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Hugh Perry, Séminaire labelisé INB / Ecole doctorale / AXE Neuroinflammation"The impact of systemic inflammation on the brain in health and disease"

Abstract :

We have all at one time or another experienced the consequences of a systemic infection, we have felt ill – we have experienced sickness behaviour.
A number of routes have been identified by which systemic inflammation communicates with the brain and this includes both neural and humoral routes. Within the brain the signals that convey information about systemic inflammation involve immune cells of the brain, the macrophages and microglia, and the communication between non-neuronal cells and neurons involves molecules that are themselves inflammatory mediators such as cytokines and prostaglandins. In the normal healthy brain the microglia are kept under tight regulation by the CNS microenvironment and are commonly thought of as having a downregulated phenotype. However, following chronic or acute neurodegeneration the microglia become activated or “primed”. We have been interested to learn how systemic inflammation may impact on the diseased brain to either exacerbate sickness behaviour or the chronic neurodegenerative disease.

Using murine prion disease as a model of chronic neurodegeneration we have shown that the activated microglia adopt a phenotype that is dominated by the presence of TGF-b1, COX-2 and MCP-1. This phenotype appears early in disease and is associated with the loss of synapses and the presence of misfolded PrPsc. We have no evidence that these cells significantly contribute to disease progression following intracerebral initiation of the disease. To mimic a systemic infection mice with prion disease were challenged systemically with LPS: the microglia rapidly switch their phenotype to an aggressive pro-inflammatory phenotype and synthesised pro-inflammatory cytokines. The onset of pro-inflammatory cytokine synthesis is associated with an exaggerated sickness behaviour response and increased neuronal degeneration. We have hypothesised that systemic infections in diseases such as Alzheimer’s disease will exacerbate acute symptoms of sickness behaviour and accelerate disease progression. Our recent clinical studies show that common systemic infections have a profound effect on patients with Alzheimer’s disease.

Selected publications

Bucks RS, Gidron Y, Harris P, Teeling J, Wesnes KA, Perry VH. Selective effects of upper respiratory tract infection on cognition, mood and emotion processing: a prospective study. Brain Behav Immun. 2008 Mar;22(3):399-407.
Galea I, Bernardes-Silva M, Forse PA, van Rooijen N, Liblau RS, Perry VH. An antigen-specific pathway for CD8 T cells across the blood-brain barrier. J Exp Med. 2007 Sep 3;204(9):2023-30.
Teeling JL, Felton LM, Deacon RM, Cunningham C, Rawlins JN, Perry VH. Sub-pyrogenic systemic inflammation impacts on brain and behavior, independent of cytokines. Brain Behav Immun. 2007 Aug;21(6):836-50.

Cunningham C, Campion S, Teeling J, Felton L, Perry VH. The sickness behaviour and CNS inflammatory mediator profile induced by systemic challenge of mice with synthetic double-stranded RNA (poly I:C). Brain Behav Immun. 2007 May;21(4):490-502.
Perry VH, Cunningham C, Holmes C. Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol. 2007 Feb;7(2):161-7.

Françoise Moos et Klaus Petry