Hemolytic uremic syndrome (HUS) caused by intestinal Shiga toxin–producing infections is a worldwide healthproblem, as dramatically exemplified by the German outbreak occurred in summer 2011 and by a constant burden of cases inchildren. Shiga toxins (Stx) play a pivotal role in HUS by triggering endothelial damage in kidney and brain through globo-triaosylceramide (Gb3Cer) receptor targeting. Moreover, Stx interact with human neutrophils, as experimentally demonstratedin vitro and as observed in patients with HUS. A neutrophil-protective role on endothelial damage (sequestration of circulatingtoxins) and a causative role in toxin delivery from the gut to the kidney (piggyback transport) have been suggested in differentstudies. However, the receptor that recognizes Stx in human neutrophils, which do not express Gb3Cer, has not been identified. Inthis study, by competition and functional experiments with appropriate agonists and antagonists (LPS, anti-TLR4 Abs, respec-tively), we have identified TLR4 as the receptor that specifically recognizes Stx1 and Stx2 in human neutrophils. Accordingly,these treatments displaced both toxin variants from neutrophils and, upon challenge with Stx1 or Stx2, neutrophils displayed thesame pattern of cytokine expression as in response to LPS (assessed by quantitative RT-PCR, ELISA, or multiplexed Luminex-based immunoassays). Moreover, data were supported by adequate controls excluding any potential interference of contaminatingLPS in Stx-binding and activation of neutrophils. The identification of the Stx-receptor on neutrophils provides additionalelements to foster the understanding of the pathophysiology of HUS and could have an important effect on the development oftherapeutic strategies

Identification of TLR4 as the Receptor That Recognizes Shiga Toxins in Human Neutrophils.

TAMASSIA, Nicola;CASSATELLA, Marco Antonio
2013

Abstract

Hemolytic uremic syndrome (HUS) caused by intestinal Shiga toxin–producing infections is a worldwide healthproblem, as dramatically exemplified by the German outbreak occurred in summer 2011 and by a constant burden of cases inchildren. Shiga toxins (Stx) play a pivotal role in HUS by triggering endothelial damage in kidney and brain through globo-triaosylceramide (Gb3Cer) receptor targeting. Moreover, Stx interact with human neutrophils, as experimentally demonstratedin vitro and as observed in patients with HUS. A neutrophil-protective role on endothelial damage (sequestration of circulatingtoxins) and a causative role in toxin delivery from the gut to the kidney (piggyback transport) have been suggested in differentstudies. However, the receptor that recognizes Stx in human neutrophils, which do not express Gb3Cer, has not been identified. Inthis study, by competition and functional experiments with appropriate agonists and antagonists (LPS, anti-TLR4 Abs, respec-tively), we have identified TLR4 as the receptor that specifically recognizes Stx1 and Stx2 in human neutrophils. Accordingly,these treatments displaced both toxin variants from neutrophils and, upon challenge with Stx1 or Stx2, neutrophils displayed thesame pattern of cytokine expression as in response to LPS (assessed by quantitative RT-PCR, ELISA, or multiplexed Luminex-based immunoassays). Moreover, data were supported by adequate controls excluding any potential interference of contaminatingLPS in Stx-binding and activation of neutrophils. The identification of the Stx-receptor on neutrophils provides additionalelements to foster the understanding of the pathophysiology of HUS and could have an important effect on the development oftherapeutic strategies
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11562/627242
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