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

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Division of Infectious Diseases and Immunology

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Animals; Gram-Negative Bacteria; Lymphocyte Antigen 96; Mice; Opsonin Proteins; *Phagocytosis; Signal Transduction; Toll-Like Receptor 4


Life Sciences | Medicine and Health Sciences


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.

DOI of Published Version



Blood. 2008 May 1;111(9):4637-45. Epub 2008 Jan 18. Link to article on publisher's site

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