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Sci. Signal., 6 September 2011
Vol. 4, Issue 189, p. ra57
[DOI: 10.1126/scisignal.2001811]

RESEARCH ARTICLES

Small Molecule–Mediated Activation of the Integrin CD11b/CD18 Reduces Inflammatory Disease

Dony Maiguel1*, Mohd Hafeez Faridi1*, Changli Wei1, Yoshihiro Kuwano2, Keir M. Balla3, Dayami Hernandez4, Constantinos J. Barth1, Geanncarlo Lugo3, Mary Donnelly1, Ali Nayer1, Luis F. Moita5, Stephan Schürer6, David Traver3, Phillip Ruiz4, Roberto I. Vazquez-Padron7, Klaus Ley2, Jochen Reiser1, and Vineet Gupta1,8{dagger}

1 Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miami, FL 33136, USA.
2 Division of Inflammation Biology, La Jolla Institute for Allergy & Immunology, La Jolla, CA 92037, USA.
3 Department of Cellular and Molecular Medicine, University of California, San Diego, CA 92093, USA.
4 Division of Transplantation, Department of Surgery, University of Miami, Miami, FL 33136, USA.
5 Cell Biology of the Immune System Unit, Instituto de Medicina Molecular, Universidade de Lisboa, 1649-028 Lisboa, Portugal.
6 Center for Computational Studies, Department of Medicine, University of Miami, Miami, FL 33136, USA.
7 Division of Vascular Biology, Department of Surgery, University of Miami, Miami, FL 33136, USA.
8 Department of Biochemistry and Molecular Biology, University of Miami, Miami, FL 33136, USA.

* These authors contributed equally to this work.

Abstract: The integrin CD11b/CD18 (also known as Mac-1), which is a heterodimer of the αM (CD11b) and β2 (CD18) subunits, is critical for leukocyte adhesion and migration and for immune functions. Blocking integrin-mediated leukocyte adhesion, although beneficial in experimental models, has had limited success in treating inflammatory diseases in humans. Here, we used an alternative strategy of inhibiting leukocyte recruitment by activating CD11b/CD18 with small-molecule agonists, which we term leukadherins. These compounds increased the extent of CD11b/CD18-dependent cell adhesion of transfected cells and of primary human and mouse neutrophils, which resulted in decreased chemotaxis and transendothelial migration. Leukadherins also decreased leukocyte recruitment and reduced arterial narrowing after injury in rats. Moreover, compared to a known integrin antagonist, leukadherins better preserved kidney function in a mouse model of experimental nephritis. Leukadherins inhibited leukocyte recruitment by increasing leukocyte adhesion to the inflamed endothelium, which was reversed with a blocking antibody. Thus, we propose that pharmacological activation of CD11b/CD18 offers an alternative therapeutic approach for inflammatory diseases.

{dagger} To whom correspondence should be addressed. E-mail: vgupta2{at}med.miami.edu

Citation: D. Maiguel, M. H. Faridi, C. Wei, Y. Kuwano, K. M. Balla, D. Hernandez, C. J. Barth, G. Lugo, M. Donnelly, A. Nayer, L. F. Moita, S. Schürer, D. Traver, P. Ruiz, R. I. Vazquez-Padron, K. Ley, J. Reiser, V. Gupta, Small Molecule–Mediated Activation of the Integrin CD11b/CD18 Reduces Inflammatory Disease. Sci. Signal. 4, ra57 (2011).

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