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Therapeutic ACPA inhibits NET formation: a potential therapy for neutrophil-mediated inflammatory diseases
Excessive release of neutrophil extracellular traps (NETs) is associated with disease severity and contributes to tissue injury, followed by severe organ damage. Pharmacological or genetic inhibition of NET release reduces pathology in multiple inflammatory disease models, indicating that NETs are p...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166830/ https://www.ncbi.nlm.nih.gov/pubmed/32203195 http://dx.doi.org/10.1038/s41423-020-0381-3 |
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author | Chirivi, Renato G. S. van Rosmalen, Jos W. G. van der Linden, Maarten Euler, Maximilien Schmets, Gonny Bogatkevich, Galina Kambas, Konstantinos Hahn, Jonas Braster, Quinte Soehnlein, Oliver Hoffmann, Markus H. Es, Helmuth H. G. van Raats, Jos M. H. |
author_facet | Chirivi, Renato G. S. van Rosmalen, Jos W. G. van der Linden, Maarten Euler, Maximilien Schmets, Gonny Bogatkevich, Galina Kambas, Konstantinos Hahn, Jonas Braster, Quinte Soehnlein, Oliver Hoffmann, Markus H. Es, Helmuth H. G. van Raats, Jos M. H. |
author_sort | Chirivi, Renato G. S. |
collection | PubMed |
description | Excessive release of neutrophil extracellular traps (NETs) is associated with disease severity and contributes to tissue injury, followed by severe organ damage. Pharmacological or genetic inhibition of NET release reduces pathology in multiple inflammatory disease models, indicating that NETs are potential therapeutic targets. Here, we demonstrate using a preclinical basket approach that our therapeutic anti-citrullinated protein antibody (tACPA) has broad therapeutic potential. Treatment with tACPA prevents disease symptoms in various mouse models with plausible NET-mediated pathology, including inflammatory arthritis (IA), pulmonary fibrosis, inflammatory bowel disease and sepsis. We show that citrulline residues in the N-termini of histones 2A and 4 are specific targets for therapeutic intervention, whereas antibodies against other N-terminal post-translational histone modifications have no therapeutic effects. Because citrullinated histones are generated during NET release, we investigated the ability of tACPA to inhibit NET formation. tACPA suppressed NET release from human neutrophils triggered with physiologically relevant human disease-related stimuli. Moreover, tACPA diminished NET release and potentially initiated NET uptake by macrophages in vivo, which was associated with reduced tissue damage in the joints of a chronic arthritis mouse model of IA. To our knowledge, we are the first to describe an antibody with NET-inhibiting properties and thereby propose tACPA as a drug candidate for NET-mediated inflammatory diseases, as it eliminates the noxious triggers that lead to continued inflammation and tissue damage in a multidimensional manner. |
format | Online Article Text |
id | pubmed-8166830 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-81668302021-06-15 Therapeutic ACPA inhibits NET formation: a potential therapy for neutrophil-mediated inflammatory diseases Chirivi, Renato G. S. van Rosmalen, Jos W. G. van der Linden, Maarten Euler, Maximilien Schmets, Gonny Bogatkevich, Galina Kambas, Konstantinos Hahn, Jonas Braster, Quinte Soehnlein, Oliver Hoffmann, Markus H. Es, Helmuth H. G. van Raats, Jos M. H. Cell Mol Immunol Article Excessive release of neutrophil extracellular traps (NETs) is associated with disease severity and contributes to tissue injury, followed by severe organ damage. Pharmacological or genetic inhibition of NET release reduces pathology in multiple inflammatory disease models, indicating that NETs are potential therapeutic targets. Here, we demonstrate using a preclinical basket approach that our therapeutic anti-citrullinated protein antibody (tACPA) has broad therapeutic potential. Treatment with tACPA prevents disease symptoms in various mouse models with plausible NET-mediated pathology, including inflammatory arthritis (IA), pulmonary fibrosis, inflammatory bowel disease and sepsis. We show that citrulline residues in the N-termini of histones 2A and 4 are specific targets for therapeutic intervention, whereas antibodies against other N-terminal post-translational histone modifications have no therapeutic effects. Because citrullinated histones are generated during NET release, we investigated the ability of tACPA to inhibit NET formation. tACPA suppressed NET release from human neutrophils triggered with physiologically relevant human disease-related stimuli. Moreover, tACPA diminished NET release and potentially initiated NET uptake by macrophages in vivo, which was associated with reduced tissue damage in the joints of a chronic arthritis mouse model of IA. To our knowledge, we are the first to describe an antibody with NET-inhibiting properties and thereby propose tACPA as a drug candidate for NET-mediated inflammatory diseases, as it eliminates the noxious triggers that lead to continued inflammation and tissue damage in a multidimensional manner. Nature Publishing Group UK 2020-03-20 2021-06 /pmc/articles/PMC8166830/ /pubmed/32203195 http://dx.doi.org/10.1038/s41423-020-0381-3 Text en © The Author(s) 2020 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Chirivi, Renato G. S. van Rosmalen, Jos W. G. van der Linden, Maarten Euler, Maximilien Schmets, Gonny Bogatkevich, Galina Kambas, Konstantinos Hahn, Jonas Braster, Quinte Soehnlein, Oliver Hoffmann, Markus H. Es, Helmuth H. G. van Raats, Jos M. H. Therapeutic ACPA inhibits NET formation: a potential therapy for neutrophil-mediated inflammatory diseases |
title | Therapeutic ACPA inhibits NET formation: a potential therapy for neutrophil-mediated inflammatory diseases |
title_full | Therapeutic ACPA inhibits NET formation: a potential therapy for neutrophil-mediated inflammatory diseases |
title_fullStr | Therapeutic ACPA inhibits NET formation: a potential therapy for neutrophil-mediated inflammatory diseases |
title_full_unstemmed | Therapeutic ACPA inhibits NET formation: a potential therapy for neutrophil-mediated inflammatory diseases |
title_short | Therapeutic ACPA inhibits NET formation: a potential therapy for neutrophil-mediated inflammatory diseases |
title_sort | therapeutic acpa inhibits net formation: a potential therapy for neutrophil-mediated inflammatory diseases |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166830/ https://www.ncbi.nlm.nih.gov/pubmed/32203195 http://dx.doi.org/10.1038/s41423-020-0381-3 |
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