{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:09:02Z","timestamp":1789171742703,"version":"build-2803163510"},"reference-count":67,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2021,2,4]],"date-time":"2021-02-04T00:00:00Z","timestamp":1612396800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["FOR2953 no. 432190414"],"award-info":[{"award-number":["FOR2953 no. 432190414"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Glia"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>\n                      Genome\u2010wide association studies demonstrated that polymorphisms in the CD33\/sialic acid\u2010binding immunoglobulin\u2010like lectin 3 gene are associated with late\u2010onset Alzheimer's disease (AD). CD33 is expressed on myeloid immune cells and mediates inhibitory signaling through protein tyrosine phosphatases, but the exact function of CD33 in microglia is still unknown. Here, we analyzed\n                      <jats:italic>CD33<\/jats:italic>\n                      knockout human THP1 macrophages and human induced pluripotent stem cell\u2010derived microglia for immunoreceptor tyrosine\u2010based activation motif pathway activation, cytokine transcription, phagocytosis, and phagocytosis\u2010associated oxidative burst. Transcriptome analysis of the macrophage lines showed that knockout of\n                      <jats:italic>CD33<\/jats:italic>\n                      as well as knockdown of the CD33 signaling\u2010associated\n                      <jats:italic>protein tyrosine phosphatase<\/jats:italic>\n                      ,\n                      <jats:italic>nonreceptor type 6<\/jats:italic>\n                      (\n                      <jats:italic>PTPN6)<\/jats:italic>\n                      led to constitutive activation of inflammation\u2010related pathways. Moreover, deletion of\n                      <jats:italic>CD33<\/jats:italic>\n                      or expression of Exon 2\u2010deleted CD33 (CD33\n                      <jats:sup>\u0394E2<\/jats:sup>\n                      \/CD33m) led to increased phosphorylation of the kinases spleen tyrosine kinase (SYK) and extracellular signal\u2010regulated kinase 1 and 2 (ERK1 and 2). Transcript analysis by quantitative real\u2010time polymerase chain reaction confirmed increased levels of\n                      <jats:italic>interleukin<\/jats:italic>\n                      (\n                      <jats:italic>IL) 1B<\/jats:italic>\n                      ,\n                      <jats:italic>IL8<\/jats:italic>\n                      , and\n                      <jats:italic>IL10<\/jats:italic>\n                      after knockout of\n                      <jats:italic>CD33<\/jats:italic>\n                      in macrophages and microglia. In addition, upregulation of the gene transcripts of the AD\u2010associated phosphatase\n                      <jats:italic>INPP5D<\/jats:italic>\n                      was observed after knockout of\n                      <jats:italic>CD33<\/jats:italic>\n                      . Functional analysis of macrophages and microglia showed that phagocytosis of aggregated amyloid\u2010\u03b2\n                      <jats:sub>1\u201042<\/jats:sub>\n                      and bacterial particles were increased after knockout of\n                      <jats:italic>CD33<\/jats:italic>\n                      or CD33\n                      <jats:sup>\u0394E2<\/jats:sup>\n                      expression and knockdown of\n                      <jats:italic>PTPN6<\/jats:italic>\n                      . Furthermore, the phagocytic oxidative burst during uptake of amyloid\u2010\u03b2\n                      <jats:sub>1\u201042<\/jats:sub>\n                      or bacterial particles was increased after\n                      <jats:italic>CD33<\/jats:italic>\n                      knockout but not in CD33\n                      <jats:sup>\u0394E2<\/jats:sup>\n                      \u2010expressing microglia. In summary, deletion of\n                      <jats:italic>CD33<\/jats:italic>\n                      or expression of CD33\n                      <jats:sup>\u0394E2<\/jats:sup>\n                      in human macrophages and microglia resulted in putative beneficial phagocytosis of amyloid \u03b2\n                      <jats:sub>1\u201042<\/jats:sub>\n                      , but potentially detrimental oxidative burst and inflammation, which was absent in CD33\n                      <jats:sup>\u0394E2<\/jats:sup>\n                      \u2010expressing microglia.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/glia.23968","type":"journal-article","created":{"date-parts":[[2021,2,7]],"date-time":"2021-02-07T20:16:33Z","timestamp":1612728993000},"page":"1393-1412","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":94,"title":["Deletion of Alzheimer's disease\u2010associated\n                    <scp>CD33<\/scp>\n                    results in an inflammatory human microglia phenotype"],"prefix":"10.1002","volume":"69","author":[{"given":"Jannis","family":"Wi\u00dffeld","sequence":"first","affiliation":[{"name":"Institute of Reconstructive Neurobiology University of Bonn Medical Faculty and University Hospital Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ichiro","family":"Nozaki","sequence":"additional","affiliation":[{"name":"Institute of Reconstructive Neurobiology University of Bonn Medical Faculty and University Hospital Bonn  Bonn Germany"},{"name":"Department of Neurology and Neurobiology of Aging Kanazawa University Graduate School of Medical Sciences  Kanazawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mona","family":"Mathews","sequence":"additional","affiliation":[{"name":"Institute of Reconstructive Neurobiology University of Bonn Medical Faculty and University Hospital Bonn  Bonn Germany"},{"name":"LIFE &amp; BRAIN GmbH, Cellomics Unit  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Raschka","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics Fraunhofer Institute for Algorithms and Scientific Computing  Sankt Augustin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Ebeling","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics Fraunhofer Institute for Algorithms and Scientific Computing  Sankt Augustin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veit","family":"Hornung","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine University of Bonn Medical Faculty and University Hospital Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Br\u00fcstle","sequence":"additional","affiliation":[{"name":"Institute of Reconstructive Neurobiology University of Bonn Medical Faculty and University Hospital Bonn  Bonn Germany"},{"name":"LIFE &amp; BRAIN GmbH, Cellomics Unit  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5071-5202","authenticated-orcid":false,"given":"Harald","family":"Neumann","sequence":"additional","affiliation":[{"name":"Institute of Reconstructive Neurobiology University of Bonn Medical Faculty and University Hospital Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,2,4]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M210602200"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.11.6841"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.12659\/MSM.895622"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-019-0698-6"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2404986"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3435"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.12.4199-4206.2003"},{"key":"e_1_2_10_9_1","first-page":"1000","article-title":"Gene expression regulation in retinal pigment epithelial cells induced by viral RNA and viral\/bacterial DNA","volume":"21","author":"Brosig A.","year":"2015","journal-title":"Molecular Vision"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.664136"},{"key":"e_1_2_10_11_1","unstructured":"Carlson M.(2019).org.Hs.eg.db: Genome wide annotation for Human."},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2211-13.2013"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST0361467"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.186.7.1027"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V85.8.2005.bloodjournal8582005"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.090147"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20071283"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.04.014"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22842"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.803"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V100.5.1852.h81702001852_1852_1859"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458507087136"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2005.02.039"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200425273"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2802"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.3109\/08820139.2011.595471"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt656"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3830-11.2012"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a002352"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-472X(02)01031-7"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.187.8.1355"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1202552"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1224-13.2013"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2008.12.001"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80071-4"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni1407"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.801"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M210698200"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1300466"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V96.2.483"},{"key":"e_1_2_10_43_1","volume-title":"RStudio: Integrated development for R","author":"RStudio Team","year":"2015"},{"key":"e_1_2_10_44_1","volume-title":"R: A language and environment for statistical computing","author":"R Core Team","year":"2018"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt666"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1093\/glycob\/10.5.477"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2014.07.006"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1003551"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-009-0472-1"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.176701.114"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-2932-0_19"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep14987"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep16800"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M117.799346"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200636830"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00695495"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20041611"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.17.11505"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajpa.10018"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-11-325050"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0607388"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3940-09.2010"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-24277-4"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1177\/1753425917694245"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.03.030"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty895"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature06901"}],"container-title":["Glia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/glia.23968","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/glia.23968","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/glia.23968","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T10:42:15Z","timestamp":1693564935000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/glia.23968"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,4]]},"references-count":67,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2021,6]]}},"alternative-id":["10.1002\/glia.23968"],"URL":"https:\/\/doi.org\/10.1002\/glia.23968","archive":["Portico"],"relation":{},"ISSN":["0894-1491","1098-1136"],"issn-type":[{"value":"0894-1491","type":"print"},{"value":"1098-1136","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,4]]},"assertion":[{"value":"2020-10-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-01-08","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-02-04","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}