Systemic challenge with the TLR3 agonist poly I:C induces amplified IFNalpha/beta and IL-1beta responses in the diseased brain and exacerbates chronic neurodegeneration.
The role of inflammation in the progression of neurodegenerative disease remains unclear. We have shown that systemic bacterial insults accelerate disease progression in animals and in patients with Alzheimer's disease. Disease exacerbation is associated with exaggerated CNS inflammatory responses to systemic inflammation mediated by microglia that become 'primed' by the underlying neurodegeneration. The impact of systemic viral insults on existing neurodegenerative disease has not been investigated. Polyinosinic:polycytidylic acid (poly I:C) is a toll-like receptor-3 (TLR3) agonist and induces type I interferons, thus mimicking inflammatory responses to systemic viral infection. In the current study we hypothesized that systemic challenge with poly I:C, during chronic neurodegenerative disease, would amplify CNS inflammation and exacerbate disease. Using the ME7 model of prion disease and systemic challenge with poly I:C (12 mg/kg i.p.) we have shown an amplified expression of IFN-alpha and beta and of the pro-inflammatory genes IL-1beta and IL-6. Similarly amplified expression of specific IFN-dependent genes confirmed that type I IFNs were secreted and active in the brain and this appeared to have anti-inflammatory consequences. However, prion-diseased animals were susceptible to heightened acute sickness behaviour and acute neurological impairments in response to poly I:C and this treatment also accelerated disease progression in diseased animals without effect in normal animals. Increased apoptosis coupled with double-stranded RNA-dependent protein kinase (PKR) and Fas transcription suggested activation of interferon-dependent, pro-apoptotic pathways in the brain of ME7+poly I:C animals. That systemic poly I:C accelerates neurodegeneration has implications for the control of systemic viral infection during chronic neurodegeneration and indicates that type I interferon responses in the brain merit further study.
Field
Robert
R
School of Biochemistry and Immunology, Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland.
Campion
Suzanne
S
Warren
Colleen
C
Murray
Carol
C
Cunningham
Colm
C
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal; D001831:Body Temperature / Q000502:physiology; D001923:Brain Chemistry / Q000187:drug effects*; D016207:Cytokines / Q000096:biosynthesis; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology / Q000523:psychology; D007369:Interferon Inducers / Q000494:pharmacology*; D016898:Interferon-alpha / Q000096:biosynthesis*; D016899:Interferon-beta / Q000096:biosynthesis*; D053583:Interleukin-1beta / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology / Q000523:psychology; D011070:Poly I-C / Q000494:pharmacology*; D017096:Prion Diseases / Q000473:pathology / Q000821:virology; D011597:Psychomotor Performance / Q000502:physiology; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013238:Stereotaxic Techniques; D051196:Toll-Like Receptor 3 / Q000819:agonists*
D000998:Antiviral Agents; D016207:Cytokines; D007369:Interferon Inducers; D016898:Interferon-alpha; D053583:Interleukin-1beta; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D012313:RNA; D016899:Interferon-beta; D011070:Poly I-C
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