Gangliosides trigger inflammatory responses via TLR4 in brain glia.
Gangliosides participate in various cellular events of the central nervous system and have been closely implicated in many neuronal diseases. However, the precise molecular mechanisms underlying the pathological activity of gangliosides are poorly understood. Here we report that toll-like receptor 4 (TLR4) may mediate the ganglioside-triggered inflammation in glia, brain resident immune cells. Gangliosides rapidly altered the cell surface expression of TLR4 in microglia and astrocytes within 3 hours. Using TLR4-specific siRNA and a dominant-negative TLR4 gene, we clearly demonstrate the functional importance of TLR4 in ganglioside-triggered activation of glia. Inhibition of TLR4 expression by TLR4-siRNA suppressed nuclear factor (NF)-kappaB-binding activity, NF-kappaB-dependent luciferase activity, and transcription of inflammatory cytokines after exposure to gangliosides. Transient transfection of dominant-negative TLR4 also attenuated NF-kappaB-binding activity and interleukin-6 promoter activity. In contrast, these activities were slightly elevated in cells with wild-type TLR4. In addition, CD14 was required for ganglioside-triggered activation of glia, and lipid raft formation may be associated with ganglioside-stimulated signal propagation. Taken together, these results suggest that TLR4 may provide an explanation for the pathological ability of gangliosides to cause inflammatory conditions in the brain.
Jou
Ilo
I
Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon, 443-721, Korea.
Lee
Jee Hoon
JH
Park
Soo Young
SY
Yoon
Hee Jung
HJ
Joe
Eun-Hye
EH
Park
Eun Jung
EJ
D000818:Animals; D001921:Brain / Q000166:cytology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D016207:Cytokines / Q000235:genetics; D005732:Gangliosides / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced*; D015850:Interleukin-6 / Q000235:genetics; D018950:Lipopolysaccharide Receptors / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D021962:Membrane Microdomains / Q000502:physiology; D018448:Models, Immunological; D019158:N-Acetylneuraminic Acid / Q000502:physiology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism*; D017942:Nitric Acid / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
D016207:Cytokines; D005732:Gangliosides; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D051197:Toll-Like Receptor 4; D017942:Nitric Acid; D019158:N-Acetylneuraminic Acid