Neuromyelitis optica (NMO), also known as Devic's disease, is an inflammatory demyelinating disease that affects selectively the optic nerves and the spinal cord, possibly mediated by an immune mechanism distinct from that of multiple sclerosis (MS). Recent studies indicate that NMO also involves the brain. Here, we studied gene expression profile of brain lesions of a patient with NMO by using DNA microarray, along with gene expression profile of the brains of Parkinson disease and amyotrophic lateral sclerosis patients. We identified more than 200 genes up-regulated in NMO brain lesions. The top 20 genes were composed of the molecules closely associated with immune regulation, among which marked up-regulation of interferon gamma-inducible protein 30 (IFI30), CD163, and secreted phosphoprotein 1 (SPP1, osteopontin) was validated by real time RT-PCR, Northern blot and Western blot analysis. Pathologically, CD68(+) macrophages and microglia expressed intense immunoreactivities for IFI30 and CD163 in NMO lesions, consisting of inflammatory demyelination, axonal loss, necrosis, cavity formation, and vascular fibrosis. KeyMolnet, a bioinformatics tool for analyzing molecular interaction on the curated knowledge database, suggested that the molecular network of up-regulated genes in NMO brain lesions involves transcriptional regulation by the nuclear factor-kappaB (NF-kappaB) and B-lymphocyte-induced maturation protein-1 (Blimp-1). These results suggest that profound activation of the macrophage-mediated proinflammatory immune mechanism plays a pivotal role in development of NMO brain lesions.