Brain-Thymus communication is a novel immunosuppressive feature of neurological insults

Abstract

Abstract Systemic immunosuppression following neurological insults including stroke, traumatic brain injury, and glioblastoma mutiforme (GBM) causes mortality and leads to failure of therapies. Exact immunological nature and the underlying mechanisms of this immunosuppression are unknown. Our goal was to define effects of neurological insults given exclusively to the brain on the thymus; a primary immune organ. Specifically, we evaluated the effects on the thymus following physical injury with intracranial PBS injection, intracranial (ic) Theiler’s Murine Encephalomyelitis Virus infection, intracranial injection with lipopolysaccharide, CNS tumors (B16 melanoma and GL261 glioma ic), and seizure induction with intraperitoneal Kainic acid injection. These insults resulted in significant thymic involution that is reversible upon clearance of the neurological insult. The extent of thymic involution correlated with the extent of brain injury. Further analysis of the brain-thymus axis in mice with GL261 gliomas was conducted using RNA-Seq. Principle component analysis of RNA-Seq data revealed unbiased separation of thymi of naïve and glioma harboring mice, suggesting that thymus is directly affected by brain injury. To determine the extent to which thymic involution was caused by a soluble factor, we employed parabiosis. This approach demonstrated a soluble factor is responsible for thymic involution. These findings are the first demonstration that neurological insults ubiquitously contribute to immune suppression. We also provide evidence that thymic involution is mediated by a soluble factor, the identification of which could be critical for ameliorating the effect of neurological injuries on immune suppression.