The Journal of Experimental Medicine
Rockland Immunochemicals for Research
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Published online 17 July 2006 doi:10.1084/jem.20060943
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 8, 1951-1961
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ARTICLE

 Oxidative stress generated by hemorrhagic shock recruits Toll-like receptor 4 to the plasma membrane in macrophages

Kinga A. Powers, Katalin Szászi, Rachel G. Khadaroo, Patrick S. Tawadros, John C. Marshall, András Kapus, and Ori D. Rotstein

Departments of Surgery, St. Michael's Hospital and University Health Network, and Department of Surgery, University of Toronto, Toronto, Ontario, M5G 2C1, Canada

CORRESPONDENCE Ori D. Rotstein: rotsteino{at}smh.toronto.on.ca

Oxidative stress generated by ischemia/reperfusion is known to prime inflammatory cells for increased responsiveness to subsequent stimuli, such as lipopolysaccharide (LPS). The mechanism(s) underlying this effect remains poorly elucidated. These studies show that alveolar macrophages recovered from rodents subjected to hemorrhagic shock/resuscitation expressed increased surface levels of Toll-like receptor 4 (TLR4), an effect inhibited by adding the antioxidant N-acetylcysteine to the resuscitation fluid. Consistent with a role for oxidative stress in this effect, in vitro H2O2 treatment of RAW 264.7 macrophages similarly caused an increase in surface TLR4. The H2O2-induced increase in surface TLR4 was prevented by depleting intracellular calcium or disrupting the cytoskeleton, suggesting the involvement of receptor exocytosis. Further, fluorescent resonance energy transfer between TLR4 and the raft marker GM1 as well as biochemical analysis of the raft components demonstrated that oxidative stress redistributes TLR4 to lipid rafts in the plasma membrane. Preventing the oxidant-induced movement of TLR4 to lipid rafts using methyl-ß-cyclodextrin precluded the increased responsiveness of cells to LPS after H2O2 treatment. Collectively, these studies suggest a novel mechanism whereby oxidative stress might prime the responsiveness of cells of the innate immune system.

Abbreviations used: AM, alveolar macrophage; BAPTA/AM, 1,2-bis-(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester; CTxB, cholera toxin B; FRET, fluorescent resonance energy transfer; MßCD, methyl-ß-cyclodextrin; MyD88, myeloid differentiation primary response gene 88; NAC, N-acetylcysteine; S/R, shock/resuscitation; TLR4, Toll-like receptor 4.


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