Cargando…

A Putative Serine Protease is Required to Initiate the RIPK3-MLKL—Mediated Necroptotic Death Pathway in Neutrophils

Adhesion receptors, such as CD44, have been shown to activate receptor interacting protein kinase-3 (RIPK3)—mixed lineage kinase-like (MLKL) signaling, leading to a non-apoptotic cell death in human granulocyte/macrophage colony-stimulating factor (GM-CSF) – primed neutrophils. The signaling events...

Descripción completa

Detalles Bibliográficos
Autores principales: Wang, Xiaoliang, Avsec, Damjan, Obreza, Aleš, Yousefi, Shida, Mlinarič-Raščan, Irena, Simon, Hans-Uwe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860068/
https://www.ncbi.nlm.nih.gov/pubmed/33551816
http://dx.doi.org/10.3389/fphar.2020.614928
_version_ 1783646865976197120
author Wang, Xiaoliang
Avsec, Damjan
Obreza, Aleš
Yousefi, Shida
Mlinarič-Raščan, Irena
Simon, Hans-Uwe
author_facet Wang, Xiaoliang
Avsec, Damjan
Obreza, Aleš
Yousefi, Shida
Mlinarič-Raščan, Irena
Simon, Hans-Uwe
author_sort Wang, Xiaoliang
collection PubMed
description Adhesion receptors, such as CD44, have been shown to activate receptor interacting protein kinase-3 (RIPK3)—mixed lineage kinase-like (MLKL) signaling, leading to a non-apoptotic cell death in human granulocyte/macrophage colony-stimulating factor (GM-CSF) – primed neutrophils. The signaling events of this necroptotic pathway, however, remain to be investigated. In the present study, we report the design, synthesis, and characterization of a series of novel serine protease inhibitors. Two of these inhibitors, compounds 1 and 3, were able to block CD44-triggered necroptosis in GM-CSF-primed neutrophils. Both inhibitors prevented the activation of MLKL, p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3’—kinase (PI3K), hence blocking the increased levels of reactive oxygen species (ROS) required for cell death. Although compounds one and three partially inhibited isolated human neutrophil elastase (HNE) activity, we obtained no pharmacological evidence that HNE is involved in the initiation of this death pathway within a cellular context. Interestingly, neither serine protease inhibitor had any effect on FAS receptor-mediated apoptosis. Taken together, these results suggest that a serine protease is involved in non-apoptotic CD44-triggered RIPK3-MLKL-dependent neutrophil cell death, but not FAS receptor-mediated caspase-dependent apoptosis. Thus, a pharmacological block on serine proteases might be beneficial for preventing exacerbation of disease in neutrophilic inflammatory responses.
format Online
Article
Text
id pubmed-7860068
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-78600682021-02-05 A Putative Serine Protease is Required to Initiate the RIPK3-MLKL—Mediated Necroptotic Death Pathway in Neutrophils Wang, Xiaoliang Avsec, Damjan Obreza, Aleš Yousefi, Shida Mlinarič-Raščan, Irena Simon, Hans-Uwe Front Pharmacol Pharmacology Adhesion receptors, such as CD44, have been shown to activate receptor interacting protein kinase-3 (RIPK3)—mixed lineage kinase-like (MLKL) signaling, leading to a non-apoptotic cell death in human granulocyte/macrophage colony-stimulating factor (GM-CSF) – primed neutrophils. The signaling events of this necroptotic pathway, however, remain to be investigated. In the present study, we report the design, synthesis, and characterization of a series of novel serine protease inhibitors. Two of these inhibitors, compounds 1 and 3, were able to block CD44-triggered necroptosis in GM-CSF-primed neutrophils. Both inhibitors prevented the activation of MLKL, p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3’—kinase (PI3K), hence blocking the increased levels of reactive oxygen species (ROS) required for cell death. Although compounds one and three partially inhibited isolated human neutrophil elastase (HNE) activity, we obtained no pharmacological evidence that HNE is involved in the initiation of this death pathway within a cellular context. Interestingly, neither serine protease inhibitor had any effect on FAS receptor-mediated apoptosis. Taken together, these results suggest that a serine protease is involved in non-apoptotic CD44-triggered RIPK3-MLKL-dependent neutrophil cell death, but not FAS receptor-mediated caspase-dependent apoptosis. Thus, a pharmacological block on serine proteases might be beneficial for preventing exacerbation of disease in neutrophilic inflammatory responses. Frontiers Media S.A. 2021-01-21 /pmc/articles/PMC7860068/ /pubmed/33551816 http://dx.doi.org/10.3389/fphar.2020.614928 Text en Copyright © 2021 Simon, Wang, Avsec, Obreza, Yousefi and Mlinaric-Rascan. http://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 Pharmacology
Wang, Xiaoliang
Avsec, Damjan
Obreza, Aleš
Yousefi, Shida
Mlinarič-Raščan, Irena
Simon, Hans-Uwe
A Putative Serine Protease is Required to Initiate the RIPK3-MLKL—Mediated Necroptotic Death Pathway in Neutrophils
title A Putative Serine Protease is Required to Initiate the RIPK3-MLKL—Mediated Necroptotic Death Pathway in Neutrophils
title_full A Putative Serine Protease is Required to Initiate the RIPK3-MLKL—Mediated Necroptotic Death Pathway in Neutrophils
title_fullStr A Putative Serine Protease is Required to Initiate the RIPK3-MLKL—Mediated Necroptotic Death Pathway in Neutrophils
title_full_unstemmed A Putative Serine Protease is Required to Initiate the RIPK3-MLKL—Mediated Necroptotic Death Pathway in Neutrophils
title_short A Putative Serine Protease is Required to Initiate the RIPK3-MLKL—Mediated Necroptotic Death Pathway in Neutrophils
title_sort putative serine protease is required to initiate the ripk3-mlkl—mediated necroptotic death pathway in neutrophils
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860068/
https://www.ncbi.nlm.nih.gov/pubmed/33551816
http://dx.doi.org/10.3389/fphar.2020.614928
work_keys_str_mv AT wangxiaoliang aputativeserineproteaseisrequiredtoinitiatetheripk3mlklmediatednecroptoticdeathpathwayinneutrophils
AT avsecdamjan aputativeserineproteaseisrequiredtoinitiatetheripk3mlklmediatednecroptoticdeathpathwayinneutrophils
AT obrezaales aputativeserineproteaseisrequiredtoinitiatetheripk3mlklmediatednecroptoticdeathpathwayinneutrophils
AT yousefishida aputativeserineproteaseisrequiredtoinitiatetheripk3mlklmediatednecroptoticdeathpathwayinneutrophils
AT mlinaricrascanirena aputativeserineproteaseisrequiredtoinitiatetheripk3mlklmediatednecroptoticdeathpathwayinneutrophils
AT simonhansuwe aputativeserineproteaseisrequiredtoinitiatetheripk3mlklmediatednecroptoticdeathpathwayinneutrophils
AT wangxiaoliang putativeserineproteaseisrequiredtoinitiatetheripk3mlklmediatednecroptoticdeathpathwayinneutrophils
AT avsecdamjan putativeserineproteaseisrequiredtoinitiatetheripk3mlklmediatednecroptoticdeathpathwayinneutrophils
AT obrezaales putativeserineproteaseisrequiredtoinitiatetheripk3mlklmediatednecroptoticdeathpathwayinneutrophils
AT yousefishida putativeserineproteaseisrequiredtoinitiatetheripk3mlklmediatednecroptoticdeathpathwayinneutrophils
AT mlinaricrascanirena putativeserineproteaseisrequiredtoinitiatetheripk3mlklmediatednecroptoticdeathpathwayinneutrophils
AT simonhansuwe putativeserineproteaseisrequiredtoinitiatetheripk3mlklmediatednecroptoticdeathpathwayinneutrophils