Inflammasome induction in Rasmussen’s encephalitis: cortical and associated white matter pathogenesis

Journal of Neuroinflammation

Christopher Power⁴  Donald W Gross⁶  Thomas Snyder¹  Ferdinand Maingat⁶  William Branton⁶  B Matt Wheatley⁵  Richard Tang-Wai³  Edward Johnson⁷  D Barry Sinclair³  John G Walsh⁶  Vijay Ramaswamy² 

[1] Department of Psychiatry, University of Alberta, Edmonton, AB, Canada;Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, ON, Canada;Division of Pediatric Neurology, University of Alberta, Edmonton, AB, Canada;Department of Medicine, University of Alberta, 6-11 Heritage Medical Research Centre, Edmonton, AB T6G 2S2, Canada;Department of Surgery (Neurosurgery), University of Alberta, Edmonton, AB, Canada;Department of Medicine (Neurology), University of Alberta, Edmonton, AB, Canada;Department of Laboratory Medicine and Pathology (Neuropathology), University of Alberta, Edmonton, AB, Canada

关键词: Innate immunity;    Inflammasome;    White matter;    Rasmussen’s encephalitis;   

Others  :  834561
DOI  :  10.1186/1742-2094-10-152

 received in 2013-09-17, accepted in 2013-11-18,  发布年份 2013

【 摘 要 】

Background

Rasmussen’s encephalitis (RE) is an inflammatory encephalopathy of unknown cause defined by seizures with progressive neurological disabilities. Herein, the pathogenesis of RE was investigated focusing on inflammasome activation in the brain.

Methods

Patients with RE at the University of Alberta, Edmonton, AB, Canada, were identified and analyzed by neuroimaging, neuropsychological, molecular, and pathological tools. Primary human microglia, astrocytes, and neurons were examined using RT-PCR, enzyme-linked immunosorbent assay (ELISA), and western blotting.

Results

Four patients with RE were identified at the University of Alberta. Magnetic resonance imaging (MRI) disclosed increased signal intensities in cerebral white matter adjacent to cortical lesions of RE patients, accompanied by a decline in neurocognitive processing speed (P <0.05). CD3ϵ, HLA-DRA, and TNFα together with several inflammasome-associated genes (IL-1β, IL-18, NLRP1, NLRP3, and CASP1) showed increased transcript levels in RE brains compared to non-RE controls (n = 6; P <0.05). Cultured human microglia displayed expression of inflammasome-associated genes and responded to inflammasome activators by releasing IL-1β, which was inhibited by the caspase inhibitor, zVAD-fmk. Major histocompatibility complex (MHC) class II, IL-1β, caspase-1, and alanine/serine/cysteine (ASC) immunoreactivity were increased in RE brain tissues, especially in white matter myeloid cells, in conjunction with mononuclear cell infiltration and gliosis. Neuroinflammation in RE brains was present in both white matter and adjacent cortex with associated induction of inflammasome components, which was correlated with neuroimaging and neuropsychological deficits.

Conclusion

Inflammasome activation likely contributes to the disease process underlying RE and offers a mechanistic target for future therapeutic interventions.

【 授权许可】

   
2013 Ramaswamy et al.; licensee BioMed Central Ltd.

【 图 表 】

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