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

被引：87

作者：

Wolf, Dennis ^{[1
,2
,3
]}

Anto-Michel, Nathaly ^{[1
,2
]}

Blankenbach, Hermann ^{[1
,2
]}

Wiedemann, Ansgar ^{[1
,2
]}

Buscher, Konrad ^{[3
]}

Hohmann, Jan David ^{[4
]}

Lim, Bock ^{[4
]}

Baeuml, Marina ^{[1
,2
]}

Marki, Alex ^{[3
]}

Mauler, Maximilian ^{[1
,2
]}

Duerschmied, Daniel ^{[1
,2
]}

Fan, Zhichao ^{[3
]}

Winkels, Holger ^{[3
]}

Sidler, Daniel ^{[5
]}

Diehl, Philipp ^{[1
,2
]}

Zajonc, Dirk M. ^{[6
]}

Hilgendorf, Ingo ^{[1
,2
]}

Stachon, Peter ^{[1
,2
]}

Marchini, Timoteo ^{[1
,2
]}

Willecke, Florian ^{[1
,2
]}

Schell, Maximilian ^{[1
,2
,3
]}

Sommer, Bjoern ^{[7
]}

von zur Muhlen, Constantin ^{[1
,2
]}

Reinoenl, Jochen ^{[1
,2
]}

Gerhardt, Teresa ^{[3
]}

Plow, Edward F. ^{[8
]}

Yakubenko, Valentin ^{[8
]}

Libby, Peter ^{[9
]}

Bode, Christoph ^{[1
,2
]}

Ley, Klaus ^{[3
]}

Peter, Karlheinz ^{[4
]}

Zirlik, Andreas ^{[1
,2
]}

机构：

[1] Univ Freiburg, Univ Heart Ctr, Cardiol & Angiol 1, D-79106 Freiburg, Germany

[2] Univ Freiburg, Med Fac, D-79106 Freiburg, Germany

[3] La Jolla Inst Allergy & Immunol, Inflammat Biol, La Jolla, CA 92037 USA

[4] Baker Heart & Diabet Inst, Atherothrombosis & Vasc Biol, Melbourne, Vic 8008, Australia

[5] Bern Univ Hosp, Div Nephrol, Inselspital, CH-3010 Bern, Switzerland

[6] La Jolla Inst Allergy & Immunol, Div Cell Biol, La Jolla, CA 92037 USA

[7] Univ Erlangen Nurnberg, Med Fac, Neurosurg, D-91054 Erlangen, Germany

[8] Cleveland Clin, Lerner Res Inst, Dept Mol Cardiol, Cleveland, OH 44195 USA

[9] Harvard Med Sch, Cardiovasc Med, Brigham & Womens Hosp, Boston, MA 02115 USA

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

英国医学研究理事会;

关键词：

INTERCELLULAR-ADHESION MOLECULE-1; NEUTROPHIL RECRUITMENT; LEUKOCYTE ADHESION; TRANSENDOTHELIAL MIGRATION; MYOCARDIAL-INFARCTION; COMPLEMENT RECEPTOR; COUNTER-RECEPTOR; INNATE IMMUNITY; BINDING-SITE; MECHANISMS;

D O I：

10.1038/s41467-018-02896-8

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：11

共 69 条

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