The immunological landscape of the area postrema in neuromyelitis optica spectrum disorders

Patients suffering from aquaporin-4 antibody-positive neuromyelitis spectrum disorder may present with radically different types of lesions in the central nervous system. They may show large tissue destructive lesions, as typically seen in medulla, spinal cord, and optic nerves, and lesions with much better tissue preservation, as seen in the area postrema. The causes for the resilience of the area postrema to the action of aquaporin 4-antibodies are currently unclear. We performed detailed immunohistochemical analysis combined with spatial transcriptomics and functional annotation clustering, and identified key differences in the immunological landscape between the area postrema and the medulla. In the area postrema, only few chemokines were upregulated in response to AQP4 antibodies. Therefore, the immune response was dominated by local microglial/macrophages which displayed a low grade of microgliosis and an overall low level of activation. Il-1β expression was below our cut-off for detection. This was in marked contrast to lesions in the medulla, which were characterized by the expression of many chemokines underlying the recruitment of macrophages and neutrophils from the periphery to this site, and by Il-1β expression. Aldehyde dehydrogenase 1 family member A2 (Aldh1a2), the key molecule for retinoic acid synthesis, was strongly expressed in the area postrema, but not in the medulla. Because retinoic acid can prevent the activation of astrocytes and microglia, can reduce the production of cytokine/chemokine transcripts, can alleviate the expression of IL-1β, and can promote an M1- to M2-transition in macrophages, our data implicate a protective role of retinoic acid at this site.