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Mol Immunol. 2004 Jan;40(10):709-16.

Microglial activation and increased synthesis of complement component C1q precedes blood-brain barrier dysfunction in rats.

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  • 1Department of Infection, Immunity and Inflammation, University of Leicester, University Road, Leicester LE1 9HN, UK. njl12@le.ac.uk

Abstract

A reliable way to visualise the state of microglial activation is to monitor the microglial gene expression profile. Microglia are the only CNS resident cells that synthesise C1q, the recognition sub-component of the classical complement pathway, in vivo. C1q biosynthesis in resting ramified microglia is often low, but it increases dramatically in activated microglia. In this study, the expression of C1q was used to monitor microglial activation at all stages of 3-chloropropanediol-induced neurotoxicity, a new model of blood-brain barrier (BBB) breakdown. In rats, 3-chloropropanediol produces very focused lesions in the brain, characterised by early astrocyte swelling and loss, followed by neuronal death and barrier dysfunction. Using in situ hybridisation, immunohistochemistry, and real-time RT-PCR, we found that increased C1q biosynthesis and microglial activation precede BBB dysfunction by at least 18 and peak 48 h after injection of 3-chloropropanediol, which coincides with the onset of active haemorrhage. Microglial activation is biphasic; an early phase of global activation is followed by a later phase in which microglial activation becomes increasingly focused in the lesions. During the early phase, expression of the pro-inflammatory mediators interleukin-1beta (IL1beta), tumour necrosis factor alpha (TNFalpha) and early growth response-1 (Egr-1) increased in parallel with C1q, but was restricted to the lesions. Expression of C1q (but not IL1beta, TNFalpha or Egr-1) remains high after BBB function is restored, and is accompanied by late up-regulation of the C1q-associated serine proteases, C1r and C1s, suggesting that microglial biosynthesis of the activation complex of the classical pathway may support the removal of cell debris by activation of complement.

PMID:
14644096
[PubMed - indexed for MEDLINE]
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