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Atypical inflammation in the central nervous system in prion disease
V Hugh Perry1, Colm Cunningham, Delphine Boche
1CNS Inflammation Group, School of Biological Sciences, University of Southampton, Southampton SO16 7PX, UK. vhp@soton.ac.uk
Abstract:
The inflammatory response in prion diseases is dominated by microglial activation. Contrary to their profile in vitro none of the pro-inflammatory cytokines interleukin-1beta, interleukin-6, or tumour necrosis factor-alpha are significantly upregulated in the ME7 model of prion disease. However, two major inflammatory mediators are elevated: transforming growth factor-beta1 and prostaglandin E2. This cytokine profile is the same as that reported for macrophages during phagocytosis of apoptotic cells and indeed transforming growth factor-beta1 and prostaglandin E2 are responsible for the downregulated phenotype of these macrophages. Transforming growth factor-beta1 may also have roles in extracellular matrix deposition and in amyloidogenesis and may play a direct role in disease pathogenesis. There is also now evidence to suggest that a peripheral infection, and its consequent systemic cytokine expression, may drive central nervous system cytokine expression and perhaps exacerbate disease.
Insights
Prion diseases show microglial activation but not typical pro-inflammatory cytokines. Instead, transforming growth factor-beta1 and prostaglandin E2 are elevated, influencing disease pathogenesis.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Prion diseases are characterized by neuroinflammation, primarily involving microglial activation.
- The typical pro-inflammatory cytokine profile (IL-1β, IL-6, TNF-α) is not observed in the ME7 prion disease model.
- Key inflammatory mediators like transforming growth factor-beta1 (TGF-β1) and prostaglandin E2 (PGE2) are significantly upregulated.
Purpose of the Study:
- To investigate the specific inflammatory mediators involved in the ME7 model of prion disease.
- To understand the role of TGF-β1 and PGE2 in the context of microglial activation and disease progression.
- To explore potential links between peripheral infections and central nervous system inflammatory responses in prion diseases.
Main Methods:
- Analysis of cytokine expression in the ME7 prion disease model.
- Comparison of observed cytokine profiles with in vitro studies and macrophage behavior during apoptosis.
- Assessment of TGF-β1's potential roles in extracellular matrix deposition, amyloidogenesis, and pathogenesis.
Main Results:
- While pro-inflammatory cytokines IL-1β, IL-6, and TNF-α were not upregulated, TGF-β1 and PGE2 were significantly elevated in the ME7 model.
- The observed cytokine profile mirrors that of macrophages phagocytosing apoptotic cells, with TGF-β1 and PGE2 contributing to a downregulated phenotype.
- TGF-β1 may be implicated in extracellular matrix deposition, amyloidogenesis, and direct disease pathogenesis.
Conclusions:
- The inflammatory response in prion diseases involves a distinct cytokine profile dominated by TGF-β1 and PGE2, rather than classical pro-inflammatory cytokines.
- TGF-β1 and PGE2 play crucial roles in modulating microglial responses and may directly contribute to prion disease pathogenesis.
- Peripheral infections could potentially exacerbate prion disease by influencing central nervous system inflammatory responses.