{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T05:12:19Z","timestamp":1792213939178,"version":"4.4.0"},"reference-count":116,"publisher":"Oxford University Press (OUP)","issue":"19","license":[{"start":{"date-parts":[[2020,9,22]],"date-time":"2020-09-22T00:00:00Z","timestamp":1600732800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012126","name":"Alzheimer's Research Foundation","doi-asserted-by":"publisher","award":["ARUK-SRF2013-7"],"award-info":[{"award-number":["ARUK-SRF2013-7"]}],"id":[{"id":"10.13039\/100012126","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012126","name":"Alzheimer's Research Foundation","doi-asserted-by":"publisher","award":["ARUK-PG2019B-018"],"award-info":[{"award-number":["ARUK-PG2019B-018"]}],"id":[{"id":"10.13039\/100012126","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/M009513\/1"],"award-info":[{"award-number":["BB\/M009513\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,11,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Genome-wide association studies have reported that, amongst other microglial genes, variants in TREM2 can profoundly increase the incidence of developing Alzheimer\u2019s disease (AD). We have investigated the role of TREM2 in primary microglial cultures from wild type mice by using siRNA to decrease Trem2 expression, and in parallel from knock-in mice heterozygous or homozygous for the Trem2 R47H AD risk variant. The prevailing phenotype of Trem2 R47H knock-in mice was decreased expression levels of Trem2 in microglia, which resulted in decreased density of microglia in the hippocampus. Overall, primary microglia with reduced Trem2 expression, either by siRNA or from the R47H knock-in mice, displayed a similar phenotype. Comparison of the effects of decreased Trem2 expression under conditions of lipopolysaccharide (LPS) pro-inflammatory or IL-4 anti-inflammatory stimulation revealed the importance of Trem2 in driving a number of the genes up-regulated in the anti-inflammatory phenotype. RNA-seq analysis showed that IL-4 induced the expression of a program of genes including Arg1 and Ap1b1 in microglia, which showed an attenuated response to IL-4 when Trem2 expression was decreased. Genes showing a similar expression profile to Arg1 were enriched for STAT6 transcription factor recognition elements in their promoter, and Trem2 knockdown decreased levels of STAT6. LPS-induced pro-inflammatory stimulation suppressed Trem2 expression, thus preventing TREM2\u2019s anti-inflammatory drive. Given that anti-inflammatory signaling is associated with tissue repair, understanding the signaling mechanisms downstream of Trem2 in coordinating the pro- and anti-inflammatory balance of microglia, particularly mediating effects of the IL-4-regulated anti-inflammatory pathway, has important implications for fighting neurodegenerative disease.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa209","type":"journal-article","created":{"date-parts":[[2020,9,21]],"date-time":"2020-09-21T15:23:12Z","timestamp":1600701792000},"page":"3224-3248","source":"Crossref","is-referenced-by-count":204,"title":["<i>Trem2<\/i>\n                    promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions"],"prefix":"10.1093","volume":"29","author":[{"given":"Wenfei","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Physiology and Pharmacology, UCL, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orjona","family":"Taso","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at UCL, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Physiology and Pharmacology, UCL, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sevinc","family":"Bayram","sequence":"additional","affiliation":[{"name":"Hitachi Rail Europe Ltd, London EC1N 2PB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew C","family":"Graham","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at UCL, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Garcia-Reitboeck","sequence":"additional","affiliation":[{"name":"Department of Neuroinflammation, Institute of Neurology, UCL, London WC1N 1PJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Mallach","sequence":"additional","affiliation":[{"name":"Department of Neuroinflammation, Institute of Neurology, UCL, London WC1N 1PJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William D","family":"Andrews","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, UCL, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas M","family":"Piers","sequence":"additional","affiliation":[{"name":"Department of Neuroinflammation, Institute of Neurology, UCL, London WC1N 1PJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan A","family":"Botia","sequence":"additional","affiliation":[{"name":"Department of Information and Communications Engineering, Universidad de Murcia, Murcia E-30100, Spain"},{"name":"Department of Neurodegenerative Diseases, Institute of Neurology, UCL, London WC1N 1PJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer M","family":"Pocock","sequence":"additional","affiliation":[{"name":"Department of Neuroinflammation, Institute of Neurology, UCL, London WC1N 1PJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5567-0907","authenticated-orcid":false,"given":"Damian M","family":"Cummings","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Physiology and Pharmacology, UCL, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Hardy","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at UCL, London WC1E 6BT, UK"},{"name":"Department of Neurodegenerative Diseases, Institute of Neurology, UCL, London WC1N 1PJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances A","family":"Edwards","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Physiology and Pharmacology, UCL, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7651-8998","authenticated-orcid":false,"given":"Dervis A","family":"Salih","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Physiology and Pharmacology, UCL, London WC1E 6BT, UK"},{"name":"UK Dementia Research Institute at UCL, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,9,22]]},"reference":[{"key":"2020120619072615900_ref1","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1038\/nn.4587","article-title":"A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease","volume":"20","author":"Huang","year":"2017","journal-title":"Nat. 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Neuro."},{"key":"2020120619072615900_ref23","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1001\/jamaneurol.2013.6237","article-title":"TREM2 variant p.R47H as a risk factor for sporadic amyotrophic lateral sclerosis","volume":"71","author":"Cady","year":"2014","journal-title":"JAMA Neurol."},{"key":"2020120619072615900_ref24","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/1750-1326-8-19","article-title":"TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson's disease","volume":"8","author":"Rayaprolu","year":"2013","journal-title":"Mol. Neurodegener."},{"key":"2020120619072615900_ref25","doi-asserted-by":"crossref","first-page":"217.e1","DOI":"10.1016\/j.neurobiolaging.2016.02.023","article-title":"A rare coding variant in TREM2 increases risk for Alzheimer's disease in Han Chinese","volume":"42","author":"Jiang","year":"2016","journal-title":"Neurobiol. 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