Related Experiment Videos
Pertussis toxin-induced reversible encephalopathy dependent on monocyte chemoattractant protein-1 overexpression in
DeRen Huang1, Marie Tani, Jintang Wang
1Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Abstract:
In this report we describe pertussis toxin-induced reversible encephalopathy dependent on monocyte chemoattractant protein-1 (MCP-1) overexpression (PREMO), a novel animal model that exhibits features of human encephalopathic complications of inflammatory disorders such as viral meningoencephalitis and Lyme neuroborreliosis as well as the mild toxic encephalopathy that commonly precedes relapses of multiple sclerosis (MS). Overexpression of the mouse MCP-1 gene product (classically termed JE) in astrocytes, the major physiological CNS cellular source of MCP-1, failed to induce neurological impairment. Unexpectedly, transgenic (tg) mice overexpressing MCP-1 at a high level (MCP-1(hi)) manifested transient, severe encephalopathy with high mortality after injections of pertussis toxin (PTx) plus complete Freund's adjuvant (CFA). Surviving mice showed markedly improved function and did not relapse during a prolonged period of observation. Tg mice that expressed lower levels of MCP-1 were affected minimally after CFA/PTx injections, and tg expression of other chemokines failed to elicit this disorder. The disorder was significantly milder in mice lacking T-cells, which therefore play a deleterious role in this encephalopathic process. Disruption of CC chemokine receptor 2 (CCR2) abolished both CNS inflammation and encephalopathy, identifying CCR2 as a relevant receptor for this disorder. Proinflammatory and type 1 cytokines including TNF-alpha, IL-1beta, IFN-gamma, IL-2, RANTES, and IP-10 were elevated in CNS tissues from mice with PREMO. These studies characterize a novel model of reversible inflammatory encephalopathy that is dependent on both genetic and environmental factors.
Insights
A novel animal model, PREMO, mimics human encephalopathy by overexpressing monocyte chemoattractant protein-1 (MCP-1). This model, dependent on MCP-1 and CC chemokine receptor 2 (CCR2), offers insights into inflammatory brain disorders.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Encephalopathic complications are seen in inflammatory disorders like viral meningoencephalitis, Lyme neuroborreliosis, and multiple sclerosis (MS).
- Existing animal models do not fully recapitulate the complex features of these human conditions.
Purpose of the Study:
- To develop and characterize a novel animal model of reversible encephalopathy.
- To investigate the role of monocyte chemoattractant protein-1 (MCP-1) and CC chemokine receptor 2 (CCR2) in inflammatory encephalopathy.
Main Methods:
- Generation of transgenic (tg) mice with varying levels of MCP-1 overexpression.
- Induction of encephalopathy using pertussis toxin (PTx) and complete Freund's adjuvant (CFA).
- Assessment of neurological function, mortality, T-cell involvement, and CCR2 disruption effects. Cytokine profiling of CNS tissues.
Main Results:
- High-level MCP-1 overexpression in tg mice (MCP-1(hi)) led to transient, severe encephalopathy with high mortality after PTx/CFA. Survivors showed functional recovery.
- The disorder was milder in T-cell deficient mice and abolished by CC chemokine receptor 2 (CCR2) disruption.
- Elevated proinflammatory cytokines (TNF-alpha, IL-1beta, IFN-gamma, IL-2, RANTES, IP-10) were observed in CNS tissues.
Conclusions:
- The study characterizes a novel model of reversible inflammatory encephalopathy (PREMO) dependent on MCP-1 and CCR2.
- This model mimics human encephalopathic complications and highlights the interplay of genetic and environmental factors.
- The findings underscore the critical role of MCP-1, CCR2, and T-cells in the pathogenesis of inflammatory encephalopathy.