Poliovirus induces indoleamine‐2,3‐dioxygenase and quinolinic acid synthesis in macaque brain

Accumulation of the neurotoxin quinolinic acid within the brain occurs in a broad spectrum of patients with inflammatory neurologic disease and may be of neuropathologic significance. The production of quinolinic acid was postulated to reflect local induction of indoleamine 2,3‐dioxygenase by cytokines in reactive cells and inflammatory cell infiltrates within the central nervous system. To test this hypothesis, macaques received an intraspinal injection of poliovirus as a model of localized inflammatory neurologic disease. Seventeen days later, spinal cord indoleamine 2,3‐dioxygenase activity and quinolinic acid concentrations in spinal cord and cerebrospinal fluid were both increased in proportion to the degree of inflammatory responses and neurologic damage in the spinal cord, as well as the severity of motor paralysis. The absolute concentrations of quinolinic acid achieved in spinal cord and cerebrospinal fluid exceeded levels reported to kill spinal cord neurons in vitro. Smaller increases in indoleamine 2,3‐dioxygenase activity and quinolinic acid concentrations also occurred in parietal cortex, a poliovirus target area. In frontal cortex, which is not a target for poliovirus, indoleamine 2,3‐dioxygenase was not affected. A monoclonal antibody to human indoleamine 2,3‐dioxygenase was used to visualize indoleamine 2,3‐dioxygenase predominantly in grey matter of poliovirus‐infected spinal cord, in conjunction with local inflammatory lesions. Macrophage/monocytes in vitro synthesized 13 C 6 quinolinic acid from 13 C 6 l ‐tryptophan, particularly when stimulated by interferon‐γ. Spinal cord slices from poliovirusinoculated macaques in vitro also converted 13 C 6 l ‐tryptophan to 13 C 6 quinolinic acid. We conclude that local synthesis of quinolinic acid from l ‐tryptophan within the central nervous system follows the induction of indoleamine‐2,3‐dioxygenase, particularly within macrophage/microglia. In view of this link between immune stimulation and the synthesis of neurotoxic amounts of quinolinic acid, we propose that attenuation of local inflammation, strategies to reduce the synthesis of neuroactive kynurenine pathway metabolites, or drugs that interfere with the neurotoxicity of quinolinic acid offer new approaches to therapy in inflammatory neurologic disease.— Heyes, M. P.; Saito, K., Jacobowitz, D.; Markey, S. P.; Takikawa, O.; Vickers, J. H. Poliovirus induces indoleamine‐2,3‐dioxygenase and quinolinic acid synthesis in macaque brain. FASEB J. 6: 2977‐2989; 1992.