Dataset Information

Indoleamine 2,3-dioxygenase 1 deletion promotes Theiler's virus-induced seizures in C57BL/6J mice.

ABSTRACT:

Objective

Viral encephalitis increases the risk for developing seizures and epilepsy. Indoleamine 2,3-dioxygenase 1 (Ido1) is induced by inflammatory cytokines and functions to metabolize tryptophan to kynurenine. Kynurenine can be further metabolized to produce kynurenic acid and the N-methyl-d-aspartate receptor agonist quinolinic acid (QuinA). In the present study, we sought to determine the role of Ido1 in promoting seizures in an animal model of viral encephalitis.

Methods

C57BL/6J and Ido1 knockout mice (Ido1-KO) were infected with Theiler's murine encephalomyelitis virus (TMEV). Quantitative real-time polymerase chain reaction was used to evaluate hippocampal expression of proinflammatory cytokines, Ido1, and viral RNA. Body weights and seizure scores were recorded daily. Elevated zero maze was used to assess differences in behavior, and hippocampal pathology was determined by immunohistochemistry.

Results

Infected C57BL/6J mice up-regulated proinflammatory cytokines, Ido1, and genes encoding the enzymatic cascade responsible for QuinA production in the kynurenine pathway prior to the onset of seizures. Seizure incidence was elevated in Ido1-KO compared to C57BL/6J mice. Infection increased locomotor activity in Ido1-KO compared to C57BL/6J mice. Furthermore, the occurrence of seizures was associated with hyperexcitability. Neither expression of proinflammatory cytokines nor viral RNA was altered as a result of genotype. Immunohistochemical analysis revealed increased hippocampal pathology in Ido1-KO mice.

Significance

Our findings suggest that Ido1 deletion promotes seizures and neuropathogenesis during acute TMEV encephalitis.

SUBMITTER: Juda MB

PROVIDER: S-EPMC8273875 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Indoleamine-2,3-dioxygenase 1 (IDO1) is the initial and rate-limiting enzyme in the metabolism of tryptophan (TRP) to kynurenine (KYN). IDO1-dependent neurotoxic KYN metabolism plays a crucial role in the pathogenesis of many neurodegenerative disorders. However, the function of IDO1 in epilepsy is still unclear. Objective: In this study, we investigated whether IDO1 deficiency could affect epilepsy in a lithium-pilocarpine-induced model. Methods: Patients with epilepsy and controls were enrolled. Male C57BL/6 mice and IDO1 knockout (KO, IDO1-/-) mice were subjected to intraperitoneal injection of lithium and pilocarpine to induce epilepsy. The levels of IDO1 and concentrations of TRP and KYN in patients with epilepsy and epileptic mice were evaluated by enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-mass spectrometry (LC-MS), respectively. Then, behavioral phenotypes related to epileptic seizures and neuronal damage were compared between KO and wild-type (WT) mice with lithium-pilocarpine-induced epilepsy. To explore the underlying pathways involved in the effects of IDO1 deficiency, the concentrations of kynurenic acid (KYNA) and quinolinic acid (QUIN), glial cell activation, the levels of major pro-inflammatory cytokines, and antioxidant enzyme activity were measured by LC-MS, immunohistochemistry, and ELISA. Results: In this study, IDO1 levels and the KYN/TRP ratio in the sera and cerebrospinal fluid (CSF) were increased in patients with epilepsy. Also, IDO1 levels, the KYN/TRP ratio, and the levels of pro-inflammatory cytokines in the sera and hippocampi were increased in mice during the acute phase and chronic phase after status epilepticus (SE). Furthermore, IDO1 was localized in microglial cells in epileptic mice. IDO1 deficiency delayed SE onset and attenuated the frequency, duration, and severity of spontaneous recurrent seizures (SRSs). Moreover, IDO1 deficiency improved neuronal survival. Additionally, IDO1-/- epileptic mice showed progressive declines in QUIN production, glial cell activation and pro-inflammatory cytokines levels, and enhanced antioxidant enzyme activity. Conclusions: IDO1 deletion suppressed seizures and alleviated neuronal damage by reducing the IDO1-dependent production of neurotoxic metabolites, which finally inhibited glial cell activation and pro-inflammatory cytokine production and improved antioxidant enzyme activity. Our study demonstrates that IDO1 may be involved in the pathogenesis of epilepsy and has the potential to be a therapeutic target for epilepsy treatment.

Project description:IntroductionNeurological diseases can stem from environmental influences such as antecedent viral infections or exposure to potential toxicants, some of which can trigger immune responses leading to neurological symptoms. Theiler's murine encephalomyelitis virus (TMEV) is used to model human neurological conditions associated with prior viral infections, with outcomes partly attributable to improper induction and regulation of the immune response. Perfluorooctanoic acid (PFOA) can alter pathologies known to influence neurological disease such as inflammatory responses, cytokine expression, and glial activation. Co-exposure to TMEV and PFOA was used to test the hypothesis that early life exposure to the potential immunotoxicant PFOA would affect immune responses so as to render TMEV-resistant C57BL/6J (B6) mice susceptible to viral-induced neurological disease.MethodsNeonate B6 mice were exposed to different treatments: non-injected, sham-infected with PBS, and TMEV-infected, with the drinking water of each group including either 70 ppt PFOA or filtered water. The effects of PFOA were evaluated by comparing neurological symptoms and changes in immune-related cytokine and chemokine production induced by viral infection. Immune responses of 23 cytokines and chemokines were measured before and after infection to determine the effects of PFOA exposure on immune response.ResultsPrior to infection, an imbalance between Th1, Th2, and Treg cytokines was observed in PFOA-exposed mice, suppressing IL-4 and IL-13 production. However, the balance was restored and characterized by an increase in pro-inflammatory cytokines in the non-infected group, and a decrease in IL-10 in the PFOA + TMEV group. Furthermore, the PFOA + TMEV group experienced an increase in seizure frequency and severity.DiscussionOverall, these findings provide insight into the complex roles of immune responses in the pathogenesis of virus-associated neurological diseases influenced by co-exposures to viruses and immunotoxic compounds.