Migration of leukocytes across endothelium and beyond: molecules involved in the transmigration and fate of monocytes.

Passage of leukocytes across the endothelial lining into sites of inflammation has been shown to be regulated largely by platelet/endothelial cell adhesion molecule-1 (PECAM/CD31). We summarize recent work from our laboratory documenting that PECAM is involved both in diapedesis and the subsequent step of migration across the basal lamina. The former process involves a homophilic interaction between the amino-terminal extracellular domains of PECAM on the leukocyte and on the endothelial cell. The latter process involves a heterophilic interaction between the membrane-proximal extracellular domain of PECAM and an unknown ligand(s) in the subendothelial basal lamina. These findings are demonstrated in both in vitro and in vivo models. For monocytes, however, transmigration is just the first step in the next phase of their lives. In addition to their specific recruitment during the inflammatory response, many monocytes constitutively leave the bloodstream to enter tissues. However, only a fraction of these become tissue macrophages. In an in vitro model of monocyte emigration, approximately half of the leukocytes that initially transmigrate an endothelial monolayer migrate back out in the basal-to-apical direction within the next 2 days. This reverse transmigration cannot be blocked by anti-PECAM reagents, but involves p-glycoprotein and tissue factor expressed on the leukocytes. The reverse transmigrating cells are phenotypically dendritic cells (DC). Their maturation to mature DC can be accelerated by inclusion of inflammatory stimuli in the co-culture. The cells that remain behind in the subendothelial collagen are phenotypically macrophages. We postulate that a major source of DC in lymph nodes is cells derived from monocytes that enter a tissue via the blood and leave several days later via afferent lymphatic channels.