Autophagy receptor SHISA9 orchestrates antiviral immune heterogeneity of brain glia cells and CNS inflammation

ABSTRACT: Brain glia cells exhibit highly heterogeneity which can modify their genetic landscape and responding sensitivity, thus achieving appropriate responses to environmental changes for maintenance of CNS homeostasis. However, technical restriction has prevented the study on the self-orchestrating activity of CNS resident immune cells. Microglia and astrocytes are predominant responding cells at early stages during CNS viral infection. Their activation not only contributes to the recruitment of peripheral immune cells that aid in viral clearance, but also increases the risk of long-term detrimental inflammatory injury associated with many neurodegenerative diseases. Optimal autophagic activity is vital to maintain brain integrity, yet the autophagy regulation of immune activity in brain glia cells remains poorly understood. Here, we identify the membrane protein SHISA9 as an autophagy cargo receptor that modulates the heterogenic immune responses during CNS infection. By 10x single-cell RNA sequencing, we identify the astrocytes with increased Shisa9 expression followed by decreased expression of inflammatory transcriptional programs. Shisa9 has temporal characteristics in modulating both antiviral and inflammatory responses in microglia and astrocytes at different stages during infection. Shisa9-/- mice are highly susceptible to herpes simplex virus encephalitis, accompanied by higher rates of pathogenic astrocytes which might contribute to neurodegeneration progression and display a more severe neuroinflammation symptoms compared to wild-type mice. Taken together, our study unravels a critical role of selective autophagy in orchestrating immune heterogeneity of different CNS resident cells through SHISA9-IKKi axis.

ORGANISM(S): Mus musculus

PROVIDER: GSE216271 | GEO | 2023/01/15

REPOSITORIES: GEO