The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS.
The immediate or innate immune response is the first line of defense against diverse microbial pathogens and requires the expression of recently discovered toll-like receptors (TLRs). TLR4 serves as a specific receptor for lipopolysaccharide (LPS) and is localized on the surface of a subset of mammalian cells. Although innate immunity is a necessary host defense against microbial pathogens, the consequences of its activation in the CNS can be deleterious, as we show here in a developing neural model. We examined the major non-neuronal cell types in the CNS for expression of TLR4 and found that microglia expressed high levels, whereas astrocytes and oligodendrocytes expressed none. Consistent with TLR4 expression solely in microglia, we show that microglia are the only CNS glial cells that bind fluorescently tagged lipopolysaccharide. Lipopolysaccharide led to extensive oligodendrocyte death in culture only under conditions in which microglia were present. To determine whether TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte death in mixed glial cultures, we studied cultures generated from mice bearing a loss-of-function mutation in the tlr4 gene. Lipopolysaccharide failed to induce oligodendrocyte death in such cultures, in contrast to the death induced in cultures from wild-type mice. Finally, stereotactic intracerebral injection of lipopolysaccharide into the developing pericallosal white matter of immature rodents resulted in loss of oligodendrocytes and hypomyelination and periventricular cysts. Our data provide a general mechanistic link between (1) lipopolysaccharide and similar microbial molecular motifs and (2) injury to oligodendrocytes and myelin as occurs in periventricular leukomalacia and multiple sclerosis.
Lehnardt
Seija
S
Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
Lachance
Christian
C
Patrizi
Silvia
S
Lefebvre
Sharon
S
Follett
Pamela L
PL
Jensen
Frances E
FE
Rosenberg
Paul A
PA
Volpe
Joseph J
JJ
Vartanian
Timothy
T
D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D029721:Drosophila Proteins; D007113:Immunity, Innate; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D008845:Microinjections; D018448:Models, Immunological; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000473:pathology; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013379:Substrate Specificity; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D029721:Drosophila Proteins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors