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

Research output: Contribution to journalArticle

Authors

  • Dennis Wolf
  • Nathaly Anto-Michel
  • Hermann Blankenbach
  • Ansgar Wiedemann
  • Konrad Buscher
  • Jan David Hohmann
  • Bock Lim
  • Marina Bäuml
  • Maximilian Mauler
  • Daniel Duerschmied
  • Holger Winkels
  • Daniel Sidler
  • Philipp Diehl
  • Dirk M. Zajonc
  • Ingo Hilgendorf
  • Peter Stachon
  • Timoteo Marchini
  • Florian Willecke
  • Maximilian Schell
  • Björn Sommer
  • Constantin Von Zur Muhlen
  • Jochen Reinöhl
  • Teresa Gerhardt
  • Edward F. Plow
  • Christoph Bode
  • Klaus Ley
  • Karlheinz Peter
  • Andreas Zirlik

External Institution(s)

  • University of Freiburg
  • La Jolla Institute for Allergy and Immunology
  • Baker Heart Research Institute
  • University of Bern
  • Friedrich-Alexander University Erlangen-Nürnberg
  • Cleveland Clinic Foundation

Details

Original languageEnglish (US)
Article number525
JournalNature communications
Volume9
Issue number1
StatusPublished - Dec 1 2018
Peer-reviewedYes

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.

Citation formats

APA

Wolf, D., Anto-Michel, N., Blankenbach, H., Wiedemann, A., Buscher, K., Hohmann, J. D., ... Zirlik, A. (2018). A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense. Nature communications, 9(1), [525]. https://doi.org/10.1038/s41467-018-02896-8

Harvard

Wolf, D, Anto-Michel, N, Blankenbach, H, Wiedemann, A, Buscher, K, Hohmann, JD, Lim, B, Bäuml, M, Marki, A, Mauler, M, Duerschmied, D, Fan, Z, Winkels, H, Sidler, D, Diehl, P, Zajonc, DM, Hilgendorf, I, Stachon, P, Marchini, T, Willecke, F, Schell, M, Sommer, B, Von Zur Muhlen, C, Reinöhl, J, Gerhardt, T, Plow, EF, Yakubenko, V, Libby, P, Bode, C, Ley, K, Peter, K & Zirlik, A 2018, 'A ligand-specific blockade of the integrin Mac-1 selectively targets pathologic inflammation while maintaining protective host-defense', Nature communications, vol. 9, no. 1, 525. https://doi.org/10.1038/s41467-018-02896-8