High neopterin and IP-10 levels in cerebrospinal fluid are associated with neurotoxic tryptophan metabolites in acute central nervous system infections

Abstract

Background: The host response to intruders in the central nervous system (CNS) may be beneficial but could also be harmful and responsible for neurologic symptoms and sequelae in CNS infections. This immune response induces the activation of the kynurenine pathway (KP) with the production of neuroactive metabolites. Herein, we explored cytokine and KP responses in cerebrospinal fluid (CSF) and serum in patients with encephalitis, aseptic, and bacterial meningitis. Methods: Cytokines were measured in CSF and serum by multiplex assay in adult patients with encephalitis of infectious, autoimmune or unknown etiology (n = 10), aseptic meningitis (ASM, n = 25), acute bacterial meningitis (ABM, n = 6), and disease control patients with similar symptoms but without pleocytosis in CSF (n = 42). Liquid chromatography-tandem mass spectrometry (LC-MS/ MS) was used to measure KP metabolites in CSF and serum. Results: A characteristic pattern of increasing cytokine levels and KP metabolites was found in CSF from encephalitis to ASM, with the highest levels in ABM. In ASM and ABM, most inflammatory mediators, including IL-6, IL-8, and IFN-inducible protein-10 (IP-10), showed markedly elevated levels in CSF compared with serum, indicating production within the CNS. In contrast to most mediators, the highest level of IP-10 was found in the ASM group, suggesting a potential role for IP-10 in aseptic/viral meningitis. Neopterin and IP-10 were associated with marked changes in KP metabolites in CSF with increasing kynurenine/tryptophan ratio reflecting indoleamine 2,3-dioxygenase activity. Neopterin, a marker of IFN-γ activity, was associated with an unfavorable balance between neuroprotective and neurotoxic tryptophan metabolites. Conclusion: We show that parenchymal and meningeal inflammations in CNS share a characteristic cytokine profile with a general immune response in the CSF with limited influence from the systemic circulation. IFN-γ activity, assessed by neopterin and IP-10 levels, may play a role in the activation of the KP pathway in these patients, potentially mediating neurotoxic effects.