Regulation of monocyte migration by amphoterin (HMGB1)

Abstract

Amphoterin (HMGB1) is a 30-kD heparinbinding protein involved in process extension and migration of cells by a mechanism involving the receptor for advanced glycation end products (RAGE). High levels of amphoterin are released to serum during septic shock. We have studied the expression of amphoterin in monocytes and the role of amphoterin and RAGE in monocyte transendothelial migration. Unactivated monocytes in suspension did not reveal amphoterin on their surface, but adherent monocytes exported amphoterin to the cell surface. Immunohistochemical staining of arterial thrombi in vivo revealed amphoterin in mononuclear cells and in surrounding extracellular matrix. Amphoterin was secreted from phorbol ester and interferon-␥ (IFN-␥)-activated macrophages, and the secretion was inhibited by blocking the adenosine 5-triphosphate (ATP)-binding cassette transporter-1, a member of the multidrug resistance protein family. Amphoterin was specifically adhesive for monocytes in peripheral blood leukocyte adhesion assay. Adhesion caused an extensive spreading of cells, which was inhibited by the dominant-negative RAGE receptor (soluble ectodomain of RAGE), and adhesion up-regulated chromogranin expression in monocytes, also suggesting a RAGE-dependent interaction. Monocyte transendothelial migration was efficiently inhibited by anti-amphoterin and anti-RAGE antibodies and by the soluble RAGE. We suggest that amphoterin is an autocrine/paracrine regulator of monocyte invasion through the endothelium. IntroductionCirculating monocytes adhere to sites of vascular injury where they participate together with other cells in the regulation of blood clotting, inflammation, and wound healing. Adhesion to other cells and extracellular matrix components is a prerequisite for migration and tissue recruitment of monocytes. 1,2 The knowledge of molecules involved in monocyte transendothelial migration is rapidly increasing. However, the overall picture of the transendothelial migration mechanism is not completely understood. 2 Amphoterin is a 30-kD heparin-binding protein widely expressed in humans and other organisms, and it is abundantly expressed in the developing brain as well as in various immature and transformed cell lines. [3][4][5][6] It was isolated as an extracellular neurite outgrowth-promoting protein, but its amino acid sequence turned out to be identical to high-mobility groupϪ1 protein. 5,7 In a new nomenclature of high-mobility group proteins amphoterin and other proteins identical in the cDNA sequence are called as HMGB1 (high-mobility group B-1). 8 We have used the designation amphoterin for the protein occurring in the extracellular space and interacting with the cell surface. 5 Surface-bound amphoterin is adhesive for neural cells and platelets, and it induces extension of membrane processes in adherent cells. 3,9,10 Amphoterin binds to plasma membrane lipids, mainly to phosphatidylserine and sulfatide, and enhances and localizes plasminogen activation. 6,9,[11][12][13] In neurons, neurite outgrowth on amphoterin s...

Serum Amyloid A Induces Monocyte Tissue Factor

“…Importantly, SAAinduced monocyte TF was markedly inhibited by anti-RAGE IgG, confirming RAGE involvement. In contrast, another proinflammatory RAGE ligand, HMGB1 (34,57), although capable of binding sRAGE (Fig. 6E), and of inducing MCP-1 mRNA (Fig.…”

High mobility group box 1 protein as a marker of hepatocellular injury in human liver transplantation

“…27 Active HMGB1 secretion from phagocytes displays delayed kinetics. 3,9,20 In experimental models of endotoxemia, HMGB1 levels increase 12 to 18 hours after peak TNF-␣ levels. 10 This delayed active HMGB1 release may partly explain some of our findings.…”

“…This does not, however, exclude neutrophils as a potential source of HMGB1 in liver transplantation. Because of the substantial delay in HMGB1 secretion from activated phagocytes, 3,9,20 it is possible that neutrophils sequestered into the graft during reperfusion may not have expressed HMGB1 at the time of liver biopsy, a few hours after reperfusion. Although we could not obtain blood samples across the hepatic circulation postoper- atively to investigate hepatic HMGB1 release, HMGB1 levels in systemic circulation declined rapidly after reperfusion, and postoperatively, HMGB1 was undetectable in most patients.…”

“…During liver transplantation, systemic arterial (A) blood samples were collected after induction of anesthesia but before surgery (A0), immediately before initial reperfusion of the graft with portal blood (A1), 10 minutes after portal vein declamping (A2), 10 minutes after hepatic artery declamping (A3), and 8, 24, and 48 hours after reperfusion. To assess changes across the graft, blood sam- 12,20 Normal plasma samples containing known amounts of recombinant HMGB1 were analyzed equally in each gel, and a standard curve was generated to calculate sample HMGB1 levels.…”

Amyloid β Interaction with Receptor for Advanced Glycation End Products Up-Regulates Brain Endothelial CCR5 Expression and Promotes T Cells Crossing the Blood-Brain Barrier

“…Through RAGE, some ligands can bind to mononuclear phagocytes and modify their functions, including expression of key inflammatory mediators (67)(68)(69)(70). Inhibition of RAGE in T cells has been found to markedly decrease its infiltration in the brain, leading to suppression of experimental autoimmune encephalomyelitis (71).…”