title: Small molecule-mediated activation of the integrin CD11b/CD18 reduces inflammatory disease.
abstract: The integrin CD11b/CD18 (also known as Mac-1), which is a heterodimer of the α(M) (CD11b) and β(2) (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.
authors: Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miami, FL 33136, USA.
authors: Dony
authors: D
authors: Maiguel
authors: Mohd Hafeez
authors: MH
authors: Faridi
authors: Changli
authors: C
authors: Wei
authors: Yoshihiro
authors: Y
authors: Kuwano
authors: Keir M
authors: KM
authors: Balla
authors: Dayami
authors: D
authors: Hernandez
authors: Constantinos J
authors: CJ
authors: Barth
authors: Geanncarlo
authors: G
authors: Lugo
authors: Mary
authors: M
authors: Donnelly
authors: Ali
authors: A
authors: Nayer
authors: Luis F
authors: LF
authors: Moita
authors: Stephan
authors: S
authors: Schürer
authors: David
authors: D
authors: Traver
authors: Phillip
authors: P
authors: Ruiz
authors: Roberto I
authors: RI
authors: Vazquez-Padron
authors: Klaus
authors: K
authors: Ley
authors: Jochen
authors: J
authors: Reiser
authors: Vineet
authors: V
authors: Gupta
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D018821:CD18 Antigens / Q000378:metabolism; D002118:Calcium; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D020014:K562 Cells; D007962:Leukocytes / Q000166:cytology / Q000502:physiology*; D016177:Macrophage-1 Antigen / Q000378:metabolism* / Q000627:therapeutic use; D008274:Magnesium; D008345:Manganese; D051379:Mice; D051381:Rats; D054852:Small Molecule Libraries / Q000627:therapeutic use*
chemical_list: D039481:CD11b Antigen; D018821:CD18 Antigens; D016177:Macrophage-1 Antigen; D054852:Small Molecule Libraries; D008345:Manganese; D008274:Magnesium; D002118:Calcium