Leukocyte cell surface proteinases: Regulation of expression, functions, and mechanisms of surface localization

Abstract

A number of proteinases are expressed on the surface of leukocytes including members of the serine, metallo-, and cysteine proteinase superfamilies. Some proteinases are anchored to the plasma membrane of leukocytes by a transmembrane domain or a glycosyl phosphatidyl inositol (GPI) anchor. Other proteinases bind with high affinity to classical receptors, or with lower affinity to integrins, proteoglycans, or other leukocyte surface molecules. Leukocyte surface levels of proteinases are regulated by: (1) cytokines, chemokines, bacterial products, and growth factors which stimulate synthesis and/or release of proteinases by cells; (2) the availability of surface binding sites for proteinases; and/or (3) internalization or shedding of surface-bound proteinases. The binding of proteinases to leukocyte surfaces serves many functions including: (1) concentrating the activity of proteinases to the immediate pericellular environment; (2) facilitating pro-enzyme activation; (3) increasing proteinase stability and retention in the extracellular space; (4) regulating leukocyte function by proteinases signaling through cell surface binding sites or other surface proteins; and (5) protecting proteinases from inhibition by extracellular proteinase inhibitors. There is strong evidence that membrane-associated proteinases on leukocytes play critical roles in wound healing, inflammation, extracellular matrix remodeling, fibrinolysis, and coagulation. This review will outline the biology of membrane-associated proteinases expressed by leukocytes and their roles in physiologic and pathologic processes.

Introduction

Leukocytes and resident tissue cells produce a diverse array of proteinases that contribute to physiologic processes such as extracellular matrix (ECM) remodeling, wound healing, inflammation, coagulation, fibrinolysis, host defense against infection, and various pathologic processes. Until recently, there has been little information available about the mechanisms by which cells use and control their proteinases to degrade extracellular proteins in vivo. Proteinases must circumvent the effects of high-affinity, extracellular proteinase inhibitors in order to cleave extracellular proteins. Inflammatory cells bathed in fluids containing physiologic proteinase inhibitors are associated with pericellular proteolysis (Fig. 1). One mechanism that enables cells to cleave or degrade proteins in their immediate environment is the localization of proteinases on cell surfaces. In vertebrates, serine, metallo-, and cysteine proteinases are expressed on the surfaces of various cell types including leukocytes, fibroblasts, epithelial cells, endothelial cells, and tumor cells (Table 1). These enzymes include members of the serine proteinase superfamily such as the leukocyte serine proteinases, proteinases involved in fibrinolysis, the type II transmembrane serine protease (TTSP) family (Qiu, Owen, Gray, Bass, & Ellis, 2007; Szabo et al., 2003), and the kallikrein/kinin system [reviewed in Schmaier & McCrae, 2007]. Serine proteases involved in the coagulation cascades can also bind to endothelial, platelet, and leukocyte cell surfaces [reviewed in Bouchard & Tracy, 2001; Doshi & Marmur, 2002 and Table 1]. Metalloproteinases and lysosomal cysteine proteinases also function as cell membrane-associated enzymes (Cavallo-Medved & Sloane, 2003). Space limitations of the journal preclude comprehensive coverage of all proteinases known to be expressed on the surface of all types of cells. Because of my interest in leukocyte-proteinase-mediated tissue injury, I will focus this review on proteinases expressed on the surface of leukocytes that play important roles in leukocyte biology. I will review the biology of leukocyte surface-bound proteinases, the advantages that cell surface binding confers upon individual proteinases, and the roles of leukocyte membrane-associated proteinases in physiologic and pathologic processes.