Innate immunity plays a critical role in degenerative diseases of the central nervous system (CNS). However, many of the molecular pathways by which innate inflammation contributes to individual diseases remain unknown. Herein, we use a combination of primary cell culture, in vivo animal studies and human data to explore two distinct pathways of neuroinflammation. The first, focuses on the role of reactive astrocytes as mediators of innate inflammation and neurodegeneration in glaucoma. The second, highlights the role of nutritional immunity, a division of the innate immune system, in iron dysregulation observed across multiple CNS diseases including age-related macular degeneration and Parkinson’s disease. Together these data highlight the multiple mechanisms by which maladaptive activation of innate immunity can contribute to CNS dysfunction and identify new targets for therapeutic intervention.