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Bruton’s tyrosine kinase inhibition attenuates disease progression by reducing renal immune cell invasion in mice with hemolytic-uremic syndrome

Hemolytic-uremic syndrome (HUS) can occur as a complication of an infection with Shiga-toxin (Stx)-producing Escherichia coli. Patients typically present with acute kidney injury, microangiopathic hemolytic anemia and thrombocytopenia. There is evidence that Stx-induced renal damage propagates a pro...

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Autores principales: Kröller, Sarah, Wissuwa, Bianka, Dennhardt, Sophie, Krieg, Nadine, Thiemermann, Christoph, Daniel, Christoph, Amann, Kerstin, Gunzer, Florian, Coldewey, Sina M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9995712/
https://www.ncbi.nlm.nih.gov/pubmed/36911665
http://dx.doi.org/10.3389/fimmu.2023.1105181
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author Kröller, Sarah
Wissuwa, Bianka
Dennhardt, Sophie
Krieg, Nadine
Thiemermann, Christoph
Daniel, Christoph
Amann, Kerstin
Gunzer, Florian
Coldewey, Sina M.
author_facet Kröller, Sarah
Wissuwa, Bianka
Dennhardt, Sophie
Krieg, Nadine
Thiemermann, Christoph
Daniel, Christoph
Amann, Kerstin
Gunzer, Florian
Coldewey, Sina M.
author_sort Kröller, Sarah
collection PubMed
description Hemolytic-uremic syndrome (HUS) can occur as a complication of an infection with Shiga-toxin (Stx)-producing Escherichia coli. Patients typically present with acute kidney injury, microangiopathic hemolytic anemia and thrombocytopenia. There is evidence that Stx-induced renal damage propagates a pro-inflammatory response. To date, therapy is limited to organ-supportive strategies. Bruton’s tyrosine kinase (BTK) plays a pivotal role in recruitment and function of immune cells and its inhibition was recently shown to improve renal function in experimental sepsis and lupus nephritis. We hypothesized that attenuating the evoked immune response by BTK-inhibitors (BTKi) ameliorates outcome in HUS. We investigated the effect of daily oral administration of the BTKi ibrutinib (30 mg/kg) and acalabrutinib (3 mg/kg) in mice with Stx-induced HUS at day 7. After BTKi administration, we observed attenuated disease progression in mice with HUS. These findings were associated with less BTK and downstream phospholipase-C-gamma-2 activation in the spleen and, subsequently, a reduced renal invasion of BTK-positive cells including neutrophils. Only ibrutinib treatment diminished renal invasion of macrophages, improved acute kidney injury and dysfunction (plasma levels of NGAL and urea) and reduced hemolysis (plasma levels of bilirubin and LDH activity). In conclusion, we report here for the first time that BTK inhibition attenuates the course of disease in murine HUS. We suggest that the observed reduction of renal immune cell invasion contributes – at least in part – to this effect. Further translational studies are needed to evaluate BTK as a potential target for HUS therapy to overcome currently limited treatment options.
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spelling pubmed-99957122023-03-10 Bruton’s tyrosine kinase inhibition attenuates disease progression by reducing renal immune cell invasion in mice with hemolytic-uremic syndrome Kröller, Sarah Wissuwa, Bianka Dennhardt, Sophie Krieg, Nadine Thiemermann, Christoph Daniel, Christoph Amann, Kerstin Gunzer, Florian Coldewey, Sina M. Front Immunol Immunology Hemolytic-uremic syndrome (HUS) can occur as a complication of an infection with Shiga-toxin (Stx)-producing Escherichia coli. Patients typically present with acute kidney injury, microangiopathic hemolytic anemia and thrombocytopenia. There is evidence that Stx-induced renal damage propagates a pro-inflammatory response. To date, therapy is limited to organ-supportive strategies. Bruton’s tyrosine kinase (BTK) plays a pivotal role in recruitment and function of immune cells and its inhibition was recently shown to improve renal function in experimental sepsis and lupus nephritis. We hypothesized that attenuating the evoked immune response by BTK-inhibitors (BTKi) ameliorates outcome in HUS. We investigated the effect of daily oral administration of the BTKi ibrutinib (30 mg/kg) and acalabrutinib (3 mg/kg) in mice with Stx-induced HUS at day 7. After BTKi administration, we observed attenuated disease progression in mice with HUS. These findings were associated with less BTK and downstream phospholipase-C-gamma-2 activation in the spleen and, subsequently, a reduced renal invasion of BTK-positive cells including neutrophils. Only ibrutinib treatment diminished renal invasion of macrophages, improved acute kidney injury and dysfunction (plasma levels of NGAL and urea) and reduced hemolysis (plasma levels of bilirubin and LDH activity). In conclusion, we report here for the first time that BTK inhibition attenuates the course of disease in murine HUS. We suggest that the observed reduction of renal immune cell invasion contributes – at least in part – to this effect. Further translational studies are needed to evaluate BTK as a potential target for HUS therapy to overcome currently limited treatment options. Frontiers Media S.A. 2023-02-23 /pmc/articles/PMC9995712/ /pubmed/36911665 http://dx.doi.org/10.3389/fimmu.2023.1105181 Text en Copyright © 2023 Kröller, Wissuwa, Dennhardt, Krieg, Thiemermann, Daniel, Amann, Gunzer and Coldewey https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Kröller, Sarah
Wissuwa, Bianka
Dennhardt, Sophie
Krieg, Nadine
Thiemermann, Christoph
Daniel, Christoph
Amann, Kerstin
Gunzer, Florian
Coldewey, Sina M.
Bruton’s tyrosine kinase inhibition attenuates disease progression by reducing renal immune cell invasion in mice with hemolytic-uremic syndrome
title Bruton’s tyrosine kinase inhibition attenuates disease progression by reducing renal immune cell invasion in mice with hemolytic-uremic syndrome
title_full Bruton’s tyrosine kinase inhibition attenuates disease progression by reducing renal immune cell invasion in mice with hemolytic-uremic syndrome
title_fullStr Bruton’s tyrosine kinase inhibition attenuates disease progression by reducing renal immune cell invasion in mice with hemolytic-uremic syndrome
title_full_unstemmed Bruton’s tyrosine kinase inhibition attenuates disease progression by reducing renal immune cell invasion in mice with hemolytic-uremic syndrome
title_short Bruton’s tyrosine kinase inhibition attenuates disease progression by reducing renal immune cell invasion in mice with hemolytic-uremic syndrome
title_sort bruton’s tyrosine kinase inhibition attenuates disease progression by reducing renal immune cell invasion in mice with hemolytic-uremic syndrome
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9995712/
https://www.ncbi.nlm.nih.gov/pubmed/36911665
http://dx.doi.org/10.3389/fimmu.2023.1105181
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