RAGE and ICAM-1 differentially control leukocyte recruitment during acute inflammation in a stimulus-dependent manner

Abstract

BackgroundThe receptor for advanced glycation endproducts, RAGE, is involved in the pathogenesis of many inflammatory conditions, which is mostly related to its strong activation of NF-κB but also due to its function as ligand for the β2-integrin Mac-1. To further dissect the stimulus-dependent role of RAGE on leukocyte recruitment during inflammation, we investigated β2-integrin-dependent leukocyte adhesion in RAGE-/- and Icam1-/- mice in different cremaster muscle models of inflammation using intravital microscopy.ResultsWe demonstrate that RAGE, but not ICAM-1 substantially contributes to N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced leukocyte adhesion in TNF-α-pretreated cremaster muscle venules in a Mac-1-dependent manner. In contrast, fMLP-stimulated leukocyte adhesion in unstimulated cremaster muscle venules is independent of RAGE, but dependent on ICAM-1 and its interaction with LFA-1. Furthermore, chemokine CXCL1-stimulated leukocyte adhesion in surgically prepared cremaster muscle venules was independent of RAGE but strongly dependent on ICAM-1 and LFA-1 suggesting a differential and stimulus-dependent regulation of leukocyte adhesion during inflammation in vivo.ConclusionOur results demonstrate that RAGE and ICAM-1 differentially regulate leukocyte adhesion in vivo in a stimulus-dependent manner.

CXCL1-Triggered Interaction of LFA1 and ICAM1 Control Glucose-Induced Leukocyte Recruitment during InflammationIn Vivo

“…In line with previous reports [31, 32] we found comparable baseline leukocyte adhesion in cremaster muscle venules of WT, LFA1-KO, and ICAM1-KO mice. In contrast to WT mice, injection of 0.5 g/kg glucose in ICAM1 −/− and in LFA1 −/− mice did not lead to significant changes of adherent leukocytes compared to baseline values (Figure 1(a)).…”

“…We and others demonstrated that injection of CXCR2-binding chemokine CXCL1 induces a significant increase of leukocyte adhesion which is mostly attributed to LFA1 activation and its subsequent ICAM1 binding [23, 31]. …”

Pulmonary receptor for advanced glycation end-products promotes asthma pathogenesis through IL-33 and accumulation of group 2 innate lymphoid cells

“…RAGE activation, however, is thought to induce NF-κB nuclear translocation and amplification of downstream signaling pathways (65, 66), including a number of which promote expression of adhesion molecules such as VCAM-1 (67) and ICAM-1 (68). Two studies exploring the relationship between RAGE and ICAM-1 expression on endothelial cells demonstrated complementary roles for ICAM-1 and RAGE in mediating leukocyte adhesion to endothelium (69, 70). It is thus possible that RAGE mediates ILC2 accumulation not directly, but by regulating other downstream mediators such as vascular adhesion molecules.…”

All the “RAGE” in lung disease: The receptor for advanced glycation endproducts (RAGE) is a major mediator of pulmonary inflammatory responses

“…In an animal model of acute peritonitis and subsequent in vitro studies, RAGE was shown to directly bind and recruit leukocytes via interactions with Mac-1 on the white blood cell surface [47]. In a follow-up study, endothelial RAGE was found to bind Mac-1 in conjunction with intercellular adhesion molecule 1 (ICAM-1) to recruit leukocytes into the tissue [62,63]. RAGE was also crucial for leukocyte adhesion in studies using blood cells from preterm infants, suggesting a role for RAGE in young, developing animals that have high receptor expression [64].…”