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TREM2 can be activated by antibodies targeting the stalk region, most likely through receptor dimerization. Endogenous ligands of TREM2 are suggested to be negatively charged apoptotic bodies, mimicked by phosphatidylserine incorporated in liposomes and other polyanionic molecules likely binding to TREM2 IgV fold. However, there has been much discrepancy in the literature on the nature of phospholipids (PLs) that can activate TREM2 and on the stability of the corresponding liposomes over time. We describe optimized liposomes as robust agonists selective for TREM2 over TREM1 in cellular system. The detailed structure\/activity relationship studies of lipid polar heads indicate that negatively charged lipid heads are required for activity and we identified the shortest maximally active PL sidechain. Optimized liposomes are active on both TREM2 common variant and TREM2 R47H mutant. Activity and selectivity were further confirmed in different native TREM2 expressing cell types including on integrated cellular responses such as stimulation of phagocytic activity. Such tool agonists will be useful in further studies of TREM2 biology in cellular systems alongside antibodies, and in the design of small molecule synthetic TREM2 agonists.<\/jats:p>","DOI":"10.1002\/glia.24252","type":"journal-article","created":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T07:22:27Z","timestamp":1659338547000},"page":"2290-2308","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Novel potent liposome agonists of triggering receptor expressed on myeloid cells 2 phenocopy antibody treatment in cells"],"prefix":"10.1002","volume":"70","author":[{"given":"Christophe","family":"Boudesco","sequence":"first","affiliation":[{"name":"Rare and Neurology TA Sanofi  Chilly\u2010Mazarin France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annelies","family":"Nonneman","sequence":"additional","affiliation":[{"name":"Neuroscience Janssen Research &amp; Development  Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Cinti","sequence":"additional","affiliation":[{"name":"Cell biology Axxam SpA  Bresso Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Picardi","sequence":"additional","affiliation":[{"name":"Cell biology Axxam SpA  Bresso Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loredana","family":"Redaelli","sequence":"additional","affiliation":[{"name":"Cell biology Axxam SpA  Bresso Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofie","family":"Swijsen","sequence":"additional","affiliation":[{"name":"In vivo Charles River Laboratories  Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Roewe","sequence":"additional","affiliation":[{"name":"Neuroscience Discovery AbbVie Deutschland GmbH &amp; Co. 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