Abstract
The pattern recognition receptor, RAGE (receptor for advanced glycation endproducts), propagates cellular dysfunction in several inflammatory disorders and diabetes. Here we show that RAGE functions as an endothelial adhesion receptor promoting leukocyte recruitment. In an animal model of thioglycollate-induced acute peritonitis, leukocyte recruitment was significantly impaired in RAGE-deficient mice as opposed to wild-type mice. In diabetic wild-type mice we observed enhanced leukocyte recruitment to the inflamed peritoneum as compared with nondiabetic wild-type mice; this phenomenon was attributed to RAGE as it was abrogated in the presence of soluble RAGE and was absent in diabetic RAGE-deficient mice. In vitro, RAGE-dependent leukocyte adhesion to endothelial cells was mediated by a direct interaction of RAGE with the β2-integrin Mac-1 and, to a lower extent, with p150,95 but not with LFA-1 or with β1-integrins. The RAGE–Mac-1 interaction was augmented by the proinflammatory RAGE-ligand, S100-protein. These results were corroborated by analysis of cells transfected with different heterodimeric β2-integrins, by using RAGE-transfected cells, and by using purified proteins. The RAGE–Mac-1 interaction defines a novel pathway of leukocyte recruitment relevant in inflammatory disorders associated with increased RAGE expression, such as in diabetes, and could provide the basis for the development of novel therapeutic applications.
Highlights
Leukocyte recruitment is an integral part of inflammatory processes or vascular remodeling and requires multistep adhesive and signaling events, including selectin-mediated rolling, leukocyte activation, and integrin-mediated firm adhesion and diapedesis [1]
To test whether receptor for AGE (RAGE) is engaged in leukocyte recruitment in vivo, we studied the role of RAGE in a mouse model of acute inflammation
RAGE is a counter-receptor for leukocyte integrins that contributes to the recruitment of inflammatory cells, under stress or pathological conditions such as in diabetes
Summary
Leukocyte recruitment is an integral part of inflammatory processes or vascular remodeling and requires multistep adhesive and signaling events, including selectin-mediated rolling, leukocyte activation, and integrin-mediated firm adhesion and diapedesis [1]. During firm adhesion of leukocytes to the endothelium, members of the 2-integrin family, LFA-1 (␣L2, CD11a/CD18), Mac-1 (␣M2, CD11b/CD18), and p150,95 (␣X2, CD11c/CD18), as well as 1-integrins on the leukocyte surface, interact with endothelial counterligands such as ICAM-1, surfaceassociated fibrinogen (FBG), or VCAM-1. In ICAM-1–deficient mice the defect in leukocyte recruitment is not complete, the existence of further 2-integrin–dependent, ICAM-1–independent mechanisms has been proposed [2]. The importance of ICAM-1–dependent and ICAM-1–independent mechanisms of leukocyte recruitment in different pathophysiological situations, such as in diabetes, has not yet been established. Abbreviations used in this paper: AGE, advanced glycation endproducts; CML, (carboxymethyl)-lysine; FBG, fibrinogen; FN, fibronectin; HK, high molecular weight kininogen; HUVEC, human umbilical vein endothelial cells; RAGE, receptor for AGE
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
