TREM2 regulates microglial lipid droplet formation and represses post-ischemic brain injury

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dc.authorid0000-0002-1222-9211
dc.contributor.authorWei, Wei
dc.contributor.authorZhang, Lin
dc.contributor.authorXin, Wenqiang
dc.contributor.authorPan, Yongli
dc.contributor.authorTatenhorst, Lars
dc.contributor.authorHao, Zhongnan
dc.contributor.authorGerner, Stefan T.
dc.contributor.authorHuber, Sabine
dc.contributor.authorJuenemann, Martin
dc.contributor.authorDoeppner, Thorsten Roland
dc.date.accessioned2023-12-18T07:49:08Z
dc.date.available2023-12-18T07:49:08Z
dc.date.issued2024
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Sağlık Bilim ve Teknolojileri Araştırma Enstitüsü
dc.description.abstractTriggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor protein predominantly expressed in microglia within the central nervous system (CNS). TREM2 regulates multiple microglial functions, including lipid metabolism, immune reaction, inflammation, and microglial phagocytosis. Recent studies have found that TREM2 is highly expressed in activated microglia after ischemic stroke. However, the role of TREM2 in the pathologic response after stroke remains unclear. Herein, TREM2-deficient microglia exhibit an impaired phagocytosis rate and cholesteryl ester (CE) accumulation, leading to lipid droplet formation and upregulation of Perilipin-2 (PLIN2) expression after hypoxia. Knockdown of TREM2 results in increased lipid synthesis (PLIN2, SOAT1) and decreased cholesterol clearance and lipid hydrolysis (LIPA, ApoE, ABCA1, NECH1, and NPC2), further impacting microglial phenotypes. In these lipid droplet-rich microglia, the TGF-?1/Smad2/3 signaling pathway is downregulated, driving microglia towards a pro-inflammatory phenotype. Meanwhile, in a neuron-microglia co-culture system under hypoxic conditions, we found that microglia lost their protective effect against neuronal injury and apoptosis when TREM2 was knocked down. Under in vivo conditions, TREM2 knockdown mice express lower TGF-?1 expression levels and a lower number of anti-inflammatory M2 phenotype microglia, resulting in increased cerebral infarct size, exacerbated neuronal apoptosis, and aggravated neuronal impairment. Our work suggests that TREM2 attenuates stroke-induced neuroinflammation by modulating the TGF-?1/Smad2/3 signaling pathway. TREM2 may play a direct role in the regulation of inflammation and also exert an influence on the post-ischemic inflammation and the stroke pathology progression via regulation of lipid metabolism processes. Thus, underscoring the therapeutic potential of TREM2 agonists in ischemic stroke and making TREM2 an attractive new clinical target for the treatment of ischemic stroke and other inflammation-related diseases.
dc.description.sponsorshipNational Natural Science Foundation of China ; Science and Technology Commission of Shanghai Municipality ; China Scholarship Councilen_US
dc.identifier.citationWei, W., Zhang, L., Xin, W., Pan, Y., Tatenhorst, L., Hao, Z. ... Doeppner, T. R. (2024). TREM2 regulates microglial lipid droplet formation and represses post-ischemic brain injury. Biomedicine and Pharmacotherapy, 170. https://dx.doi.org/10.1016/j.biopha.2023.115962
dc.identifier.doi10.1016/j.biopha.2023.115962
dc.identifier.issn0753-3322
dc.identifier.issn1950-6007
dc.identifier.pmid38042110
dc.identifier.scopus2-s2.0-85179107580
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://dx.doi.org/10.1016/j.biopha.2023.115962
dc.identifier.urihttps://hdl.handle.net/20.500.12511/12018
dc.identifier.volume170
dc.identifier.wos001134145800001en_US
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorDoeppner, Thorsten Roland
dc.language.isoen
dc.publisherElsevier Masson s.r.l.
dc.relation.ispartofBiomedicine and Pharmacotherapyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsAttribution-NonCommercial-NoDerivs 4.0 International*
dc.rightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectIschemic Stroke
dc.subjectLipid Droplet
dc.subjectMicroglia
dc.subjectTGF-?1
dc.subjectInflammation
dc.subjectTREM2
dc.titleTREM2 regulates microglial lipid droplet formation and represses post-ischemic brain injury
dc.typeArticle

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