Brain profiling in murine colitis and human epilepsy reveals neutrophils and TNFα as mediators of neuronal hyperexcitability

Journal of Neuroinflammation

Marion S. Buckwalter¹  Kristy A. Zera¹  Sarah E. Barnes²  Edgar G. Engleman²  Geoffrey T. Ivison³ 

[1] Department of Neurology, Stanford University, Stanford, CA, USA;Department of Pathology, Stanford University, Stanford, CA, USA;Department of Pathology, Stanford University, Stanford, CA, USA;Department of Infectious Diseases, Stanford University, Stanford, CA, USA;

关键词: Colitis;    Inflammatory bowel disease;    Epilepsy;    Neuronal hyperexcitability;    Neutrophils;    TNFα;   

DOI  :  10.1186/s12974-021-02262-4

来源: Springer

【 摘 要 】

BackgroundPatients with chronic inflammatory disorders such as inflammatory bowel disease frequently experience neurological complications including epilepsy, depression, attention deficit disorders, migraines, and dementia. However, the mechanistic basis for these associations is unknown. Given that many patients are unresponsive to existing medications or experience debilitating side effects, novel therapeutics that target the underlying pathophysiology of these conditions are urgently needed.MethodsBecause intestinal disorders such as inflammatory bowel disease are robustly associated with neurological symptoms, we used three different mouse models of colitis to investigate the impact of peripheral inflammatory disease on the brain. We assessed neuronal hyperexcitability, which is associated with many neurological symptoms, by measuring seizure threshold in healthy and colitic mice. We profiled the neuroinflammatory phenotype of colitic mice and used depletion and neutralization assays to identify the specific mediators responsible for colitis-induced neuronal hyperexcitability. To determine whether our findings in murine models overlapped with a human phenotype, we performed gene expression profiling, pathway analysis, and deconvolution on microarray data from hyperexcitable human brain tissue from patients with epilepsy.ResultsWe observed that murine colitis induces neuroinflammation characterized by increased pro-inflammatory cytokine production, decreased tight junction protein expression, and infiltration of monocytes and neutrophils into the brain. We also observed sustained neuronal hyperexcitability in colitic mice. Colitis-induced neuronal hyperexcitability was ameliorated by neutrophil depletion or TNFα blockade. Gene expression profiling of hyperexcitable brain tissue resected from patients with epilepsy also revealed a remarkably similar pathology to that seen in the brains of colitic mice, including neutrophil infiltration and high TNFα expression.ConclusionsOur results reveal neutrophils and TNFα as central regulators of neuronal hyperexcitability of diverse etiology. Thus, there is a strong rationale for evaluating anti-inflammatory agents, including clinically approved TNFα inhibitors, for the treatment of neurological and psychiatric symptoms present in, and potentially independent of, a diagnosed inflammatory disorder.

【 授权许可】

CC BY