eprintid: 10062399 rev_number: 33 eprint_status: archive userid: 608 dir: disk0/10/06/23/99 datestamp: 2018-11-28 10:42:07 lastmod: 2021-09-21 22:06:51 status_changed: 2018-11-28 16:06:43 type: working_paper metadata_visibility: show creators_name: Liu, W creators_name: Taso, O creators_name: Wang, R creators_name: Garcia-Reitboeck, P creators_name: Andrews, WD creators_name: Piers, TM creators_name: Pocock, JM creators_name: Cummings, DM creators_name: Hardy, J creators_name: Edwards, FA creators_name: Salih, D title: Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions ispublished: unpub divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F86 divisions: F87 divisions: C08 divisions: D09 divisions: G02 divisions: D10 divisions: G10 keywords: TREM2, microglia, Alzheimer’s, inflammation, interleukin, STAT6, Arginase note: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. abstract: Recent genome-wide association studies have reported that, amongst other microglial genes, variants in TREM2 can profoundly increase the incidence of developing Alzheimer's 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 (from the Jackson laboratories). 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 LPS pro-inflammatory or IL4 anti-inflammatory stimulation revealed the importance of Trem2 in driving a number of the genes up-regulated in the anti-inflammatory phenotype, whether treated with RNAi or performed with microglia carrying the R47H variant. In particular, Trem2 knockdown decreased levels of the transcription factor STAT6. STAT6 is the key mediator downstream from IL4 and controls expression of genes including Arg1, which also showed decreased IL4-induced expression when Trem2 expression was decreased. LPS-induced pro-inflammatory stimulation suppressed Trem2 expression, thus preventing TREM2's anti-inflammatory drive. The importance of Trem2 activity in regulating the pro- and anti-inflammatory balance of microglia, particularly mediating effects of the IL4-regulated anti-inflammatory pathway, has important implications for fighting neurodegenerative disease. date: 2018-10-22 date_type: published publisher: bioRxiv official_url: https://doi.org/10.1101/449884 oa_status: green full_text_type: other language: eng primo: open primo_central: open_green article_type_text: Article verified: verified_manual elements_id: 1604882 doi: 10.1101/449884 language_elements: English lyricists_name: Andrews, William lyricists_name: Cummings, Damian lyricists_name: Edwards, Frances lyricists_name: Hardy, John lyricists_name: Liu, Wenfei lyricists_name: Pocock, Jennifer lyricists_name: Salih, Dervis lyricists_name: Smalley, June lyricists_name: Wang, Rui lyricists_id: WDAND87 lyricists_id: DMCUM02 lyricists_id: FAEDW40 lyricists_id: JHARD28 lyricists_id: WLIUX92 lyricists_id: JMPOC52 lyricists_id: DAMSA48 lyricists_id: JASMA87 lyricists_id: RWANA98 actors_name: Cummings, Damian actors_id: DMCUM02 actors_role: owner full_text_status: public publication: bioRxiv citation: Liu, W; Taso, O; Wang, R; Garcia-Reitboeck, P; Andrews, WD; Piers, TM; Pocock, JM; ... Salih, D; + view all <#> Liu, W; Taso, O; Wang, R; Garcia-Reitboeck, P; Andrews, WD; Piers, TM; Pocock, JM; Cummings, DM; Hardy, J; Edwards, FA; Salih, D; - view fewer <#> (2018) Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions. bioRxiv Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10062399/1/Cummings_Trem2%20promotes%20anti-inflammatory%20responses%20in%20microglia%20and%20is%20suppressed%20under%20pro-inflammatory%20conditions_AAM.pdf