Small molecule agonists of integrin CD11b/CD18 do not induce global conformational changes and are significantly better than activating antibodies in reducing vascular injury.
Small molecule agonists of integrin CD11b/CD18 do not induce global conformational changes and are significantly better than activating antibodies in reducing vascular injury.
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DOI：
10.1016/j.bbagen.2013.02.018
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发表时间：
2013-06
影响因子：
3
通讯作者：
Gupta, Vineet
中科院分区：
文献类型：
--
作者：
Faridi, Mohd Hafeez;Altintas, Mehmet M.;Gomez, Camilo;Duque, Juan Camilo;Vazquez-Padron, Roberto I.;Gupta, Vineet
CD11b/CD18 is a key adhesion receptor that mediates leukocyte adhesion, migration and immune functions. We recently identified novel compounds, leukadherins, that allosterically enhance CD11b/CD18-dependent cell adhesion and reduce inflammation in vivo, suggesting integrin activation to be a novel mechanism of action for the development of anti-inflammatory therapeutics. Since a number of well-characterized anti-CD11b/CD18 activating antibodies are currently available, we wondered if such biological agonists could also become therapeutic leads following this mechanism of action. We compared the two types of agonists using in vitro cell adhesion and wound-healing assays and using animal model systems. We also studied effects of the two types of agonists on outside-in signaling in treated cells. Both types of agonists similarly enhanced integrin-mediated cell adhesion and decreased cell migration. However, unlike leukadherins, the activating antibodies produced significant CD11b/CD18 macro clustering and induced phosphorylation of key proteins involved in outside-in signaling. Studies using conformation reporter antibodies showed that leukadherins did not induce global conformational changes in CD11b/CD18 explaining the reason behind their lack of ligand-mimetic outside-in signaling. In vivo, leukadherins reduced vascular injury in a dose-dependent fashion, but, surprisingly, the anti-CD11b activating antibody ED7 was ineffective. Our results suggest that small molecule allosteric agonists of CD11b/CD18 have clear advantages over the biologic activating antibodies and provide a mechanistic basis for the difference. CD11b/CD18 activation represents a novel strategy for reducing inflammatory injury. Our study establishes small molecule leukadherins as preferred agonists over activating antibodies for future development as novel anti-inflammatory therapeutics.
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影响因子：
15.9
作者：
Gao, Cunji;Boylan, Brian;Newman, Peter J.
通讯作者：
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影响因子：
5.4
作者：
HUITINGA, I;DAMOISEAUX, JGMC;DIJKSTRA, CD
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DIJKSTRA, CD
影响因子：
5.5
作者：
DAMOISEAUX, JGMC;DOPP, EA;DIJKSTRA, CD
通讯作者：
DIJKSTRA, CD
影响因子：
6.4
作者：
Draskovic-Pavlovic, B;Van der Laan, LJW;Colic, M
通讯作者：
Colic, M
影响因子：
2.1
作者：
Gabeler, Edward E E;van Hillegersberg, Richard;van Urk, Hero
通讯作者：
van Urk, Hero