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Journal Article

Phagocytosis and intracellular killing of MD-2 opsonized Gram-negative bacteria depend on TLR4 signaling

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Jain, V., Halle, A., Halmen, K. A., Lien, E., Charrel-Dennis, M., Ram, S., et al. (2008). Phagocytosis and intracellular killing of MD-2 opsonized Gram-negative bacteria depend on TLR4 signaling. Blood, 111(9), 4637-4645.

Cite as: https://hdl.handle.net/11858/00-001M-0000-0028-647F-3
Both Toll-like receptor 4 (TLR4)- and MD-2-deficient mice succumb to otherwise nonfatal Gram-negative bacteria inocula, demonstrating the pivotal role played by these proteins in antibacterial defense in mammals. MD-2 is a soluble endogenous ligand for TLR4 and a receptor for lipopolysaccharide (LPS). LPS-bound MD-2 transmits an activating signal onto TLR4. In this report, we show that both recombinant and endogenous soluble MD-2 bind tightly to the surface of live Gram-negative bacteria. As a consequence, MD-2 enhances cellular activation, bacterial internalization, and intracellular killing, all in a TLR4-dependent manner. The enhanced internalization of MD-2-coated bacteria was not observed in macrophages expressing Lps(d), a signaling-incompetent mutant form of TLR4, suggesting that the enhanced phagocytosis observed is dependent on signal transduction. The data confirm the notion that soluble MD-2 is a genuine opsonin that enhances proinflammatory opsonophagocytosis by bridging live Gram-negative bacteria to the LPS transducing complex. The presented results extend our understanding of the role of the TLR4/MD-2 signaling axis in bacterial recognition by phagocytes