In this work, we present a thorough investigation of the role of CD83 in microglia, both under homeostatic and pathologic conditions. Using CD83eGFP reporter mice, we disclose that in a healthy CNS, CD83 is almost exclusively expressed in microglia although not being uniformly distributed. In the experimental autoimmune encephalitis (EAE) model of neuroinflammation, CD83 expression increases under inflammatory conditions and remains elevated throughout the complete course of the disease. In vitro, we demonstrate that microglial expression of Cd83 relies on TGF-β and can be strongly induced by IL-4. Targeted deletion of CD83 in microglia reveals a disturbed phenotype and aberrant response to myelin debris. Using the EAE model, we show that specific deletion of CD83 (CD83ΔMG) in microglia results in aggravated autoimmune neuroinflammation, which is marked by a profound influx of monocytic cells into the CNS. Using single-cell RNA sequencing (scRNA-Seq), we disclosed that CD83-deficient microglia display an over-activated phenotype. These cells express higher levels of chemokines and create a TNF-α-driven pro-inflammatory milieu, which causes more severe damage in the brain by higher expression of Mmp9. Collectively, we reveal that
