunology; D045744:Cell Line, Tumor; D019453:Escherichia coli O157; D029968:Escherichia coli Proteins / Q000633:toxicity*; D006460:Hemolysin Proteins / Q000633:toxicity*; D006463:Hemolytic-Uremic Syndrome / Q000276:immunology* / Q000473:pathology; D006801:Humans; D058847:Inflammasomes / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D013045:Species Specificity
chemical_list: D002352:Carrier Proteins; D029968:Escherichia coli Proteins; D006460:Hemolysin Proteins; C508585:IL1B protein, human; C587672:IL1B protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; C066219:enterohemolysin; C533912:CTSB protein, human; D002401:Cathepsin B; C533915:Ctsb protein, mouse; D020170:Caspase 1
keywords: enterohaemolysin; enterohaemorrhagic Escherichia coli; human; inflammasomes; interleukin-1β; mouse