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The iRhom2/ADAM17 Axis Attenuates Bacterial Uptake by Phagocytes in a Cell Autonomous Manner

Uptake of bacteria by phagocytes is a crucial step in innate immune defence. Members of the disintegrin and metalloproteinase (ADAM) family critically control the immune response by limited proteolysis of surface expressed mediator molecules. Here, we investigated the significance of ADAM17 and its...

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Autores principales: Seifert, Anke, Wozniak, Justyna, Düsterhöft, Stefan, Kasparek, Petr, Sedlacek, Radislav, Dreschers, Stephan, Orlikowsky, Thorsten W., Yildiz, Daniela, Ludwig, Andreas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503280/
https://www.ncbi.nlm.nih.gov/pubmed/32825187
http://dx.doi.org/10.3390/ijms21175978
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author Seifert, Anke
Wozniak, Justyna
Düsterhöft, Stefan
Kasparek, Petr
Sedlacek, Radislav
Dreschers, Stephan
Orlikowsky, Thorsten W.
Yildiz, Daniela
Ludwig, Andreas
author_facet Seifert, Anke
Wozniak, Justyna
Düsterhöft, Stefan
Kasparek, Petr
Sedlacek, Radislav
Dreschers, Stephan
Orlikowsky, Thorsten W.
Yildiz, Daniela
Ludwig, Andreas
author_sort Seifert, Anke
collection PubMed
description Uptake of bacteria by phagocytes is a crucial step in innate immune defence. Members of the disintegrin and metalloproteinase (ADAM) family critically control the immune response by limited proteolysis of surface expressed mediator molecules. Here, we investigated the significance of ADAM17 and its regulatory adapter molecule iRhom2 for bacterial uptake by phagocytes. Inhibition of metalloproteinase activity led to increased phagocytosis of pHrodo labelled Gram-negative and -positive bacteria (E. coli and S. aureus, respectively) by human and murine monocytic cell lines or primary phagocytes. Bone marrow-derived macrophages showed enhanced uptake of heat-inactivated and living E. coli when they lacked either ADAM17 or iRhom2 but not upon ADAM10-deficiency. In monocytic THP-1 cells, corresponding short hairpin RNA (shRNA)-mediated knockdown confirmed that ADAM17, but not ADAM10, promoted phagocytosis of E. coli. The augmented bacterial uptake occurred in a cell autonomous manner and was accompanied by increased release of the chemokine CXCL8, less TNFα release and only minimal changes in the surface expression of the receptors TNFR1, TLR6 and CD36. Inhibition experiments indicated that the enhanced bacterial phagocytosis after ADAM17 knockdown was partially dependent on TNFα-activity but not on CXCL8. This novel role of ADAM17 in bacterial uptake needs to be considered in the development of ADAM17 inhibitors as therapeutics.
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spelling pubmed-75032802020-09-23 The iRhom2/ADAM17 Axis Attenuates Bacterial Uptake by Phagocytes in a Cell Autonomous Manner Seifert, Anke Wozniak, Justyna Düsterhöft, Stefan Kasparek, Petr Sedlacek, Radislav Dreschers, Stephan Orlikowsky, Thorsten W. Yildiz, Daniela Ludwig, Andreas Int J Mol Sci Article Uptake of bacteria by phagocytes is a crucial step in innate immune defence. Members of the disintegrin and metalloproteinase (ADAM) family critically control the immune response by limited proteolysis of surface expressed mediator molecules. Here, we investigated the significance of ADAM17 and its regulatory adapter molecule iRhom2 for bacterial uptake by phagocytes. Inhibition of metalloproteinase activity led to increased phagocytosis of pHrodo labelled Gram-negative and -positive bacteria (E. coli and S. aureus, respectively) by human and murine monocytic cell lines or primary phagocytes. Bone marrow-derived macrophages showed enhanced uptake of heat-inactivated and living E. coli when they lacked either ADAM17 or iRhom2 but not upon ADAM10-deficiency. In monocytic THP-1 cells, corresponding short hairpin RNA (shRNA)-mediated knockdown confirmed that ADAM17, but not ADAM10, promoted phagocytosis of E. coli. The augmented bacterial uptake occurred in a cell autonomous manner and was accompanied by increased release of the chemokine CXCL8, less TNFα release and only minimal changes in the surface expression of the receptors TNFR1, TLR6 and CD36. Inhibition experiments indicated that the enhanced bacterial phagocytosis after ADAM17 knockdown was partially dependent on TNFα-activity but not on CXCL8. This novel role of ADAM17 in bacterial uptake needs to be considered in the development of ADAM17 inhibitors as therapeutics. MDPI 2020-08-19 /pmc/articles/PMC7503280/ /pubmed/32825187 http://dx.doi.org/10.3390/ijms21175978 Text en © 2020 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Seifert, Anke
Wozniak, Justyna
Düsterhöft, Stefan
Kasparek, Petr
Sedlacek, Radislav
Dreschers, Stephan
Orlikowsky, Thorsten W.
Yildiz, Daniela
Ludwig, Andreas
The iRhom2/ADAM17 Axis Attenuates Bacterial Uptake by Phagocytes in a Cell Autonomous Manner
title The iRhom2/ADAM17 Axis Attenuates Bacterial Uptake by Phagocytes in a Cell Autonomous Manner
title_full The iRhom2/ADAM17 Axis Attenuates Bacterial Uptake by Phagocytes in a Cell Autonomous Manner
title_fullStr The iRhom2/ADAM17 Axis Attenuates Bacterial Uptake by Phagocytes in a Cell Autonomous Manner
title_full_unstemmed The iRhom2/ADAM17 Axis Attenuates Bacterial Uptake by Phagocytes in a Cell Autonomous Manner
title_short The iRhom2/ADAM17 Axis Attenuates Bacterial Uptake by Phagocytes in a Cell Autonomous Manner
title_sort irhom2/adam17 axis attenuates bacterial uptake by phagocytes in a cell autonomous manner
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503280/
https://www.ncbi.nlm.nih.gov/pubmed/32825187
http://dx.doi.org/10.3390/ijms21175978
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