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Extracellular matrix degradation in SIV encephalitis induces IRF‐1 signaling in astrocytes
Author(s) -
BonnehBarkay Dafna,
Starkey Adam,
Wang Wanda,
Wiley Clayton A
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.439.2
Subject(s) - extracellular matrix , microbiology and biotechnology , microglia , biology , astrocyte , extracellular , chemistry , immunology , central nervous system , inflammation , neuroscience
The neuropathological changes associated with HIV encephalitis (HIVE) include activated and infected macrophages, astrocytosis and loss of perineuronal nets (PNNs) indicating of extracellular matrix (ECM) disruption. The aim of this study was to explore the kinetics of ECM degradation, identify the ECM degrading enzymes involved, study whether IRF‐1 and its target genes are induced by ECM degradation and whether they play a role in nerurodegeneration. Longitudinal analysis of SIV‐infected pigtailed macaques showed an increase in CSF ECM degradation products. Consistent with these findings, the ECM degrading enzyme hyaluronidase and heparinase were upregulated in brain homogenates commensurate with the severity of encephalitis. Microarray analysis showed induction of the transcription factor IRF‐1 in encephalitic animals that was confirmed by semi‐quantitative RT‐PCR. In situ hybridization combined with immunohistochemistry showed that IRF‐1 was induced in astrocytes. Primary human astrocyte cultures exposed to hyaluronidase and heparitinase showed induction of IRF‐1 as well as toll‐like receptor 4 (TLR4) mRNA. Initial screening of the target genes that are induced by ECM degrading enzymes include ADAM8, caspase 1 & 3. We conclude that ECM degradation in SIVE results in the formation of HA and HS fragments that can activate TLR signaling and subsequent IRF‐1 induction in astrocytes.