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Diseases caused by genetic disruption of cholesterol biosynthesis, such as Smith\u2013Lemli\u2013Opitz syndrome, which is caused by mutations in 7-dehydrocholesterol reductase (DHCR7), frequently result in broad neurological deficits. Although astrocytes regulate multiple neural processes ranging from cell migration to network-level communication, immunological activation of astrocytes is a hallmark pathology in many diseases. However, the impact of DHCR7 on astrocyte function and immune activation remains unknown. We demonstrate that astrocytes from Dhcr7 mutant mice display hallmark signs of reactivity, including increased expression of glial fibrillary acidic protein (GFAP) and cellular hypertrophy. Transcript analyses demonstrate extensive Dhcr7 astrocyte immune activation, hyper-responsiveness to glutamate stimulation and altered calcium flux. We further determine that the impacts of Dhcr7 are not astrocyte intrinsic but result from non-cell-autonomous effects of microglia. Our data suggest that astrocyte\u2013microglia crosstalk likely contributes to the neurological phenotypes observed in disorders of cholesterol biosynthesis. Additionally, these data further elucidate a role for cholesterol metabolism within the astrocyte\u2013microglia immune axis, with possible implications in other neurological diseases.<\/jats:p>","DOI":"10.1242\/dmm.049843","type":"journal-article","created":{"date-parts":[[2022,12,16]],"date-time":"2022-12-16T08:30:56Z","timestamp":1671179456000},"source":"Crossref","is-referenced-by-count":19,"title":["Sterol dysregulation in Smith\u2013Lemli\u2013Opitz syndrome causes astrocyte immune reactivity through microglia crosstalk"],"prefix":"10.1242","volume":"15","author":[{"given":"Bethany A.","family":"Freel","sequence":"first","affiliation":[{"name":"Basic Biomedical Sciences, University of South Dakota 1 , Vermillion, SD 57069 , USA"},{"name":"Cellular Therapies and Stem Cell Biology Group, Sanford Research 2 , Sioux Falls, SD 57104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin A.","family":"Kelvington","sequence":"additional","affiliation":[{"name":"Cellular Therapies and Stem Cell Biology Group, Sanford Research 2 , Sioux Falls, SD 57104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonali","family":"Sengupta","sequence":"additional","affiliation":[{"name":"Cellular Therapies and Stem Cell Biology Group, Sanford Research 2 , Sioux Falls, SD 57104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malini","family":"Mukherjee","sequence":"additional","affiliation":[{"name":"Functional Genomics and Bioinformatics Core, Sanford Research 3 , Sioux Falls, SD 57104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3636-7264","authenticated-orcid":false,"given":"Kevin R.","family":"Francis","sequence":"additional","affiliation":[{"name":"Cellular Therapies and Stem Cell Biology Group, Sanford Research 2 , Sioux Falls, SD 57104 , USA"},{"name":"Sanford School of Medicine, University of South Dakota 4 Department of Pediatrics , , Sioux Falls, SD 57105 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2022,12,16]]},"reference":[{"key":"2022121608303484100_DMM049843C1","doi-asserted-by":"publisher","first-page":"139","DOI":"10.3389\/fphar.2012.00139","article-title":"Calcium signaling and gliotransmission in normal vs. reactive astrocytes","volume":"3","author":"Agulhon","year":"2012","journal-title":"Front. 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