Powers KA, Szaszi K, Khadaroo RG, Tawadros PS, Marshall JC, Kapus A, Rotstein ODOxidative stress generated by hemorrhagic shock recruits Toll-like receptor 4 to the plasma membrane in macrophages. J Exp Med 203:1951-1961

Departments of Surgery, St. Michael's Hospital and University Health Network, and Department of Surgery, University of Toronto, Toronto, Ontario, M5G 2C1, Canada
Journal of Experimental Medicine (Impact Factor: 12.52). 09/2006; 203(8):1951-61. DOI: 10.1084/jem.20060943
Source: PubMed


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-beta-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.

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Available from: Katalin Szaszi, Jul 24, 2014
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    • "TLRs can either be activated by microbial compounds or cellular debris in the context of IR injury [42, 45–47]. One of the most widely investigated pattern recognition molecules is TLR4 usually mediating inflammatory response to gram negative lipopolysaccharide particles (LPS); however, TLR4 activation is significantly enhanced by oxidative stress occurring during IR injury [59]. TAK-242, an inhibitor of TLR4, shows efficacy in reduction of IR injury in large animal trials [60] (Table 4). "
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    • "It has also been shown that lipid raft formation is involved in cell activation induced by oxidized lipids[38], production of pro-inflammatory cytokines[39] and uptake of acetyl LDL[40]. The following results indicate that the interaction of CD36 and PAFR occurs within lipid raft domains of the BMDM membrane: a) Disruption of lipid rafts by treatment with MβCD reduced the oxLDL uptake and IL-10 production; b) oxLDL induced co-immunoprecipitation of PAFR and CD36 with the constitutive raft protein, flotillin-1[23] and colocalization of PAFR and CD36 with the lipid raft marker GM1-ganglioside[41]. Data presented by others have been shown that CD36 is recruited to lipid rafts in a ligand-dependent manner[22,42]. "
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