Ido1 or Ido2 deficiency in myeloid-derived cells attenuates TMEV-induced ictogenesis.

Viral encephalitis is a serious medical condition that causes neuroinflammation, neurodegeneration, cognitive deficits and seizures (ictogenesis), predisposing patients to epilepsy. In a preclinical setting, intracranial infection of C57BL/6 mice with Theiler's murine encephalomyelitis virus (TMEV) is the best-characterized animal model of viral encephalitis resulting in ictogenesis and temporal lobe epilepsy. Macrophages play a critical yet unclear role during encephalomyelitis: macrophage depletion reduces TMEV-induced ictogenesis, whereas prevention of macrophage infiltration into the brain reduces hippocampal damage without changing seizure incidence. Here, we explore the roles of indoleamine-2,3-dioxygenase (Ido) 1 and 2 from myeloid-derived cells (i.e. monocytes, macrophages and monocyte-derived dendritic cells) in the context of TMEV-induced ictogenesis and hippocampal gene expression. Ido1 and Ido2 gene expression is induced by inflammation. IDO1 and IDO2 proteins initiate the kynurenine pathway, by which tryptophan is converted into kynurenine but both proteins have poorly characterized non-enzymatic actions with unknown consequences during encephalomyelitis. In this study, we found that Ido1 and Ido2 deficiencies within myeloid-derived cells reduced ictogenesis without altering hippocampal inflammation-associated gene expression. In vitro infection of peritoneal macrophages demonstrated that genotype does not impact TMEV replication or cytokine expression, suggesting that the direct response of macrophages to infection is not the mechanism for the observed attenuation of ictogenesis in mice with myeloid Ido1 or Ido2 deficiencies.