Contribution of CD11a/CD18, CD11b/CD18, ICAM-1 (CD54) and −2 (CD102) to human monocyte migration through endothelium and connective tissue fibroblast barriers

Abstract

Recently we reported that monocyte migration through a barrier of human synovial fibroblasts (HSF) is mediated by the CD11/CD18 (beta2) integrins, and the beta1 integrins VLA-4 and VLA-5 on monocytes. Here we investigated in parallel the role of beta2 integrin family members, LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) on monocytes, and the immunoglobulin supergene family members, ICAM-1 and ICAM-2 on HSF and on human umbilical vein endothelial cells (HUVEC), in monocyte migration through HSF and HUVEC monolayers. Using function blocking monoclonal antibodies (mAb), when both VLA-4 and VLA-5 on monocytes were blocked, treatment of monocytes with mAb to both LFA-1 and to Mac-1 completely inhibited monocyte migration across HSF barriers, although blocking either of these beta2 integrins alone had no effect on migration, even when VLA-4 and VLA-5 were blocked. This indicates that optimal beta2 integrin-dependent monocyte migration in synovial connective tissue may be mediated by either LFA-1 or Mac-1. Both ICAM-1 and ICAM-2 were constitutively expressed on HSF and on HUVEC, although ICAM-2 was only minimally expressed on HSF. Based on results of mAb blockade, ICAM-1 appeared to be the major ligand for LFA-1-dependent migration through the HSF. In contrast, both ICAM-1 and ICAM-2 mediated LFA-1-dependent monocyte migration through HUVEC. However, neither ICAM-1 nor ICAM-2 was required for Mac-1 -dependent monocyte migration through either cell barrier, indicating that Mac-1 can utilize ligands distinct from ICAM-1 and ICAM-2 on HSF and on HUVEC during monocyte transmigration.

The Cutaneous Reverse Arthus Reaction Requires Intercellular Adhesion Molecule 1 and L-Selectin Expression

“…Augmented ICAM-1 expression is also observed on keratinocytes, fibroblasts, and infiltrating leukocytes in the inflamed skin in vivo (52,53). Furthermore, ICAM-1 expression by fibroblasts may mediate neutrophil migration through fibroblast layers within tissues (54,55), and ICAM-1 expressed on lung epithelial cells supports the adhesion and retention of neutrophils (56). Therefore, it is possible that ICAM-1 expression on cells other than endothelial cells might be involved in the migration or retention of leukocytes within the perivascular area of inflamed skin during the Arthus reaction.…”

β2 integrins are required for skin homing of primed T cells but not for priming naive T cells

“…Since significant numbers of monocytes were present in inflamed skin of CD18 -/-mice, our data suggest that these cells can transmigrate through vascular endothelium using β 2 integrin-independent mechanisms. Likewise, Shang and Issekutz reported that β 1 and β 2 integrins can both mediate monocyte transmigration through a monolayer of synovial fibroblasts (22)(23)(24). Thus, in our experiments, the β 1 integrins VLA-4 and VLA-5, interacting with vascular cell adhesion molecule-1, appear to be able to fully compensate for the lack of functional β 2 integrins on monocytes.…”

Intercellular Adhesion Molecule (ICAM)-1, But Not ICAM-2, Activates RhoA and Stimulates c-fos and rhoA Transcription in Endothelial Cells

“…ICAM-2 can, however, contribute to monocyte transmigration through unstimulated endothelial cell monolayers (8), and transmigration of different T cell populations across ICAM-1-deficient endothelium (9). In the light of this evidence, and because ICAM-2 binds to the leukocyte integrin LFA-1, it had been proposed that ICAM-2 is involved in leukocyte recirculation.…”

“…ICAM-1 is essential for stable adhesion and transmigration of leukocytes in nearly all types of inflammatory response (1), and ICAM-1-deficient mice have impaired inflammatory and immune responses (7). In contrast, in vitro studies indicate that ICAM-2 contributes to leukocyte transendothelial migration under noninflammatory conditions and therefore could play a role in leukocyte recirculation (8,9). Although lymphocyte homing to lymph nodes was apparently unimpaired in ICAM-2-deficient mice (10), it has recently been reported that ICAM-2 plays an important role in mediating DC transmigration across resting endothelium (5), and thus it may contribute to the tissue recruitment of a subset of hemopoietic cell types.…”