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Nat Commun. 2018 Feb 6;9(1):525. doi: 10.1038/s41467-018-02896-8.

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

Author information

1
Cardiology and Angiology I, University Heart Center, and Medical Faculty, University of Freiburg, Freiburg, 79106, Germany.
2
Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, 92037, USA.
3
Atherothrombosis and Vascular Biology, Baker Heart and Diabetes Institute, Melbourne, 8008, VIC, Australia.
4
Division of Nephrology, Inselspital, Bern University Hospital, Bern, 3010, Switzerland.
5
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, 92037, USA.
6
Neurosurgery, Medical Faculty of the University of Erlangen, Erlangen, 91054, Germany.
7
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
8
Brigham and Women's Hospital, Cardiovascular Medicine, Harvard Medical School, Boston, MA, 02115, USA.
9
Atherothrombosis and Vascular Biology, Baker Heart and Diabetes Institute, Melbourne, 8008, VIC, Australia. karlheinz.peter@baker.edu.au.

Abstract

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.

PMID:
29410422
PMCID:
PMC5802769
DOI:
10.1038/s41467-018-02896-8
[Indexed for MEDLINE]
Free PMC Article

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