TY - JOUR
T1 - A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense
AU - Wolf, Dennis
AU - Anto-Michel, Nathaly
AU - Blankenbach, Hermann
AU - Wiedemann, Ansgar
AU - Buscher, Konrad
AU - Hohmann, Jan David
AU - Lim, Bock
AU - Bäuml, Marina
AU - Marki, Alex
AU - Mauler, Maximilian
AU - Duerschmied, Daniel
AU - Fan, Zhichao
AU - Winkels, Holger
AU - Sidler, Daniel
AU - Diehl, Philipp
AU - Zajonc, Dirk M.
AU - Hilgendorf, Ingo
AU - Stachon, Peter
AU - Marchini, Timoteo
AU - Willecke, Florian
AU - Schell, Maximilian
AU - Sommer, Björn
AU - Von Zur Muhlen, Constantin
AU - Reinöhl, Jochen
AU - Gerhardt, Teresa
AU - Plow, Edward F.
AU - Yakubenko, Valentin
AU - Libby, Peter
AU - Bode, Christoph
AU - Ley, Klaus
AU - Peter, Karlheinz
AU - Zirlik, Andreas
N1 - Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-02896-8
DO - 10.1038/s41467-018-02896-8
M3 - Article
C2 - 29410422
AN - SCOPUS:85041660755
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 525
ER -