Enolase-1 promotes plasminogen-mediated recruitment of monocytes to the acutely inflamed lung

Abstract

Cell surface-associated proteolysis plays a crucial role in the migration of mononuclear phagocytes to sites of inflammation. The glycolytic enzyme enolase-1 (ENO-1) binds plasminogen at the cell surface, enhancing local plasmin production. This study addressed the role played by ENO-1 in lipopolysaccharide (LPS)-driven chemokine-directed monocyte migration and matrix invasion in vitro, as well as recruitment of monocytes to the alveolar compartment in vivo. LPS rapidly up-regulated ENO-1 cell-surface expression on human blood monocytes and U937 cells due to protein translocation from cytosolic pools, which increased plasmin generation, enhanced monocyte migration through epithelial monolayers, and promoted matrix degradation. These effects were abrogated by antibodies directed against the plasminogen binding site of ENO-1. Overexpression of ENO-1 in U937 cells increased their migratory and matrix-penetrating capacity, which was suppressed by overexpression of a truncated ENO-1 variant lacking the plasminogen binding site (ENO-1⌬PLG). In vivo, intratracheal LPS application in mice promoted alveolar recruitment of monocytic cells that overexpressed ENO-1, but not of cells overexpressing ENO-1⌬PLG. Consistent with these data, pneumoniapatients exhibited increased ENO-1 cellsurface expression on blood monocytes and intense ENO-1 staining of mononuclear cells in the alveolar space. These data suggest an important mechanism of inflammatory cell invasion mediated by increased cell-surface expression of ENO-1. (Blood. 2009;113:5588-5598) IntroductionMonocytes are circulating mononuclear phagocytes with a broad spectrum of activities and functions. In pathologic conditions associated with acute or chronic inflammation, monocytes migrate into the affected tissues and differentiate into tissue macrophages. 1,2 Thus, monocytes and tissue macrophages are critical cellular components of the host defense system against infectious diseases, including forms of pneumonia, and have important functions in both native and acquired immunity. They are responsible for the phagocytosis and clearance of invading microorganisms, regulate antimicrobial programs of gene expression, are a potent source of inflammatory cytokines, and interact with T cells through cell-cell or cytokine-mediated mechanisms, thereby facilitating acquired immunity to specific pathogens. [1][2][3][4][5][6][7] In atherosclerosis, monocytes infiltrate atherosclerotic plaques, accumulate lipidrich material, and differentiate into macrophage-type foam cells. 8 Moreover, tumor-infiltrating monocytes may play a role in tumor progression and metastasis by different mechanisms, including regulation of angiogenesis. 9 Many of these activities depend upon the ability of monocytes to localize and regulate cell surfaceassociated proteolytic activity.The enzymes of the fibrinolytic system represent one of the most broadly distributed cell surface-associated protease systems. The accumulation of plasminogen (PLG) and its activators, namely urokinase (u-PA) and tissue-plasminog...

Peptidylarginine deiminase and protein citrullination in prion diseases

“…A well-known function of enolase is the binding of plasminogen, which enhances the activation of plasminogen 55 and facilitates the invasion and dissemination of pathogens into host cells. 56 In addition, plasminogen has (Marburg variant), more than 80% of the MBP containing 18 citrulline residues was citrullinated. 36 However, in other neurological disorders, including AD, Parkinson disease, Huntington disease and amyotrophic lateral sclerosis, the citrullinated form remained at 20% of the total.…”

Treponema denticola enolase contributes to the production of antibodies against ENO1 but not to the progression of periodontitis

“…Gingival tissues with chronic periodontitis are heavily infiltrated with activated T cells, B cells, monocytes, and neutrophils [26]. The anti-ENO1/mEno1 antibodies produced by molecular mimicry would contribute to tissue destruction through the induction of TNFα from activated leukocytes and immune complex-mediated tissue injury [15,16]. Meanwhile, as shown in T. forsythia and Streptococcus pneumoniae , bacterial enolases have pathogenic potential because they facilitate bacterial invasion and induce inflammatory cytokine production in monocytes [27,28].…”

“…Antibodies to ENO1 have been reported in a variety of infectious and autoimmune diseases, including RA [14]. Although ENO1 is a glycolytic enzyme ubiquitously expressed in the cytosol, it is also expressed on the surface of stimulated leukocytes, such as neutrophils, lymphocytes, and monocytes [15]. Inflammatory stimuli induce rapid translocation of ENO1 from the cytosol to the cell surface, and cell-surface ENO1 serves as a receptor and activator of plasminogen, which assists inflammatory cell infiltration [15].…”

“…Although ENO1 is a glycolytic enzyme ubiquitously expressed in the cytosol, it is also expressed on the surface of stimulated leukocytes, such as neutrophils, lymphocytes, and monocytes [15]. Inflammatory stimuli induce rapid translocation of ENO1 from the cytosol to the cell surface, and cell-surface ENO1 serves as a receptor and activator of plasminogen, which assists inflammatory cell infiltration [15]. In addition, stimulation of cell surface ENO1 with anti-ENO1 antibodies induces the robust production of inflammatory cytokines from mononuclear leukocytes [16].…”

Caught in the act – protein adaptation and the expanding roles of the PACS proteins in tissue homeostasis and disease

“…Human GAPDH participates in as many as 20 different cellular functions ranging from the regulation of membrane traffic to the maintenance of genome integrity (Sirover, 2011). Human enolase can be present on the cell surface of activated monocytes where it serves as a plasminogen receptor that promotes recruitment of inflammatory cells to sites of tissue injury (Wygrecka et al, 2009).…”