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Free keywords:
ALTERNATIVELY SPLICED SEGMENTS; CEREBROSPINAL-FLUID;
STAPHYLOCOCCUS-AUREUS; POLYMORPHONUCLEAR NEUTROPHILS;
BACTERIAL-MENINGITIS; BINDING PROTEIN; IN-VIVO; INTEGRIN; ISOFORM; CELLSInnate immunity; Bacterial infection; Phagocytosis; Fibronectin; EDB;
EIIIB; alpha v beta 3 integrin; Circulation; Plasma fibronectin;
Abstract:
Plasma fibronectin is a circulating protein that facilitates phagocytosis by connecting bacteria to immune cells. A fibronectin isoform, which includes a sequence of 90 AA called extra-domain B (EDB), is synthesized de novo at the messenger RNA (mRNA) level in immune cells, but the reason for its expression remains elusive. We detected an 80-fold increase in EDB-containing fibronectin in the cerebrospinal fluid of patients with bacterial meningitis that was most pronounced in staphylococcal infections. A role for this isoform in phagocytosis was further suggested by enhanced EDB fibronectin release after internalization of Staphylococcus aureus in vitro. Using transgenic mouse models, we established that immune cell production of fibronectin contributes to phagocytosis, more so than circulating plasma fibronectin, and that accentuated release of EDB-containing fibronectin by immune cells improved phagocytosis. In line with this, administration of EDB fibronectin enhanced in vitro phagocytosis to a larger extent than plasma fibronectin. This enhancement was mediated by alpha v beta 3 integrin as shown using inhibitors or cells from beta 3 integrin knockout mice. Thus, we identified both a novel function for EDB fibronectin in augmenting phagocytosis over circulating plasma fibronectin, as well as the mediating receptor. Our data also establish for the first time, a direct role for beta 3 integrin in bacterial phagocytosis in mammals.
aEuro cent Fibronectin containing an extra domain called EDB is released in bacterial meningitis.
aEuro cent EDB-containing fibronectin enhances phagocytosis more than plasma fibronectin.
aEuro cent The enhancement is mediated by activation of alpha v beta 3 integrin in the presence of EDB.
