The Toll-Like Receptor TLR4 Is Necessary for Lipopolysaccharide-Induced Oligodendrocyte Injury in the CNS

Abstract

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.

The Synthetic Peroxisome Proliferator-Activated Receptor-γ Agonist Ciglitazone Attenuates Neuroinflammation and Accelerates Encapsulation in Bacterial Brain Abscesses

“…However, the sustained production of these same mediators can also negatively impact cellular survival as demonstrated by others (31)(32)(33)(34)(35)(36). Based on the fact that proinflammatory mediator expression continues during the later stages of brain abscess in the face of relatively few surviving bacteria (22), we propose that this persistent cytokine response is deleterious, possibly confounding disease through the exaggerated destruction of normal brain parenchyma surrounding the abscess.…”

TLR Ligands in the Local Treatment of Established Intracerebral Murine Gliomas

“…We indicate that higher amounts of LPS (Ͼ 5 g/mouse) were not used in this study to minimize the potential risk of acute neurotoxicity (50,51). Moreover, as previously demonstrated in a different murine glioma model, even higher amounts of LPS (100 g/mouse) only showed modest antitumoral effects after local administration and failed to induce long-term survivors (52).…”

Anti-inflammatory effects of 8-hydroxydeoxyguanosine in LPS-induced microglia activation: suppression of STAT3-mediated intercellular adhesion molecule-1 expression

“…This reaction is critical to the innate immune response . TLR4 is traditionally accepted as the primary (LPS) receptor (Lien et al, 2000) and has been reported to be critical for the microglial response to LPS (Lehnardt et al, 2002). It has been reported that LPS is effective in rapidly up-regulating the expression of the endothelial ICAM-1 and the vascular cell-adhesion molecule (VCAM) (Bell et al, 1995).…”

“…Activated microglia are observed in various neurological diseases, multiple sclerosis, and Alzheimer's disease (Kreutzberg et al, 1996). The Toll-like receptor 4 (TLR4) is traditionally accepted as the primary (LPS) receptor (Lien et al, 2000) and has been reported as critical for the microglial response to LPS (Lehnardt et al, 2002). Thus, it may be functionally important to tightly regulate the degree of microglial activation after injury and during inflammatory disease.…”