Systemic challenge with the TLR3 agonist poly I:C induces amplified IFNα/β and IL-1β responses in the diseased brain and exacerbates chronic neurodegeneration

Abstract

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-α and β and of the pro-inflammatory genes IL-1β 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.

Contributions of central and systemic inflammation to the pathophysiology of Parkinson's disease

“…To mimic a response to viral rather than a bacterial infection, challenges with polyriboinosinicpolyribocytidilic acid (Poly I:C), a TLR-3 agonist and synthetic analogue of double-stranded RNA have been used in rats. Results have revealed an increase in the production of proinflammatory cytokines in the brain , an exacerbation of chronic neurodegeneration (Field et al, 2010), and an induction of nigrostriatal dopaminergic neurodegeneration in adult rats (Deleidi et al, 2010). When administered early in gestation to mice, acute poly I:C induced maternal immune activation and a subsequent increase in the numbers of dopaminergic neurons in the foetal brains during middle and late foetal development (Meyer et al, 2008a).…”

Immune–neural connections: how the immune system’s response to infectious agents influences behavior

“…This physiological response is associated with neuroinflammation, especially type I IFN/ expression, within the brain. This neuroinflammatory response mimics the peripheral inflammatory response (Field et al, 2010). Poly I:C administration to mice induces a transient slight increase in core body temperature but a strong sickness behavioral response, assessed as a decrease in LMA and burrowing activity .…”

Innate Inflammation in Parkinson's Disease

“…In the healthy adult brain, the signaling from the periphery to the brain is transient, and there is no evidence that it leads to tissue damage. In brains with ongoing chronic neurodegeneration, there is a growing body of evidence to show that the microglia are not only increased in number and have an activated phenotype, but appear to be "primed" by the ongoing pathology such that systemic inflammation leads to an exaggerated synthesis of pro-inflammatory cytokines Cunningham et al 2009;Field et al 2010). The switch in the microglia phenotype during systemic inflammation has been described in pre-clinical models of both acute (Palin et al 2008) and chronic (Cunningham et al 2005;Lunnon et al 2011) neurodegeneration.…”