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© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Shiga toxin (Stx)-producing Escherichia coli (STEC) infection is the most common cause of hemolytic uremic syndrome (HUS), one of the main causes of acute kidney injury in children. Stx plays an important role in endothelium damage and pathogenesis of STEC-HUS. However, the effects of Stx on neutrophils and neutrophil extracellular trap (NET) formation are not well understood. In this study, we investigated how Stx2a affects NET formation and NETotic pathways (NADPH or NOX-dependent and -independent) using neutrophils isolated from healthy donors and patients with STEC-HUS, during the acute and recovery phase of the disease. Stx2a dose-dependently induced NETosis in neutrophils isolated from both healthy controls and STEC-HUS patients. NETosis kinetics and mechanistic data with pathway-specific inhibitors including diphenyleneiodonium (DPI)-, ERK-, and P38-inhibitors showed that Stx2a-induced NETosis via the NOX-dependent pathway. Neutrophils from STEC-HUS patients in the acute phase showed less ROS and NETs formation compared to neutrophils of the recovery phase of the disease and in healthy controls. NETs induced by Stx2a may lead to the activation of endothelial cells, which might contribute to the manifestation of thrombotic microangiopathy in STEC-HUS.

Details

Title
Shiga Toxin 2a Induces NETosis via NOX-Dependent Pathway
Author
Feitz, Wouter J C 1 ; Suntharalingham, Samuel 2 ; Khan, Meraj 3 ; Ortiz-Sandoval, Carolina G 4 ; Palaniyar, Nades 5   VIAFID ORCID Logo  ; Lambert P van den Heuvel 6 ; Nicole C A J van de Kar 7   VIAFID ORCID Logo  ; Licht, Christoph 8   VIAFID ORCID Logo 

 Department of Pediatric Nephrology, Amalia Children’s Hospital, Radboud Institute for Molecular Life Sciences, Radboudumc, 6525 GA Nijmegen, The Netherlands; [email protected] (W.J.C.F.); [email protected] (L.P.v.d.H.); [email protected] (N.C.A.J.v.d.K.); Cell Biology Program, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada; [email protected] (S.S.); [email protected] (C.G.O.-S.) 
 Cell Biology Program, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada; [email protected] (S.S.); [email protected] (C.G.O.-S.); Program in Translational Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada; [email protected] (M.K.); [email protected] (N.P.) 
 Program in Translational Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada; [email protected] (M.K.); [email protected] (N.P.) 
 Cell Biology Program, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada; [email protected] (S.S.); [email protected] (C.G.O.-S.) 
 Program in Translational Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada; [email protected] (M.K.); [email protected] (N.P.); Department of Laboratory Medicine and Pathobiology, Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada 
 Department of Pediatric Nephrology, Amalia Children’s Hospital, Radboud Institute for Molecular Life Sciences, Radboudumc, 6525 GA Nijmegen, The Netherlands; [email protected] (W.J.C.F.); [email protected] (L.P.v.d.H.); [email protected] (N.C.A.J.v.d.K.); Department of Pediatric Nephrology, Academic Hospitals Leuven, 3000 Leuven, Belgium; Department of Development and Regeneration, Academic Hospitals Leuven, 3000 Leuven, Belgium 
 Department of Pediatric Nephrology, Amalia Children’s Hospital, Radboud Institute for Molecular Life Sciences, Radboudumc, 6525 GA Nijmegen, The Netherlands; [email protected] (W.J.C.F.); [email protected] (L.P.v.d.H.); [email protected] (N.C.A.J.v.d.K.) 
 Cell Biology Program, The Hospital for Sick Children Research Institute, Toronto, ON M5G 1X8, Canada; [email protected] (S.S.); [email protected] (C.G.O.-S.); Department of Laboratory Medicine and Pathobiology, Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada; Division of Nephrology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5S 1A8, Canada 
First page
1807
Publication year
2021
Publication date
2021
Publisher
MDPI AG
e-ISSN
22279059
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2612752438
Copyright
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.