The same endothelial receptor controls lymphocyte traffic both in vascular and lymphatic vessels

Abstract

The mechanisms controlling the exit of lymphocytes from tissues via lymphatics are practically unknown. We have now identified a 270-300-kDa molecule designated common lymphatic endothelial and vascular endothelial receptor-1 (CLEVER-1) on human lymphatic endothelium and high endothelial venules. We show that it mediates binding of lymphocytes both to high endothelial venules and to lymphatic vessels. Moreover, blocking of the function of CLEVER-1 results in significant reduction of lymphocyte traffic in vivo. Notably, CLEVER-1 is also an inducible vascular adhesion molecule for other classes of leukocytes at sites of inflammation in peripheral tissues. These findings suggest that CLEVER-1 is involved in regulation of lymphocyte recirculation and migration of leukocytes to sites of inflammation and is a potential new target to control inflammation.

Clever‐1/Stabilin‐1 regulates lymphocyte migration within lymphatics and leukocyte entrance to sites of inflammation

“…The lack or low expression of Clever-1/Stabilin-1 on HEV in mouse is in a striking contrast to the situation in rabbit and man. This is in agreement to our earlier findings obtained using in vitro binding assays, in which we can efficiently block lymphocyte binding to human HEV with anti-Clever-1/Stabilin-1 Ab [8]. Based on our observations Clever-1/Stabilin-1 is practically absent from type II murine macrophages in normal conditions but according to the earlier findings are abundantly present in cancer and wound healing [25].…”

“…The following anti-Clever-1/Stabilin-1 Ab were used: 3-372 Ab recognizing human and rabbit Clever-1/Stabilin-1 [8] and clone 1.26 [25] recognizing mouse Clever-1/Stabilin-1. Negative control Ab used were class-matched (AK1, from In Vivo BioTech Services and NS-1 from ATCC).…”

“…It is also present both on afferent and efferent lymphatic endothelial cells and sinusoidal endothelial cells in the liver and spleen [7][8][9][10]. In man, it is brightly expressed on high endothelial venules (HEV), which are the specific vessels within organized lymphatic tissues mediating lymphocyte entrance into the tissues, and on sinusoidal macrophages.…”

“…Moreover, at sites of inflammation its expression is induced in flat-walled vessels. On lymphatic vasculature it is able to bind lymphocytes and certain tumor cells and on inflamed blood vessel endothelium it can mediate adhesion of lymphocytes, granulocytes and monocytes [8,11]. In vitro analyses have indicated it to be important in the transmigration step during the leukocyte extravasation process [12].…”

“…the injected lymphocytes have had enough time to enter into the draining lymph nodes and most of them have not yet left the node via efferent lymphatics) [17,18]. We first used our function-blocking anti-human Clever-1/Stabilin-1 Ab that cross-reacts with the rabbit homolog [8,12]. Ab treatment efficiently blocked trafficking of normal lymphocytes from the footpad to the popliteal lymph nodes in rabbits ( Fig.…”