Fatty acids modulate Toll-like receptor 4 activation through regulation of receptor dimerization and recruitment into lipid rafts in a reactive oxygen species-dependent manner.
The saturated fatty acids acylated on Lipid A of lipopolysaccharide (LPS) or bacterial lipoproteins play critical roles in ligand recognition and receptor activation for Toll-like Receptor 4 (TLR4) and TLR2. The results from our previous studies demonstrated that saturated and polyunsaturated fatty acids reciprocally modulate the activation of TLR4. However, the underlying mechanism has not been understood. Here, we report for the first time that the saturated fatty acid lauric acid induced dimerization and recruitment of TLR4 into lipid rafts, however, dimerization was not observed in non-lipid raft fractions. Similarly, LPS and lauric acid enhanced the association of TLR4 with MD-2 and downstream adaptor molecules, TRIF and MyD88, into lipid rafts leading to the activation of downstream signaling pathways and target gene expression. However, docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, inhibited LPS- or lauric acid-induced dimerization and recruitment of TLR4 into lipid raft fractions. Together, these results demonstrate that lauric acid and DHA reciprocally modulate TLR4 activation by regulation of the dimerization and recruitment of TLR4 into lipid rafts. In addition, we showed that TLR4 recruitment to lipid rafts and dimerization were coupled events mediated at least in part by NADPH oxidase-dependent reactive oxygen species generation. These results provide a new insight in understanding the mechanism by which fatty acids differentially modulate TLR4-mediated signaling pathway and consequent inflammatory responses which are implicated in the development and progression of many chronic diseases.
Wong
Scott W
SW
Western Human Nutrition Research Center, the Agricultural Research Service (ARS)-United States Department of Agriculture, and Department of Nutrition, University of California, Davis, California 95616, USA.
Kwon
Myung-Ja
MJ
Choi
Augustine M K
AM
Kim
Hong-Pyo
HP
Nakahira
Kiichi
K
Hwang
Daniel H
DH
D000818:Animals; D002460:Cell Line; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology*; D006801:Humans; D007850:Lauric Acids / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051218:Lymphocyte Antigen 96 / Q000378:metabolism; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects*; D020836:Protein Structure, Quaternary / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000737:chemistry* / Q000378:metabolism*
D005227:Fatty Acids; D007850:Lauric Acids; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D017382:Reactive Oxygen Species; D051197:Toll-Like Receptor 4; C030358:lauric acid; D004281:Docosahexaenoic Acids; D019255:NADPH Oxidases