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Blood, 1 May 2008, Vol. 111, No. 9, pp. 4637-4645.
Prepublished online as a Blood First Edition Paper on January 18, 2008; DOI 10.1182/blood-2007-11-126862.
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IMMUNOBIOLOGY
Phagocytosis and intracellular killing of MD-2 opsonized Gram-negative bacteria depend on TLR4 signaling
Vishal Jain1,
Annett Halle1,
Kristen A. Halmen1,
Egil Lien1,
Marie Charrel-Dennis1,
Sanjay Ram1,
Douglas T. Golenbock*,1, and
Alberto Visintin*,1
1 Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester
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 Lpsd, 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.
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