The mast cell tumor necrosis factor α response to FimH-expressingEscherichia coliis mediated by the glycosylphosphatidylinositol-anchored molecule CD48

Abstract

Mast cells are well known for their harmful role in IgE-mediated hypersensitivity reactions, but their physiological role remains a mystery. Several recent studies have reported that mast cells play a critical role in innate immunity in mice by releasing tumor necrosis factor ␣ (TNF-␣) to recruit neutrophils to sites of enterobacterial infection. In some cases, the mast cell TNF-␣ response was triggered when these cells directly bound FimH on the surface of Escherichia coli. We have identified CD48, a glycosylphosphatidylinositol-anchored molecule, to be the complementary FimH-binding moiety in rodent mast cell membrane fractions. We showed that (i) pretreatment of mast cell membranes with antibodies to CD48 or phospholipase C inhibited binding of FimH ؉ E. coli, (ii) FimH ؉ E. coli but not a FimH ؊ derivative bound isolated CD48 in a mannose-inhibitable manner, (iii) binding of FimH ؉ bacteria to Chinese hamster ovary (CHO) cells was markedly increased when these cells were transfected with CD48 cDNA, and (iv) antibodies to CD48 specifically blocked the mast cell TNF-␣ response to FimH ؉ E. coli. Thus, CD48 is a functionally relevant microbial receptor on mast cells that plays a role in triggering inf lammation.

Does β-Hexosaminidase Function Only as a Degranulation Indicator in Mast Cells? The Primary Role of β-Hexosaminidase in Mast Cell Granules

“…Other enzymes, such as proteases, are known to exert microbicidal effects through cytokine production (42)(43)(44). Our findings in this study imply that proteases may not be the primary antimicrobial component in mast cells.…”

“…For instance, mast cells sense the type 1 fimbriae of E. coli through surface-expressed CD48, resulting in release of the potent neutrophil chemoattractant TNF-a in a process that is pivotal for elimination of the bacteria (42). Additionally, mast cell tryptase b I reportedly plays a central role in the host defenses of the lung by recruiting neutrophils (43), and cecal ligation and puncture models demonstrated that mast cell chymase is essential for survival in cases of septic peritonitis (44).…”

A Comparison of Reactive Oxygen Species Generation by Rat Peritoneal Macrophages and Mast Cells Using the Highly Sensitive Real-Time Chemiluminescent Probe Pholasin: Inhibition of Antigen-Induced Mast Cell Degranulation by Macrophage-Derived Hydrogen Peroxide

“…In specific immunity, they respond to Ag via receptor-bound IgE to release multiple mediators including histamine, eicosanoids, and cytokines, which together contribute to immediate allergic reactions and inflammatory cell recruitment (1,2). In innate immunity, mast cells release TNF in response to direct interaction with bacterial adhesion molecules, and this cytokine induces neutrophil recruitment with subsequent bacterial clearance through phagocytosis (3)(4)(5). A key element of phagocytosis and killing of bacteria, and possibly of importance also in mediating and regulating inflammation, is the production of reactive oxygen species (ROS) 3 (6 -8).…”

“…NADPH oxidase of phagocytic cells can also be activated by protein kinase C agonists such as PMA (12). Because mast cells are pivotal to neutrophil-mediated defense against certain bacteria (3)(4)(5) and both neutrophils and macrophages phagocytose and kill bacteria by ROS production (9 -11), the possible contribution of mast cells themselves to ROS production is an important issue. Although mucosal mast cells can phagocytose and kill bacteria, evidently via generation of ROS (13), the question of whether mast cell ROS generation accompanies degranulation is less clear cut.…”

Internalization of FimH+ Escherichia coli by the human mast cell line (HMC-1 5C6) involves protein kinase C

“…It was recently shown that mouse mast cells bind various enteric bacteria by specifically recognizing a 29-kDa mannose-binding lectin, FimH [3], presented on the tips of hair-like appendages of the bacteria [35]. The identity of the FimH binding moiety on the rodent mast cell membrane was recently shown to be CD48, a GPI-linked moiety of the immunoglobulin superfamily [36]. This study attempted to identify the ligand in the bacteria responsible for binding of human mast cells.…”