{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T13:30:18Z","timestamp":1790256618563,"version":"4.1.0"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T00:00:00Z","timestamp":1669852800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T00:00:00Z","timestamp":1669852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI139544"],"award-info":[{"award-number":["R01AI139544"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Neuroinflammation"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Aicardi\u2013Gouti\u00e8res syndrome (AGS) is a severe neurodegenerative disease with clinical features of early-onset encephalopathy and progressive loss of intellectual abilities and motor control. Gene mutations in seven protein-coding genes have been found to be associated with AGS. However, the causative role of these mutations in the early-onset neuropathogenesis has not been demonstrated in animal models, and the mechanism of neurodegeneration of AGS remains ambiguous.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Via CRISPR\/Cas-9 technology, we established a mutant mouse model in which a genetic mutation found in AGS patients at the ADAR1 coding gene (<jats:italic>Adar<\/jats:italic>) loci was introduced into the mouse genome. A mouse model carrying double gene mutations encoding ADAR1 and MDA-5 was prepared using a breeding strategy. Phenotype, gene expression, RNA sequencing, innate immune pathway activation, and pathologic studies including RNA in situ hybridization (ISH) and immunohistochemistry were used for characterization of the mouse models to determine potential disease mechanisms.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We established a mouse model bearing a mutation in the catalytic domain of ADAR1, the D1113H mutation found in AGS patients. With this mouse model, we demonstrated a causative role of this mutation for the early-onset brain injuries in AGS and determined the signaling pathway underlying the neuropathogenesis. First, this mutation altered the RNA editing profile in neural transcripts and led to robust IFN-stimulated gene (ISG) expression in the brain. By ISH, the brains of mutant mice showed an unusual, multifocal increased expression of ISGs that was cell-type dependent. Early-onset astrocytosis and microgliosis and later stage calcification in the deep white matter areas were observed in the mutant mice. Brain ISG activation and neuroglial reaction were completely prevented in the <jats:italic>Adar D1113H<\/jats:italic> mutant mice by blocking RNA sensing through deletion of the cytosolic RNA receptor MDA-5.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>The <jats:italic>Adar D1113H<\/jats:italic> mutation in the ADAR1 catalytic domain results in early-onset and MDA5-dependent encephalopathy with IFN pathway activation in the mouse brain.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12974-022-02646-0","type":"journal-article","created":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T18:14:47Z","timestamp":1669918487000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["An AGS-associated mutation in ADAR1 catalytic domain results in early-onset and MDA5-dependent encephalopathy with IFN pathway activation in the brain"],"prefix":"10.1186","volume":"19","author":[{"given":"Xinfeng","family":"Guo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Steinman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Sheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guodong","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clayton A.","family":"Wiley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingde","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,12,1]]},"reference":[{"key":"2646_CR1","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.1038\/ng.2414","volume":"44","author":"GI Rice","year":"2012","unstructured":"Rice GI, et al. Mutations in ADAR1 cause Aicardi-Goutieres syndrome associated with a type I interferon signature. Nat Genet. 2012;44:1243\u20138. https:\/\/doi.org\/10.1038\/ng.2414.","journal-title":"Nat Genet"},{"key":"2646_CR2","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1186\/s12974-021-02217-9","volume":"18","author":"X Guo","year":"2021","unstructured":"Guo X, et al. Aicardi-Goutieres syndrome-associated mutation at ADAR1 gene locus activates innate immune response in mouse brain. J Neuroinflammation. 2021;18:169. https:\/\/doi.org\/10.1186\/s12974-021-02217-9.","journal-title":"J Neuroinflammation"},{"key":"2646_CR3","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1002\/ajmg.a.36887","volume":"167A","author":"YJ Crow","year":"2015","unstructured":"Crow YJ, et al. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. Am J Med Genet A. 2015;167A:296\u2013312. https:\/\/doi.org\/10.1002\/ajmg.a.36887.","journal-title":"Am J Med Genet A"},{"key":"2646_CR4","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1055\/s-0036-1592307","volume":"47","author":"JH Livingston","year":"2016","unstructured":"Livingston JH, Crow YJ. Neurologic phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1: Aicardi-Goutieres syndrome and beyond. Neuropediatrics. 2016;47:355\u201360. https:\/\/doi.org\/10.1055\/s-0036-1592307.","journal-title":"Neuropediatrics"},{"key":"2646_CR5","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1111\/dmcn.14268","volume":"62","author":"YJ Crow","year":"2020","unstructured":"Crow YJ, Shetty J, Livingston JH. Treatments in Aicardi-Goutieres syndrome. Dev Med Child Neurol. 2020;62:42\u20137. https:\/\/doi.org\/10.1111\/dmcn.14268.","journal-title":"Dev Med Child Neurol"},{"key":"2646_CR6","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1002\/ana.410150109","volume":"15","author":"J Aicardi","year":"1984","unstructured":"Aicardi J, Goutieres F. A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol. 1984;15:49\u201354. https:\/\/doi.org\/10.1002\/ana.410150109.","journal-title":"Ann Neurol"},{"key":"2646_CR7","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1086\/521373","volume":"81","author":"G Rice","year":"2007","unstructured":"Rice G, et al. Clinical and molecular phenotype of Aicardi-Goutieres syndrome. Am J Hum Genet. 2007;81:713\u201325. https:\/\/doi.org\/10.1086\/521373.","journal-title":"Am J Hum Genet"},{"key":"2646_CR8","doi-asserted-by":"publisher","first-page":"1971","DOI":"10.3174\/ajnr.A1694","volume":"30","author":"C Uggetti","year":"2009","unstructured":"Uggetti C, et al. Aicardi-Goutieres syndrome: neuroradiologic findings and follow-up. AJNR Am J Neuroradiol. 2009;30:1971\u20136. https:\/\/doi.org\/10.3174\/ajnr.A1694.","journal-title":"AJNR Am J Neuroradiol"},{"key":"2646_CR9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/cei.12115","volume":"175","author":"YJ Crow","year":"2014","unstructured":"Crow YJ, Vanderver A, Orcesi S, Kuijpers TW, Rice GI. Therapies in Aicardi-Goutieres syndrome. Clin Exp Immunol. 2014;175:1\u20138. https:\/\/doi.org\/10.1111\/cei.12115.","journal-title":"Clin Exp Immunol"},{"key":"2646_CR10","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1055\/s-0037-1601449","volume":"48","author":"GI Rice","year":"2017","unstructured":"Rice GI, et al. Genetic, phenotypic, and interferon biomarker status in ADAR1-related neurological disease. Neuropediatrics. 2017;48:166\u201384. https:\/\/doi.org\/10.1055\/s-0037-1601449.","journal-title":"Neuropediatrics"},{"key":"2646_CR11","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1038\/nri3850","volume":"15","author":"YJ Crow","year":"2015","unstructured":"Crow YJ, Manel N. Aicardi-Goutieres syndrome and the type I interferonopathies. Nat Rev Immunol. 2015;15:429\u201340. https:\/\/doi.org\/10.1038\/nri3850.","journal-title":"Nat Rev Immunol"},{"key":"2646_CR12","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-021-00633-9","author":"YJ Crow","year":"2021","unstructured":"Crow YJ, Stetson DB. The type I interferonopathies: 10 years on. Nat Rev Immunol. 2021. https:\/\/doi.org\/10.1038\/s41577-021-00633-9.","journal-title":"Nat Rev Immunol"},{"key":"2646_CR13","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1038\/nature04734","volume":"441","author":"H Kato","year":"2006","unstructured":"Kato H, et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature. 2006;441:101\u20135. https:\/\/doi.org\/10.1038\/nature04734.","journal-title":"Nature"},{"key":"2646_CR14","doi-asserted-by":"publisher","first-page":"8459","DOI":"10.1073\/pnas.0603082103","volume":"103","author":"L Gitlin","year":"2006","unstructured":"Gitlin L, et al. Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. Proc Natl Acad Sci U S A. 2006;103:8459\u201364. https:\/\/doi.org\/10.1073\/pnas.0603082103.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2646_CR15","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.coi.2008.01.002","volume":"20","author":"O Takeuchi","year":"2008","unstructured":"Takeuchi O, Akira S. MDA5\/RIG-I and virus recognition. Curr Opin Immunol. 2008;20:17\u201322. https:\/\/doi.org\/10.1016\/j.coi.2008.01.002.","journal-title":"Curr Opin Immunol"},{"key":"2646_CR16","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1016\/j.cell.2008.06.032","volume":"134","author":"DB Stetson","year":"2008","unstructured":"Stetson DB, Ko JS, Heidmann T, Medzhitov R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell. 2008;134:587\u201398. https:\/\/doi.org\/10.1016\/j.cell.2008.06.032.","journal-title":"Cell"},{"key":"2646_CR17","doi-asserted-by":"publisher","first-page":"4952","DOI":"10.1074\/jbc.M310162200","volume":"279","author":"Q Wang","year":"2004","unstructured":"Wang Q, et al. Stress-induced apoptosis associated with null mutation of ADAR1 RNA editing deaminase gene. J Biol Chem. 2004;279:4952\u201361. https:\/\/doi.org\/10.1074\/jbc.M310162200.","journal-title":"J Biol Chem"},{"key":"2646_CR18","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1126\/science.aac7049","volume":"349","author":"BJ Liddicoat","year":"2015","unstructured":"Liddicoat BJ, et al. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science. 2015;349:1115\u201320. https:\/\/doi.org\/10.1126\/science.aac7049.","journal-title":"Science"},{"key":"2646_CR19","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1016\/j.immuni.2015.11.001","volume":"43","author":"K Pestal","year":"2015","unstructured":"Pestal K, et al. Isoforms of RNA-editing enzyme ADAR1 independently control nucleic acid sensor MDA5-driven autoimmunity and multi-organ development. Immunity. 2015;43:933\u201344. https:\/\/doi.org\/10.1016\/j.immuni.2015.11.001.","journal-title":"Immunity"},{"key":"2646_CR20","doi-asserted-by":"publisher","first-page":"1961","DOI":"10.1016\/j.immuni.2021.08.011","volume":"54","author":"Q Tang","year":"2021","unstructured":"Tang Q, et al. Adenosine-to-inosine editing of endogenous Z-form RNA by the deaminase ADAR1 prevents spontaneous MAVS-dependent type I interferon responses. Immunity. 2021;54:1961-1975 e1965. https:\/\/doi.org\/10.1016\/j.immuni.2021.08.011.","journal-title":"Immunity"},{"key":"2646_CR21","doi-asserted-by":"publisher","first-page":"1948","DOI":"10.1016\/j.immuni.2021.07.001","volume":"54","author":"M Maurano","year":"2021","unstructured":"Maurano M, et al. Protein kinase R and the integrated stress response drive immunopathology caused by mutations in the RNA deaminase ADAR1. Immunity. 2021;54:1948-1960 e1945. https:\/\/doi.org\/10.1016\/j.immuni.2021.07.001.","journal-title":"Immunity"},{"key":"2646_CR22","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109500","volume":"36","author":"R de Reuver","year":"2021","unstructured":"de Reuver R, et al. ADAR1 interaction with Z-RNA promotes editing of endogenous double-stranded RNA and prevents MDA5-dependent immune activation. Cell Rep. 2021;36: 109500. https:\/\/doi.org\/10.1016\/j.celrep.2021.109500.","journal-title":"Cell Rep"},{"key":"2646_CR23","doi-asserted-by":"publisher","first-page":"1976","DOI":"10.1016\/j.immuni.2021.08.022","volume":"54","author":"T Nakahama","year":"2021","unstructured":"Nakahama T, et al. Mutations in the adenosine deaminase ADAR1 that prevent endogenous Z-RNA binding induce Aicardi-Goutieres-syndrome-like encephalopathy. Immunity. 2021;54:1976-1988 e1977. https:\/\/doi.org\/10.1016\/j.immuni.2021.08.022.","journal-title":"Immunity"},{"key":"2646_CR24","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2100526","author":"M Inoue","year":"2021","unstructured":"Inoue M, et al. An Aicardi-Goutieres Syndrome-causative point mutation in Adar1 gene invokes multiorgan inflammation and late-onset encephalopathy in mice. J Immunol. 2021. https:\/\/doi.org\/10.4049\/jimmunol.2100526.","journal-title":"J Immunol"},{"key":"2646_CR25","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1080\/15476286.2016.1267097","volume":"14","author":"AJ Fisher","year":"2017","unstructured":"Fisher AJ, Beal PA. Effects of Aicardi-Goutieres syndrome mutations predicted from ADAR-RNA structures. RNA Biol. 2017;14:164\u201370. https:\/\/doi.org\/10.1080\/15476286.2016.1267097.","journal-title":"RNA Biol"},{"key":"2646_CR26","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1038\/35017558","volume":"406","author":"M Higuchi","year":"2000","unstructured":"Higuchi M, et al. Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2. Nature. 2000;406:78\u201381. https:\/\/doi.org\/10.1038\/35017558.","journal-title":"Nature"},{"key":"2646_CR27","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1261\/rna.072728.119","volume":"26","author":"PH Costa Cruz","year":"2020","unstructured":"Costa Cruz PH, Kato Y, Nakahama T, Shibuya T, Kawahara Y. A comparative analysis of ADAR mutant mice reveals site-specific regulation of RNA editing. RNA. 2020;26:454\u201369. https:\/\/doi.org\/10.1261\/rna.072728.119.","journal-title":"RNA"},{"key":"2646_CR28","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1186\/s13059-017-1301-4","volume":"18","author":"JE Heraud-Farlow","year":"2017","unstructured":"Heraud-Farlow JE, et al. Protein recoding by ADAR1-mediated RNA editing is not essential for normal development and homeostasis. Genome Biol. 2017;18:166. https:\/\/doi.org\/10.1186\/s13059-017-1301-4.","journal-title":"Genome Biol"},{"key":"2646_CR29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1009516","volume":"17","author":"JI Kim","year":"2021","unstructured":"Kim JI, et al. RNA editing at a limited number of sites is sufficient to prevent MDA5 activation in the mouse brain. PLoS Genet. 2021;17: e1009516. https:\/\/doi.org\/10.1371\/journal.pgen.1009516.","journal-title":"PLoS Genet"},{"key":"2646_CR30","doi-asserted-by":"publisher","first-page":"1482","DOI":"10.1016\/j.celrep.2014.10.041","volume":"9","author":"NM Mannion","year":"2014","unstructured":"Mannion NM, et al. The RNA-editing enzyme ADAR1 controls innate immune responses to RNA. Cell Rep. 2014;9:1482\u201394. https:\/\/doi.org\/10.1016\/j.celrep.2014.10.041.","journal-title":"Cell Rep"},{"key":"2646_CR31","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.202101191","author":"X Guo","year":"2022","unstructured":"Guo X, et al. ADAR1 RNA editing regulates endothelial cell functions via the MDA-5 RNA sensing signaling pathway. Life Sci Alliance. 2022. https:\/\/doi.org\/10.26508\/lsa.202101191.","journal-title":"Life Sci Alliance"},{"key":"2646_CR32","doi-asserted-by":"publisher","first-page":"4894","DOI":"10.1074\/jbc.M311347200","volume":"279","author":"JC Hartner","year":"2004","unstructured":"Hartner JC, et al. Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1. J Biol Chem. 2004;279:4894\u2013902. https:\/\/doi.org\/10.1074\/jbc.M311347200.","journal-title":"J Biol Chem"},{"key":"2646_CR33","doi-asserted-by":"publisher","first-page":"1765","DOI":"10.1126\/science.290.5497.1765","volume":"290","author":"Q Wang","year":"2000","unstructured":"Wang Q, Khillan J, Gadue P, Nishikura K. Requirement of the RNA editing deaminase ADAR1 gene for embryonic erythropoiesis. Science. 2000;290:1765\u20138. https:\/\/doi.org\/10.1126\/science.290.5497.1765.","journal-title":"Science"},{"key":"2646_CR34","doi-asserted-by":"publisher","first-page":"17763","DOI":"10.1073\/pnas.0903324106","volume":"106","author":"R XuFeng","year":"2009","unstructured":"XuFeng R, et al. ADAR1 is required for hematopoietic progenitor cell survival via RNA editing. Proc Natl Acad Sci U S A. 2009;106:17763\u20138. https:\/\/doi.org\/10.1073\/pnas.0903324106.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2646_CR35","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1038\/ni.1680","volume":"10","author":"JC Hartner","year":"2009","unstructured":"Hartner JC, Walkley CR, Lu J, Orkin SH. ADAR1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling. Nat Immunol. 2009;10:109\u201315. https:\/\/doi.org\/10.1038\/ni.1680.","journal-title":"Nat Immunol"},{"key":"2646_CR36","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1073\/pnas.1017241108","volume":"108","author":"SV Ward","year":"2011","unstructured":"Ward SV, et al. RNA editing enzyme adenosine deaminase is a restriction factor for controlling measles virus replication that also is required for embryogenesis. Proc Natl Acad Sci U S A. 2011;108:331\u20136. https:\/\/doi.org\/10.1073\/pnas.1017241108.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2646_CR37","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1111\/j.1365-2990.2010.01089.x","volume":"36","author":"M Muller","year":"2010","unstructured":"Muller M, Carter S, Hofer MJ, Campbell IL. Review: the chemokine receptor CXCR3 and its ligands CXCL9, CXCL10 and CXCL11 in neuroimmunity\u2014a tale of conflict and conundrum. Neuropathol Appl Neurobiol. 2010;36:368\u201387. https:\/\/doi.org\/10.1111\/j.1365-2990.2010.01089.x.","journal-title":"Neuropathol Appl Neurobiol"},{"key":"2646_CR38","doi-asserted-by":"publisher","first-page":"1505","DOI":"10.4049\/jimmunol.169.3.1505","volume":"169","author":"K Boztug","year":"2002","unstructured":"Boztug K, et al. Leukocyte infiltration, but not neurodegeneration, in the CNS of transgenic mice with astrocyte production of the CXC chemokine ligand 10. J Immunol. 2002;169:1505\u201315. https:\/\/doi.org\/10.4049\/jimmunol.169.3.1505.","journal-title":"J Immunol"},{"key":"2646_CR39","doi-asserted-by":"publisher","first-page":"1866","DOI":"10.1089\/neu.2015.4272","volume":"33","author":"CA Wiley","year":"2016","unstructured":"Wiley CA, et al. Ultrastructure of Diaschisis Lesions after traumatic brain injury. J Neurotrauma. 2016;33:1866\u201382. https:\/\/doi.org\/10.1089\/neu.2015.4272.","journal-title":"J Neurotrauma"},{"key":"2646_CR40","doi-asserted-by":"publisher","first-page":"2735","DOI":"10.1084\/jem.20090222","volume":"206","author":"JD Brien","year":"2009","unstructured":"Brien JD, Uhrlaub JL, Hirsch A, Wiley CA, Nikolich-Zugich J. Key role of T cell defects in age-related vulnerability to West Nile virus. J Exp Med. 2009;206:2735\u201345. https:\/\/doi.org\/10.1084\/jem.20090222.","journal-title":"J Exp Med"}],"container-title":["Journal of Neuroinflammation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12974-022-02646-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12974-022-02646-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12974-022-02646-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T18:19:46Z","timestamp":1669918786000},"score":1,"resource":{"primary":{"URL":"https:\/\/jneuroinflammation.biomedcentral.com\/articles\/10.1186\/s12974-022-02646-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,1]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["2646"],"URL":"https:\/\/doi.org\/10.1186\/s12974-022-02646-0","relation":{},"ISSN":["1742-2094"],"issn-type":[{"value":"1742-2094","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,1]]},"assertion":[{"value":"11 May 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 November 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 December 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing financial interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"285"}}