A vicious cycle involving release of heat shock protein 60 from injured cells and activation of toll-like receptor 4 mediates neurodegeneration in the CNS

被引：221

作者：

Lehnardt, Seija ^{[1
,2
]}

Schott, Eckart ^{[3
]}

Trimbuch, Thorsten ^{[1
]}

Laubisch, Dinah ^{[1
]}

Krueger, Christina ^{[1
]}

Wulczyn, Gregory ^{[1
]}

Nitsch, Robert ^{[1
]}

Weber, Joerg R. ^{[1
]}

机构：

[1] Charite Univ Med Berlin, Ctr Anat, Inst Cell Biol & Neurobiol, D-10117 Berlin, Germany

[2] Charite Univ Med Berlin, Cecilie Vogt Clin Neurol, D-10117 Berlin, Germany

[3] Charite Univ Med Berlin, Dept Gastroenterol & Hepatol, Campus Virchow Klinikum, D-13353 Berlin, Germany

来源：

JOURNAL OF NEUROSCIENCE | 2008年 / 28卷 / 10期

关键词：

innate immunity; toll-like receptor; neurodegeneration; inflammation; heat shock protein; microglia;

D O I：

10.1523/JNEUROSCI.4760-07.2008

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Infection, ischemia, trauma, and neoplasia elicit a similar inflammatory response in the CNS characterized by activation of microglia, the resident CNS monocyte. The molecular events leading from CNS injury to the activation of innate immunity is not well understood. We show here that the intracellular chaperone heat shock protein 60 (HSP60) serves as a signal of CNS injury by activating microglia through a toll-like receptor 4 (TLR4)-dependent and myeloid differentiation factor 88 (MyD88)-dependent pathway. HSP60 is released from CNS cells undergoing necrotic or apoptotic cell death and specifically binds to microglia. HSP60-induced synthesis of neurotoxic nitric oxide by microglia is dependent on TLR4. HSP60 induces extensive axonal loss and neuronal death in CNS cultures from wild-type but not TLR4 or MyD88 loss-of-function mutant mice. This is the first evidence of an endogenous molecular pathway common to many forms of neuronal injury that bidirectionally links CNS inflammation with neurodegeneration.

引用

页码：2320 / 2331

页数：12