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

By S. Lehnardt, C. Lachance, Silvia Patrizi, S. Lefebvre, Pamela L. Follett, F. Jensen, P. Rosenberg, Joseph J. Volpe, T. Vartanian. Journal of Neuroscience, 2002

689 citations recorded by the source corpus.

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.

Subfields: Immunology, Neurology, Pediatrics, Perinatology and Child Health

View Paper: https://www.semanticscholar.org/paper/d290341b4a7efa62fbb513ab44500211619a34f2

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. M. Block
2. Jau-Shyong Hong
3. Yuanqing Liu
4. S. Rivest
5. S. Lehnardt
6. Céline Vaure
7. P. Carpentier
8. T. Palmer

In Neurology

1. M. Block
2. S. Lehnardt
3. Jau-Shyong Hong
4. S. Rivest
5. A. Bessis
6. P. Carpentier
7. T. Palmer
8. P. Whitton

Citations in the corpus

• Microglia-mediated neurotoxicity: uncovering the molecular mechanisms (2007, background): “, and is reported to be a crucial contributor to the microglial response to LP”
• Innate immunity and neuroinflammation in the CNS: The role of microglia in Toll‐like receptor‐mediated neuronal injury (2009, background): “Making use of highly purified cultures of microglia, astrocytes, oligodendrocytes, and neurons from the forebrain of newborn rats, our group reported that microglia but no other CNS cells express TLR4 (Lehnardt et al., 2002, 2003).”
• Broad Expression of Toll‐Like Receptors in the Human Central Nervous System (2002, background): “Since previous findings indicate that murine astrocytes and oligodendrocytes are not able to express TLR4 (18), human glial cells do not necessarily display the same TLR profile as rodent glial cells.”
• Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission (2011, methodology): “First, we confirmed that TLR4, the LPS receptor, is only expressed by microglia (46, 61) using pure microglia cultures and binding experiments.”
• A Comparative Review of Toll-Like Receptor 4 Expression and Functionality in Different Animal Species (2014, background): “Thus, microglia appears to be the major cell type in the rat CNS able to transduce LPS signals (76, 85).”
• Regulation of innate immune responses in the brain (2009, background): “Although a single injection of LPS is probably not sufficient to cause neurodegeneration, long-term exposure to PAMPs, as occurs during severe meningitis for example, has profound effects on the nervous tissu”