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Here, we used mouse genetic tools to induce astrocyte-specific deletion, overexpression, and chemogenetic activation of RIPK3 to demonstrate an anti-inflammatory function for astrocytic RIPK3. RIPK3 activation in astrocytes promoted host survival during flavivirus encephalitis by limiting immune cell recruitment to the CNS. Despite inducing a proinflammatory transcriptional program, astrocytic RIPK3 restrained neuroinflammation by increasing the abundance of the protease inhibitor SerpinA3N, which preserved blood-brain barrier integrity, reduced leukocyte infiltration, and improved survival outcomes during flavivirus encephalitis. These findings highlight a previously unappreciated role for astrocytic RIPK3 in suppressing pathologic neuroinflammation.<\/jats:p>","DOI":"10.1126\/scisignal.adq6422","type":"journal-article","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T17:58:42Z","timestamp":1752602322000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":10,"title":["Astrocytic RIPK3 exerts protective anti-inflammatory activity in mice with viral encephalitis by transcriptional induction of serpins"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7563-943X","authenticated-orcid":true,"given":"Marissa","family":"Lindman","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, 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