A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense

Autores: Wolf, Dennis; Anto-Michel, Nathaly; Blankenbach, Hermann; Wiedemann, Ansgar; Buscher, Konrad; Hohmann, Jan David; Lim, Bock; Bäuml, Marina; Marki, Alex; Mauler, Maximilian; Duerschmied, Daniel; Fan, Zhichao; Winkels, Holger; Sidler, Daniel; Diehl, Philipp; Zajonc, Dirk M; Hilgendorf, Ingo; Stachon, Peter; Marchini, Timoteo Oscar; Willecke, Florian; Schell, Maximilian; Sommer, Björn; Von Zur Muhlen, Constantin; Reinöhl, Jochen; Gerhardt, Teresa; Plow, Edward F.; Yakubenko, Valentin; Libby, Peter; Bode, Christoph; Ley, Klaus; Peter, Karlheinz; Zirlik, Andreas
Año de publicación: 2018
Idioma: inglés
Tipo de recurso: artículo
Estado: versión publicada
Descripción: Integrin-based therapeutics have garnered considerable interest in the medical treatment of inflammation. Integrins mediate the fast recruitment of monocytes and neutrophils to the site of inflammation, but are also required for host defense, limiting their therapeutic use. Here, we report a novel monoclonal antibody, anti-M7, that specifically blocks the interaction of the integrin Mac-1 with its pro-inflammatory ligand CD40L, while not interfering with alternative ligands. Anti-M7 selectively reduces leukocyte recruitment in vitro and in vivo. In contrast, conventional anti-Mac-1 therapy is not specific and blocks a broad repertoire of integrin functionality, inhibits phagocytosis, promotes apoptosis, and fuels a cytokine storm in vivo. Whereas conventional anti-integrin therapy potentiates bacterial sepsis, bacteremia, and mortality, a ligand-specific intervention with anti-M7 is protective. These findings deepen our understanding of ligand-specific integrin functions and open a path for a new field of ligand-targeted anti-integrin therapy to prevent inflammatory conditions.
Fil: Wolf, Dennis. La Jolla Institute for Allergy and Immunology; Estados Unidos. Universitat Freiburg Im Breisgau; Alemania
Fil: Anto-Michel, Nathaly. Universitat Freiburg Im Breisgau; Alemania
Fil: Blankenbach, Hermann. Universitat Freiburg Im Breisgau; Alemania
Fil: Wiedemann, Ansgar. Universitat Freiburg Im Breisgau; Alemania
Fil: Buscher, Konrad. La Jolla Institute for Allergy and Immunology; Estados Unidos
Fil: Hohmann, Jan David. Baker Heart And Diabetes Institute; Australia
Fil: Lim, Bock. Baker Heart And Diabetes Institute; Australia
Fil: Bäuml, Marina. Universitat Freiburg Im Breisgau; Alemania
Fil: Marki, Alex. La Jolla Institute for Allergy and Immunology; Estados Unidos
Fil: Mauler, Maximilian. Universitat Freiburg Im Breisgau; Alemania
Fil: Duerschmied, Daniel. Universitat Freiburg Im Breisgau; Alemania
Fil: Fan, Zhichao. La Jolla Institute for Allergy and Immunology; Estados Unidos
Fil: Winkels, Holger. La Jolla Institute for Allergy and Immunology; Estados Unidos
Fil: Sidler, Daniel. Universitatsspital Bern; Suiza
Fil: Diehl, Philipp. Universitat Freiburg Im Breisgau; Alemania
Fil: Zajonc, Dirk M. La Jolla Institute for Allergy and Immunology; Estados Unidos
Fil: Hilgendorf, Ingo. Universitat Freiburg Im Breisgau; Alemania
Fil: Stachon, Peter. Universitat Freiburg Im Breisgau; Alemania
Fil: Marchini, Timoteo Oscar. Universitat Freiburg Im Breisgau; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina
Fil: Willecke, Florian. Universitat Freiburg Im Breisgau; Alemania
Fil: Schell, Maximilian. Universitat Freiburg Im Breisgau; Alemania. La Jolla Institute for Allergy and Immunology; Estados Unidos
Fil: Sommer, Björn. Universitat Erlangen-Nuremberg; Alemania
Fil: Von Zur Muhlen, Constantin. Universitat Freiburg Im Breisgau; Alemania
Fil: Reinöhl, Jochen. Universitat Freiburg Im Breisgau; Alemania
Fil: Gerhardt, Teresa. La Jolla Institute for Allergy and Immunology; Estados Unidos
Fil: Plow, Edward F.. Cleveland Clinic Foundation; Estados Unidos
Fil: Yakubenko, Valentin. Cleveland Clinic Foundation; Estados Unidos
Fil: Libby, Peter. Brigham And Women's Hospital; Estados Unidos
Fil: Bode, Christoph. Universitat Freiburg Im Breisgau; Alemania
Fil: Ley, Klaus. La Jolla Institute for Allergy and Immunology; Estados Unidos
Fil: Peter, Karlheinz. Baker Heart And Diabetes Institute; Australia
Fil: Zirlik, Andreas. Universitat Freiburg Im Breisgau; Alemania
Materia: Mac-1
Integrin
Inflammation
Nivel de accesibilidad: acceso abierto
Condiciones de uso: https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
Institución: Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador: oai:ri.conicet.gov.ar:11336/88324

Acceder

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repository_id_str	3498
network_name_str	CONICET Digital (CONICET)
spelling	A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defenseWolf, DennisAnto-Michel, NathalyBlankenbach, HermannWiedemann, AnsgarBuscher, KonradHohmann, Jan DavidLim, BockBäuml, MarinaMarki, AlexMauler, MaximilianDuerschmied, DanielFan, ZhichaoWinkels, HolgerSidler, DanielDiehl, PhilippZajonc, Dirk MHilgendorf, IngoStachon, PeterMarchini, Timoteo OscarWillecke, FlorianSchell, MaximilianSommer, BjörnVon Zur Muhlen, ConstantinReinöhl, JochenGerhardt, TeresaPlow, Edward F.Yakubenko, ValentinLibby, PeterBode, ChristophLey, KlausPeter, KarlheinzZirlik, AndreasMac-1IntegrinInflammationhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Integrin-based therapeutics have garnered considerable interest in the medical treatment of inflammation. Integrins mediate the fast recruitment of monocytes and neutrophils to the site of inflammation, but are also required for host defense, limiting their therapeutic use. Here, we report a novel monoclonal antibody, anti-M7, that specifically blocks the interaction of the integrin Mac-1 with its pro-inflammatory ligand CD40L, while not interfering with alternative ligands. Anti-M7 selectively reduces leukocyte recruitment in vitro and in vivo. In contrast, conventional anti-Mac-1 therapy is not specific and blocks a broad repertoire of integrin functionality, inhibits phagocytosis, promotes apoptosis, and fuels a cytokine storm in vivo. Whereas conventional anti-integrin therapy potentiates bacterial sepsis, bacteremia, and mortality, a ligand-specific intervention with anti-M7 is protective. These findings deepen our understanding of ligand-specific integrin functions and open a path for a new field of ligand-targeted anti-integrin therapy to prevent inflammatory conditions.Fil: Wolf, Dennis. La Jolla Institute for Allergy and Immunology; Estados Unidos. Universitat Freiburg Im Breisgau; AlemaniaFil: Anto-Michel, Nathaly. Universitat Freiburg Im Breisgau; AlemaniaFil: Blankenbach, Hermann. Universitat Freiburg Im Breisgau; AlemaniaFil: Wiedemann, Ansgar. Universitat Freiburg Im Breisgau; AlemaniaFil: Buscher, Konrad. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Hohmann, Jan David. Baker Heart And Diabetes Institute; AustraliaFil: Lim, Bock. Baker Heart And Diabetes Institute; AustraliaFil: Bäuml, Marina. Universitat Freiburg Im Breisgau; AlemaniaFil: Marki, Alex. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Mauler, Maximilian. Universitat Freiburg Im Breisgau; AlemaniaFil: Duerschmied, Daniel. Universitat Freiburg Im Breisgau; AlemaniaFil: Fan, Zhichao. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Winkels, Holger. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Sidler, Daniel. Universitatsspital Bern; SuizaFil: Diehl, Philipp. Universitat Freiburg Im Breisgau; AlemaniaFil: Zajonc, Dirk M. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Hilgendorf, Ingo. Universitat Freiburg Im Breisgau; AlemaniaFil: Stachon, Peter. Universitat Freiburg Im Breisgau; AlemaniaFil: Marchini, Timoteo Oscar. Universitat Freiburg Im Breisgau; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Willecke, Florian. Universitat Freiburg Im Breisgau; AlemaniaFil: Schell, Maximilian. Universitat Freiburg Im Breisgau; Alemania. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Sommer, Björn. Universitat Erlangen-Nuremberg; AlemaniaFil: Von Zur Muhlen, Constantin. Universitat Freiburg Im Breisgau; AlemaniaFil: Reinöhl, Jochen. Universitat Freiburg Im Breisgau; AlemaniaFil: Gerhardt, Teresa. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Plow, Edward F.. Cleveland Clinic Foundation; Estados UnidosFil: Yakubenko, Valentin. Cleveland Clinic Foundation; Estados UnidosFil: Libby, Peter. Brigham And Women's Hospital; Estados UnidosFil: Bode, Christoph. Universitat Freiburg Im Breisgau; AlemaniaFil: Ley, Klaus. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Peter, Karlheinz. Baker Heart And Diabetes Institute; AustraliaFil: Zirlik, Andreas. Universitat Freiburg Im Breisgau; AlemaniaNature2018-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/88324Wolf, Dennis; Anto-Michel, Nathaly; Blankenbach, Hermann; Wiedemann, Ansgar; Buscher, Konrad; et al.; A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense; Nature; Nature Communications; 9; 525; 12-2018; 1-112041-1723CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1038/s41467-018-02896-8info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41467-018-02896-8info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:43:03Zoai:ri.conicet.gov.ar:11336/88324instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:43:03.916CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv	A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense
title	A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense
spellingShingle	A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense Wolf, Dennis Mac-1 Integrin Inflammation
title_short	A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense
title_full	A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense
title_fullStr	A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense
title_full_unstemmed	A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense
title_sort	A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense
dc.creator.none.fl_str_mv	Wolf, Dennis Anto-Michel, Nathaly Blankenbach, Hermann Wiedemann, Ansgar Buscher, Konrad Hohmann, Jan David Lim, Bock Bäuml, Marina Marki, Alex Mauler, Maximilian Duerschmied, Daniel Fan, Zhichao Winkels, Holger Sidler, Daniel Diehl, Philipp Zajonc, Dirk M Hilgendorf, Ingo Stachon, Peter Marchini, Timoteo Oscar Willecke, Florian Schell, Maximilian Sommer, Björn Von Zur Muhlen, Constantin Reinöhl, Jochen Gerhardt, Teresa Plow, Edward F. Yakubenko, Valentin Libby, Peter Bode, Christoph Ley, Klaus Peter, Karlheinz Zirlik, Andreas
author	Wolf, Dennis
author_facet	Wolf, Dennis Anto-Michel, Nathaly Blankenbach, Hermann Wiedemann, Ansgar Buscher, Konrad Hohmann, Jan David Lim, Bock Bäuml, Marina Marki, Alex Mauler, Maximilian Duerschmied, Daniel Fan, Zhichao Winkels, Holger Sidler, Daniel Diehl, Philipp Zajonc, Dirk M Hilgendorf, Ingo Stachon, Peter Marchini, Timoteo Oscar Willecke, Florian Schell, Maximilian Sommer, Björn Von Zur Muhlen, Constantin Reinöhl, Jochen Gerhardt, Teresa Plow, Edward F. Yakubenko, Valentin Libby, Peter Bode, Christoph Ley, Klaus Peter, Karlheinz Zirlik, Andreas
author_role	author
author2	Anto-Michel, Nathaly Blankenbach, Hermann Wiedemann, Ansgar Buscher, Konrad Hohmann, Jan David Lim, Bock Bäuml, Marina Marki, Alex Mauler, Maximilian Duerschmied, Daniel Fan, Zhichao Winkels, Holger Sidler, Daniel Diehl, Philipp Zajonc, Dirk M Hilgendorf, Ingo Stachon, Peter Marchini, Timoteo Oscar Willecke, Florian Schell, Maximilian Sommer, Björn Von Zur Muhlen, Constantin Reinöhl, Jochen Gerhardt, Teresa Plow, Edward F. Yakubenko, Valentin Libby, Peter Bode, Christoph Ley, Klaus Peter, Karlheinz Zirlik, Andreas
author2_role	author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author
dc.subject.none.fl_str_mv	Mac-1 Integrin Inflammation
topic	Mac-1 Integrin Inflammation
purl_subject.fl_str_mv	https://purl.org/becyt/ford/3.1 https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv	Integrin-based therapeutics have garnered considerable interest in the medical treatment of inflammation. Integrins mediate the fast recruitment of monocytes and neutrophils to the site of inflammation, but are also required for host defense, limiting their therapeutic use. Here, we report a novel monoclonal antibody, anti-M7, that specifically blocks the interaction of the integrin Mac-1 with its pro-inflammatory ligand CD40L, while not interfering with alternative ligands. Anti-M7 selectively reduces leukocyte recruitment in vitro and in vivo. In contrast, conventional anti-Mac-1 therapy is not specific and blocks a broad repertoire of integrin functionality, inhibits phagocytosis, promotes apoptosis, and fuels a cytokine storm in vivo. Whereas conventional anti-integrin therapy potentiates bacterial sepsis, bacteremia, and mortality, a ligand-specific intervention with anti-M7 is protective. These findings deepen our understanding of ligand-specific integrin functions and open a path for a new field of ligand-targeted anti-integrin therapy to prevent inflammatory conditions. Fil: Wolf, Dennis. La Jolla Institute for Allergy and Immunology; Estados Unidos. Universitat Freiburg Im Breisgau; Alemania Fil: Anto-Michel, Nathaly. Universitat Freiburg Im Breisgau; Alemania Fil: Blankenbach, Hermann. Universitat Freiburg Im Breisgau; Alemania Fil: Wiedemann, Ansgar. Universitat Freiburg Im Breisgau; Alemania Fil: Buscher, Konrad. La Jolla Institute for Allergy and Immunology; Estados Unidos Fil: Hohmann, Jan David. Baker Heart And Diabetes Institute; Australia Fil: Lim, Bock. Baker Heart And Diabetes Institute; Australia Fil: Bäuml, Marina. Universitat Freiburg Im Breisgau; Alemania Fil: Marki, Alex. La Jolla Institute for Allergy and Immunology; Estados Unidos Fil: Mauler, Maximilian. Universitat Freiburg Im Breisgau; Alemania Fil: Duerschmied, Daniel. Universitat Freiburg Im Breisgau; Alemania Fil: Fan, Zhichao. La Jolla Institute for Allergy and Immunology; Estados Unidos Fil: Winkels, Holger. La Jolla Institute for Allergy and Immunology; Estados Unidos Fil: Sidler, Daniel. Universitatsspital Bern; Suiza Fil: Diehl, Philipp. Universitat Freiburg Im Breisgau; Alemania Fil: Zajonc, Dirk M. La Jolla Institute for Allergy and Immunology; Estados Unidos Fil: Hilgendorf, Ingo. Universitat Freiburg Im Breisgau; Alemania Fil: Stachon, Peter. Universitat Freiburg Im Breisgau; Alemania Fil: Marchini, Timoteo Oscar. Universitat Freiburg Im Breisgau; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; Argentina Fil: Willecke, Florian. Universitat Freiburg Im Breisgau; Alemania Fil: Schell, Maximilian. Universitat Freiburg Im Breisgau; Alemania. La Jolla Institute for Allergy and Immunology; Estados Unidos Fil: Sommer, Björn. Universitat Erlangen-Nuremberg; Alemania Fil: Von Zur Muhlen, Constantin. Universitat Freiburg Im Breisgau; Alemania Fil: Reinöhl, Jochen. Universitat Freiburg Im Breisgau; Alemania Fil: Gerhardt, Teresa. La Jolla Institute for Allergy and Immunology; Estados Unidos Fil: Plow, Edward F.. Cleveland Clinic Foundation; Estados Unidos Fil: Yakubenko, Valentin. Cleveland Clinic Foundation; Estados Unidos Fil: Libby, Peter. Brigham And Women's Hospital; Estados Unidos Fil: Bode, Christoph. Universitat Freiburg Im Breisgau; Alemania Fil: Ley, Klaus. La Jolla Institute for Allergy and Immunology; Estados Unidos Fil: Peter, Karlheinz. Baker Heart And Diabetes Institute; Australia Fil: Zirlik, Andreas. Universitat Freiburg Im Breisgau; Alemania
description	Integrin-based therapeutics have garnered considerable interest in the medical treatment of inflammation. Integrins mediate the fast recruitment of monocytes and neutrophils to the site of inflammation, but are also required for host defense, limiting their therapeutic use. Here, we report a novel monoclonal antibody, anti-M7, that specifically blocks the interaction of the integrin Mac-1 with its pro-inflammatory ligand CD40L, while not interfering with alternative ligands. Anti-M7 selectively reduces leukocyte recruitment in vitro and in vivo. In contrast, conventional anti-Mac-1 therapy is not specific and blocks a broad repertoire of integrin functionality, inhibits phagocytosis, promotes apoptosis, and fuels a cytokine storm in vivo. Whereas conventional anti-integrin therapy potentiates bacterial sepsis, bacteremia, and mortality, a ligand-specific intervention with anti-M7 is protective. These findings deepen our understanding of ligand-specific integrin functions and open a path for a new field of ligand-targeted anti-integrin therapy to prevent inflammatory conditions.
publishDate	2018
dc.date.none.fl_str_mv	2018-12
dc.type.none.fl_str_mv	info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	http://hdl.handle.net/11336/88324 Wolf, Dennis; Anto-Michel, Nathaly; Blankenbach, Hermann; Wiedemann, Ansgar; Buscher, Konrad; et al.; A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense; Nature; Nature Communications; 9; 525; 12-2018; 1-11 2041-1723 CONICET Digital CONICET
url	http://hdl.handle.net/11336/88324
identifier_str_mv	Wolf, Dennis; Anto-Michel, Nathaly; Blankenbach, Hermann; Wiedemann, Ansgar; Buscher, Konrad; et al.; A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense; Nature; Nature Communications; 9; 525; 12-2018; 1-11 2041-1723 CONICET Digital CONICET
dc.language.none.fl_str_mv	eng
language	eng
dc.relation.none.fl_str_mv	info:eu-repo/semantics/altIdentifier/doi/10.1038/s41467-018-02896-8 info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41467-018-02896-8
dc.rights.none.fl_str_mv	info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv	openAccess
rights_invalid_str_mv	https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv	application/pdf application/pdf
dc.publisher.none.fl_str_mv	Nature
publisher.none.fl_str_mv	Nature
dc.source.none.fl_str_mv	reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas
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repository.name.fl_str_mv	CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv	dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score	13.070432

A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense

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