A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense
| Autor: | Karlheinz Peter, Valentin P. Yakubenko, Bock Lim, Philipp Diehl, Alex Marki, Klaus Ley, Björn Sommer, Jochen Reinöhl, Jan David Hohmann, Constantin von zur Mühlen, Maximilian Mauler, Peter Stachon, Ansgar Wiedemann, Holger Winkels, Daniel Duerschmied, Peter Libby, Dirk M. Zajonc, Andreas Zirlik, Daniel Sidler, Florian Willecke, Zhichao Fan, Maximilian Schell, Marina Bäuml, Nathaly Anto-Michel, Ingo Hilgendorf, Christoph Bode, Teresa Gerhardt, Dennis Wolf, Timoteo Marchini, Konrad Buscher, Hermann Blankenbach, Edward F. Plow |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Neutrophils General Physics and Astronomy Integrin 030204 cardiovascular system & hematology 0302 clinical medicine Leukocytes Medicine Molecular Targeted Therapy lcsh:Science Multidisciplinary biology Antibodies Monoclonal purl.org/becyt/ford/3.1 [https] 3. Good health Medicina Básica Host-Pathogen Interactions purl.org/becyt/ford/3 [https] medicine.symptom CIENCIAS MÉDICAS Y DE LA SALUD Phagocytosis Science Intercellular Adhesion Molecule-1 CD40 Ligand Inmunología Macrophage-1 Antigen Inflammation General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences In vivo Sepsis Animals Humans Innate immune system Binding Sites business.industry General Chemistry medicine.disease Mice Inbred C57BL 030104 developmental biology Mac-1 Macrophage-1 antigen biology.protein Cancer research lcsh:Q business Cytokine storm |
| Zdroj: | Nature Communications, Vol 9, Iss 1, Pp 1-11 (2018) Nature Communications CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET |
| ISSN: | 2041-1723 |
| Popis: | 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. Integrin-based therapeutics could block inflammatory processes but they also impair host defence, limiting their usefulness. Here the authors report an anti-Mac1 antibody that blocks its interaction with pro-inflammatory ligand CD40L but not other ligands, and show that it can protect against sepsis in mice. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|