Expression of the inducible nitric oxide synthase. Correlation with neuropathology and clinical features in mice with lymphocytic choriomeningitis.

Nitric oxide (NO) synthesized by the cytokine-inducible enzyme, nitric oxide synthase (iNOS), is thought to be a key mediator in the host immune response to infection, in which it may have protective, as well as injurious, actions. We sought evidence for a role of NO in the pathogenesis of lymphocytic choriomeningitis by examining the cerebral expression of the iNOS gene in mice after intracranial inoculation of lymphocytic choriomeningitis virus. In euthymic, but not athymic, mice, elevated expression of iNOS mRNA was observed in the brain by day 5 and increased further to high levels by day 6 postinfection. Of the peripheral organs, only the spleen showed significant increases in iNOS mRNA at day 3 postinfection. In situ hybridization revealed that iNOS RNA expression was restricted to cells within the inflammatory infiltrates and in proximity to areas of lymphocytic choriomeningitis virus infection in the brain. Immunostaining for iNOS protein identified numerous positive cells within the inflammatory infiltrates present in the meninges and choroid plexus. Phenotypic analysis revealed the majority of the iNOS containing cells to be Mac-1 positive. T lymphocytes that belonged to the CD8+ and CD4+ subsets were negative for iNOS expression. The kinetics and distribution of cerebral iNOS expression in lymphocytic choriomeningitis are consistent with a major role for the iNOS/NO pathway in the pathogenesis of this immune-mediated neurologic disease.