Annexin II mediates plasminogen-dependent matrix invasion by human monocytes: enhanced expression by macrophages

Abstract

Monocytes and macrophages participate in a wide variety of host defense mechanisms. Annexin II, a fibrinolytic receptor, binds plasminogen and tissue plasminogen activator (t-PA) independently at the cell surface, thereby enhancing the catalytic efficiency of plasmin production. We demonstrated previously that annexin II on the surface of both cultured monocytoid cells and monocyte-derived macrophages promotes their ability to remodel extracellular matrix. Here, we demonstrate that human peripheral blood monocytes represent the major circulating annexin II-expressing cell. Annexin II supported t-PA-dependent generation of cell surface plasmin and the matrixpenetrating activity of human monocytes. Compared to polymorphonuclear leukocytes, monocytes supported a 12.9-fold greater rate of plasmin generation in the presence of exogenous t-PA, and this activity was largely attributable to annexin II. Likewise, anti-annexin II IgG directed against the t-PA-binding tail domain inhibited plasminogen-dependent, cytokine-directed monocyte migration through extracellular matrix. On differentiation of monocytes to macrophages, there was a 2.4-fold increase in annexin II-specific mRNA, and a 7.9-fold increase in surface annexin II. Thioglycolate-elicited peritoneal macrophages, furthermore, displayed an additional 3.8-fold increase in annexin II surface expression compared with resident cells. Thus, annexin II-mediated assembly of plasminogen and t-PA on monocyte/macrophages contributes to plasmin generation, matrix remodeling, and directed migration. IntroductionAnnexin II belongs to a family of widely distributed, phospholipidbinding, calcium-regulated, peripheral membrane proteins known as the annexins. 1 Annexin II is richly expressed in the epithelial cells of intestine and lung and is also found on the cell surface of vascular endothelial cells, myelomonocytic leukemia cells, 2 and cells of several monocyte-like lines. 3 Through the expression of independent binding sites for both plasminogen and tissue plasminogen activator (t-PA), annexin II assembles these 2 proteins on the cell surface, thereby accelerating the production of plasmin. 4 Kinetic studies indicate that annexin II enhances the catalytic efficiency (k cat /K m ) of t-PA-dependent plasminogen activation by 60-fold, 5 suggesting that endothelial cell surface generation of plasmin likely contributes to fibrinolytic surveillance, thereby promoting blood vessel patency.Monocytes and macrophages are large, motile, phagocytic cells that have a wide range of biosynthetic and secretory activities depending on their exposure to local stimuli and mediators. 6 They participate routinely in host defense mechanisms, including antigen presentation and clearance of debris, and contribute critically to acute and chronic inflammatory responses, pathogen clearance, and wound healing. 7,8 In many pathologic processes, such as atherosclerosis or disorders of lipid metabolism, furthermore, lipid-laden macrophages accumulate in tissues. 9 The monocyte/macrophage, moreover, ma...

Proteomic analysis in monocytes of antiphospholipid syndrome patients: Deregulation of proteins related to the development of thrombosis

“…By functioning as a receptor for ␤ 2 GPI, annexin II is a target not only for anti-annexin II antibodies but also for anti-␤ 2 GPI antibodies, which are direct inducers of TF overexpression and thus are significantly associated with thrombosis in the setting of APS (18). Recently, it has also been demonstrated that annexin II plays an important role in human monocyte/macrophage-directed migration and recruitment and that it is activated on progression from monocytes to macrophages (24). Thus, annexin II might constitute a common receptor for aPL induction of monocyte activation.…”

Urokinase-Type Plasminogen Activator Stimulation of Monocyte Matrix Metalloproteinase-1 Production Is Mediated by Plasmin-Dependent Signaling through Annexin A2 and Inhibited by Inactive Plasmin

“…Recently, the annexin A2 heterotetramer has been identified as a receptor for plasmin-induced signaling in human monocytes (25). Moreover, annexin A2 has been linked to plasminogen-dependent matrix invasion by monocytes (46,47). Annexin A2, a member of a family of proteins that bind anionic phospholipids in a Ca 2ϩ -dependent manner, exists in three forms, a monomer (p36), a heterodimer, or a heterotetramer.…”

Role of Annexin A2 in the EGF-induced epithelial-mesenchymal transition in human CaSki cells

“…Previous studies have implicated ANXA2 in various biological functions, including mitogenic signal transduction, fibrinolysis, immune response, proliferation, carcinogenesis and tumor progression (7)(8)(9)(10)(11). ANXA2 has been demonstrated to be a co-receptor for both plasminogen and tissue-type plasminogen activator, which cleaves inactive plasminogen to yield the active serine proteinase, plasmin (12,13). Subsequent studies elucidated that the conversion of plasminogen to plasmin is induced by ANXA2 promoting metastasis, which leads to the activation of metalloproteinases, degradation of extracellular matrix components, and promotion of neoangiogenesis (14)(15)(16)(17).…”