{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T14:04:51Z","timestamp":1793109891137,"version":"4.5.0"},"reference-count":78,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2019,1,25]],"date-time":"2019-01-25T00:00:00Z","timestamp":1548374400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AG050626"],"award-info":[{"award-number":["R01 AG050626"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["09\/09\/07"],"award-info":[{"award-number":["09\/09\/07"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Glia"],"published-print":{"date-parts":[[2019,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Type I interferons (IFN\u2010I) are the principal antiviral molecules of the innate immune system and can be made by most cell types, including central nervous system cells. IFN\u2010I has been implicated in neuroinflammation during neurodegeneration, but its mechanism of induction and its consequences remain unclear. In the current study, we assessed expression of IFN\u2010I in murine prion disease (ME7) and examined the contribution of the IFN\u2010I receptor IFNAR1 to disease progression. The data indicate a robust IFN\u03b2 response, specifically in microglia, with evidence of IFN\u2010dependent genes in both microglia and astrocytes. This IFN\u2010I response was absent in stimulator of interferon genes (STING<jats:sup>\u2212\/\u2212<\/jats:sup>) mice. Microglia showed increased numbers and activated morphology independent of genotype, but transcriptional signatures indicated an IFNAR1\u2010dependent neuroinflammatory phenotype. Isolation of microglia and astrocytes demonstrated disease\u2010associated microglial induction of <jats:italic>Tnf\u03b1<\/jats:italic>, <jats:italic>Tgfb1<\/jats:italic>, and of phagolysosomal system transcripts including those for cathepsins, <jats:italic>Cd68<\/jats:italic>, <jats:italic>C1qa<\/jats:italic>, <jats:italic>C3<\/jats:italic>, and <jats:italic>Trem2<\/jats:italic>, which were diminished in IFNAR1 and STING deficient mice. Microglial increases in activated cathepsin D, and CD68 were significantly reduced in IFNAR1<jats:sup>\u2212\/\u2212<\/jats:sup> mice, particularly in white matter, and increases in COX\u20101 expression, and prostaglandin synthesis were significantly mitigated. Disease progressed more slowly in IFNAR1<jats:sup>\u2212\/\u2212<\/jats:sup> mice, with diminished synaptic and neuronal loss and delayed onset of neurological signs and death but without effect on proteinase K\u2010resistant PrP levels. Therefore, STING\u2010dependent IFN\u2010I influences microglial phenotype and influences neurodegenerative progression despite occurring secondary to initial degenerative changes. These data expand our mechanistic understanding of IFN\u2010I induction and its impact on microglial function during chronic neurodegeneration.<\/jats:p>","DOI":"10.1002\/glia.23592","type":"journal-article","created":{"date-parts":[[2019,1,25]],"date-time":"2019-01-25T09:47:08Z","timestamp":1548409628000},"page":"1254-1276","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":133,"title":["Chronic neurodegeneration induces type I interferon synthesis via STING, shaping microglial phenotype and accelerating disease progression"],"prefix":"10.1002","volume":"67","author":[{"given":"Arshed","family":"Nazmi","sequence":"first","affiliation":[{"name":"School of Biochemistry and Immunology Trinity College Institute of Neuroscience &amp; Trinity Biomedical Sciences Institute, Trinity College Dublin  Dublin Republic of Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert H.","family":"Field","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology Trinity College Institute of Neuroscience &amp; Trinity Biomedical Sciences Institute, Trinity College Dublin  Dublin Republic of Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eadaoin W.","family":"Griffin","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology Trinity College Institute of Neuroscience &amp; Trinity Biomedical Sciences Institute, Trinity College Dublin  Dublin Republic of Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orla","family":"Haugh","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology Trinity College Institute of Neuroscience &amp; Trinity Biomedical Sciences Institute, Trinity College Dublin  Dublin Republic of Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edel","family":"Hennessy","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology Trinity College Institute of Neuroscience &amp; Trinity Biomedical Sciences Institute, Trinity College Dublin  Dublin Republic of Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donal","family":"Cox","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology Trinity College Institute of Neuroscience &amp; Trinity Biomedical Sciences Institute, Trinity College Dublin  Dublin Republic of Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata","family":"Reis","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology Trinity College Institute of Neuroscience &amp; Trinity Biomedical Sciences Institute, Trinity College Dublin  Dublin Republic of Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas","family":"Tortorelli","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology Trinity College Institute of Neuroscience &amp; Trinity Biomedical Sciences Institute, Trinity College Dublin  Dublin Republic of Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol L.","family":"Murray","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology Trinity College Institute of Neuroscience &amp; Trinity Biomedical Sciences Institute, Trinity College Dublin  Dublin Republic of Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Belen","family":"Lopez\u2010Rodriguez","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology Trinity College Institute of Neuroscience &amp; Trinity Biomedical Sciences Institute, Trinity College Dublin  Dublin Republic of Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine University of Florida  Gainesville Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ed C.","family":"Lavelle","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology Trinity College Institute of Neuroscience &amp; Trinity Biomedical Sciences Institute, Trinity College Dublin  Dublin Republic of Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aisling","family":"Dunne","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology Trinity College Institute of Neuroscience &amp; Trinity Biomedical Sciences Institute, Trinity College Dublin  Dublin Republic of Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1423-5209","authenticated-orcid":false,"given":"Colm","family":"Cunningham","sequence":"additional","affiliation":[{"name":"School of Biochemistry and Immunology Trinity College Institute of Neuroscience &amp; Trinity Biomedical Sciences Institute, Trinity College Dublin  Dublin Republic of Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,1,25]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-018-1354-7"},{"key":"e_1_2_7_3_1","doi-asserted-by":"crossref","first-page":"5016","DOI":"10.4049\/jimmunol.161.9.5016","article-title":"Transgenic expression of IFN\u2010alpha in the central nervous system of mice protects against lethal neurotropic viral infection but induces inflammation and neurodegeneration","volume":"161","author":"Akwa Y.","year":"1998","journal-title":"Journal of Immunology"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1977.tb22003.x"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1080\/13550280490261761"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1252945"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2005.09.008"},{"issue":"4","key":"e_1_2_7_8_1","first-page":"495","article-title":"Pharmacological manipulation of early PrPres accumulation in the spleen of scrapie\u2010infected mice","volume":"190","author":"Beringue V.","year":"2000","journal-title":"Archives of Virology. Supplementum"},{"issue":"1","key":"e_1_2_7_9_1","doi-asserted-by":"crossref","first-page":"63","DOI":"10.3758\/BF03332100","article-title":"Behavioural consequences of prion disease targeted to the hippocampus in a mouse model of scrapie","volume":"27","author":"Betmouni S.","year":"1999","journal-title":"Psychobiology"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.04.005"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5002-13.2014"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(99)01328-1"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.02.004"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3558"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22786"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.2003.02662.x"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2004.08.015"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2006.12.007"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/62.2.208"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1097\/00001756-200107030-00052"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.08.069"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI1112"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2005.03.008"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2010.04.004"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M605146200"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(01)00517-6"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201490791"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4440-12.2013"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.58.2.169"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2009.04.001"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.6361-11.2013"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.02.006"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2013.04.004"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.01.012"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2015.01.004"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-015-0203-5"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad8373"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0203-12.2012"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.21070"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.24.11284"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.736991"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1098\/rspb.1957.0048"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08476"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100088"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI77487"},{"issue":"1276","key":"e_1_2_7_46_1","first-page":"e1217","article-title":"A unique microglia type associated with restricting development of Alzheimer's disease","volume":"169","author":"Keren\u2010Shaul H.","year":"2017","journal-title":"Cell"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0901753"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-015-1418-z"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1808-05.2005"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0804277"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1203450"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23028"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2016.410"},{"issue":"1290","key":"e_1_2_7_54_1","first-page":"e1296","article-title":"Activation of the STING\u2010dependent type I interferon response reduces microglial reactivity and neuroinflammation","volume":"96","author":"Mathur V.","year":"2017","journal-title":"Neuron"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.09.039"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2015.06.008"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-016-0341-4"},{"key":"e_1_2_7_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11058"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3006767"},{"key":"e_1_2_7_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2015.04.009"},{"key":"e_1_2_7_61_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1003600"},{"key":"e_1_2_7_62_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22608"},{"key":"e_1_2_7_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2007.11.012"},{"key":"e_1_2_7_64_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.56.070187.003455"},{"key":"e_1_2_7_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.03.011"},{"key":"e_1_2_7_66_1","doi-asserted-by":"publisher","DOI":"10.1111\/nan.12232"},{"key":"e_1_2_7_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2004.08.124"},{"key":"e_1_2_7_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2011.10.008"},{"key":"e_1_2_7_69_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5577-06.2007"},{"key":"e_1_2_7_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)62336-X"},{"key":"e_1_2_7_71_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12640-013-9410-7"},{"key":"e_1_2_7_72_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.091037"},{"key":"e_1_2_7_73_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.10.036"},{"key":"e_1_2_7_74_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-2-5"},{"key":"e_1_2_7_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2013.10.089"},{"key":"e_1_2_7_76_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1432-1327.2001.02273.x"},{"key":"e_1_2_7_77_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mp.4002013"},{"key":"e_1_2_7_78_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.21167"},{"key":"e_1_2_7_79_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2667"}],"container-title":["Glia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fglia.23592","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/glia.23592","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/glia.23592","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/glia.23592","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,10]],"date-time":"2023-09-10T22:09:28Z","timestamp":1694383768000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/glia.23592"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,25]]},"references-count":78,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2019,7]]}},"alternative-id":["10.1002\/glia.23592"],"URL":"https:\/\/doi.org\/10.1002\/glia.23592","archive":["Portico"],"relation":{},"ISSN":["0894-1491","1098-1136"],"issn-type":[{"value":"0894-1491","type":"print"},{"value":"1098-1136","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,1,25]]},"assertion":[{"value":"2017-08-31","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-12-28","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-01-25","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}