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Medientyp:
E-Artikel
Titel:
Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway
Beteiligte:
Lehnardt, Seija;
Massillon, Leon;
Follett, Pamela;
Jensen, Frances E.;
Ratan, Rajiv;
Rosenberg, Paul A.;
Volpe, Joseph J.;
Vartanian, Timothy
Erschienen:
Proceedings of the National Academy of Sciences, 2003
Erschienen in:Proceedings of the National Academy of Sciences
Sprache:
Englisch
DOI:
10.1073/pnas.1432609100
ISSN:
0027-8424;
1091-6490
Entstehung:
Anmerkungen:
Beschreibung:
<jats:p>Innate immunity is an evolutionarily ancient system that provides organisms with immediately available defense mechanisms through recognition of pathogen-associated molecular patterns. We show that in the CNS, specific activation of innate immunity through a Toll-like receptor 4 (TLR4)-dependent pathway leads to neurodegeneration. We identify microglia as the major lipopolysaccharide (LPS)-responsive cell in the CNS. TLR4 activation leads to extensive neuronal death<jats:italic>in vitro</jats:italic>that depends on the presence of microglia. LPS leads to dramatic neuronal loss in cultures prepared from wild-type mice but does not induce neuronal injury in CNS cultures derived from<jats:italic>tlr4</jats:italic>mutant mice. In an<jats:italic>in vivo</jats:italic>model of neurodegeneration, stimulating the innate immune response with LPS converts a subthreshold hypoxic-ischemic insult from no discernable neuronal injury to severe axonal and neuronal loss. In contrast, animals bearing a loss-of-function mutation in the<jats:italic>tlr4</jats:italic>gene are resistant to neuronal injury in the same model. The present study demonstrates a mechanistic link among innate immunity, TLRs, and neurodegeneration.</jats:p>