TGFbeta1 regulates the inflammatory response during chronic neurodegeneration.
The ME7 model of murine prion disease shows an atypical inflammatory response characterized by morphologically activated microglia and an anti-inflammatory cytokine profile with a marked expression of TGFbeta1. The investigation of the role of TGFbeta1 during a time course disease shows that its expression is correlated with (i) the onset of behavioral abnormalities, (ii) increased activated microglia, (iii) thickening of the basement membrane, and (iv) is associated with increased PrP(sc) deposition. Increasing TGFbeta1 using an adenoviral vector has no significant impact on prion-associated behavioral impairments or on neuropathology. In contrast, inhibition of TGFbeta1 activity using an adenovirus expressing decorin induces severe cerebral inflammation, expression of inducible nitric oxide synthase and acute neuronal death in prion-diseased animals only. These data suggest that TGFbeta1 plays a critical role in the downregulation of microglial responses minimizing brain inflammation and thus avoiding exacerbation of brain damage.
Boche
Delphine
D
CNS Inflammation Group, Southampton Neurosciences Group, School of Biological Sciences, University of Southampton, Southampton, SO16 7PX Hampshire, UK. D.Boche@soton.ac.uk
Cunningham
Colm
C
Docagne
Fabian
F
Scott
Helen
H
Perry
V Hugh
VH
D000818:Animals; D001522:Behavior, Animal; D015153:Blotting, Western; D001921:Brain / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016923:Cell Death; D002908:Chronic Disease; D058575:Decorin; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007797:Laminin / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D009410:Nerve Degeneration / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D018620:PrPSc Proteins / Q000378:metabolism; D017096:Prion Diseases / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000276:immunology* / Q000378:metabolism; D053773:Transforming Growth Factor beta1
C546879:Dcn protein, mouse; D058575:Decorin; D016326:Extracellular Matrix Proteins; D007797:Laminin; D017395:Plasminogen Activator Inhibitor 1; D018620:PrPSc Proteins; D011509:Proteoglycans; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D052247:Nitric Oxide Synthase Type II; D005947:Glucose