{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T15:52:15Z","timestamp":1792511535722,"version":"4.5.0"},"reference-count":69,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,11,20]],"date-time":"2020-11-20T00:00:00Z","timestamp":1605830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:p>Microglia are the main immune cells of the central nervous system (CNS), and they are devoted to the active surveillance of the CNS during homeostasis and disease. In the last years, the microglial receptor Triggering Receptor Expressed on Myeloid cells-2 (TREM2) has been defined to mediate several microglial functions, including phagocytosis, survival, proliferation, and migration, and to be a key regulator of a new common microglial signature induced under neurodegenerative conditions and aging, also known as disease-associated microglia (DAM). Although microglial TREM2 has been mainly studied in chronic neurodegenerative diseases, few studies address its regulation and functions in acute inflammatory injuries. In this context, the present work aims to study the regulation of TREM2 and its functions after reparative axonal injuries, using two-well established animal models of anterograde and retrograde neuronal degeneration: the perforant pathway transection (PPT) and the facial nerve axotomy (FNA). Our results indicate the appearance of a subpopulation of microglia expressing TREM2 after both anterograde and retrograde axonal injury. TREM2+ microglia were not directly related to proliferation, instead, they were associated with specific recognition and\/or phagocytosis of myelin and degenerating neurons, as assessed by immunohistochemistry and flow cytometry. Characterization of TREM2+ microglia showed expression of CD16\/32, CD68, and occasional Galectin-3. However, specific singularities within each model were observed in P2RY12 expression, which was only downregulated after PPT, and in ApoE, where <jats:italic>de novo<\/jats:italic> expression was detected only in TREM2+ microglia after FNA. Finally, we report that the pro-inflammatory or anti-inflammatory cytokine microenvironment, which may affect phagocytosis, did not directly modify the induction of TREM2+ subpopulation in any injury model, although it changed TREM2 levels due to modification of the microglial activation pattern. In conclusion, we describe a unique TREM2+ microglial subpopulation induced after axonal injury, which is directly associated with phagocytosis of specific cell remnants and show different phenotypes, depending on the microglial activation status and the degree of tissue injury.<\/jats:p>","DOI":"10.3389\/fncel.2020.567404","type":"journal-article","created":{"date-parts":[[2020,11,20]],"date-time":"2020-11-20T06:19:35Z","timestamp":1605853175000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["Differential Roles of TREM2+ Microglia in Anterograde and Retrograde Axonal Injury Models"],"prefix":"10.3389","volume":"14","author":[{"given":"Gemma","family":"Manich","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariadna Regina","family":"G\u00f3mez-L\u00f3pez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Almolda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N\u00e0dia","family":"Villacampa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mireia","family":"Recasens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalpana","family":"Shrivastava","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berta","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernardo","family":"Castellano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2020,11,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1006\/exnr.1997.6593","article-title":"Quantitative analysis of microglial reaction to a cortical excitotoxic lesion in the early postnatal brain","volume":"147","author":"Acarin","year":"1997","journal-title":"Exp. Neurol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.jneuroim.2009.01.026","article-title":"CD4 microglial expression correlates with spontaneous clinical improvement in the acute Lewis rat EAE model","volume":"209","author":"Almolda","year":"2009","journal-title":"J. Neuroimmunol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.bbi.2014.10.015","article-title":"Alterations in microglial phenotype and hippocampal neuronal function in transgenic mice with astrocyte-targeted production of interleukin-10","volume":"45","author":"Almolda","year":"2015","journal-title":"Brain Behav. Immun."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.1002\/glia.22668","article-title":"Effects of astrocyte-targeted production of interleukin-6 in the mouse on the host response to nerve injury","volume":"62","author":"Almolda","year":"2014","journal-title":"Glia"},{"key":"B5","doi-asserted-by":"publisher","first-page":"26043","DOI":"10.1074\/jbc.M115.679043","article-title":"Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2)","volume":"290","author":"Atagi","year":"2015","journal-title":"J. Biol. Chem."},{"key":"B6","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1007\/s00401-019-02013-z","article-title":"Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer\u2019s disease","volume":"138","author":"Boza-Serrano","year":"2019","journal-title":"Acta Neuropathol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"10061","DOI":"10.1073\/pnas.90.21.10061","article-title":"Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6","volume":"90","author":"Campbell","year":"1993","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"B8","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1007\/s00401-015-1388-1","article-title":"TREM2 regulates microglial cell activation in response to demyelination in vivo","volume":"129","author":"Cantoni","year":"2015","journal-title":"Acta Neuropathol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1007\/s00401-020-02193-z","article-title":"TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis","volume":"140","author":"Cignarella","year":"2020","journal-title":"Acta Neuropathol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1038\/nri1106","article-title":"TREMs in the immune system and beyond","volume":"3","author":"Colonna","year":"2003","journal-title":"Nat. Rev. Immunol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1146\/annurev-immunol-051116-052358","article-title":"Microglia function in the central nervous system during health and neurodegeneration","volume":"35","author":"Colonna","year":"2017","journal-title":"Annu. Rev. Immunol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s13024-018-0262-8","article-title":"The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer\u2019s disease","volume":"13","author":"Cheng-Hathaway","year":"2018","journal-title":"Mol. Neurodegener."},{"key":"B13","doi-asserted-by":"publisher","first-page":"e72083","DOI":"10.1371\/journal.pone.0072083","article-title":"Differential modulation of TREM2 protein during postnatal brain development in mice","volume":"8","author":"Chertoff","year":"2013","journal-title":"PLoS One"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1016\/j.cell.2018.05.003","article-title":"Disease-associated microglia: a universal immune sensor of neurodegeneration","volume":"173","author":"Deczkowska","year":"2018","journal-title":"Cell"},{"key":"B15","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1016\/S0079-6123(07)63027-1","article-title":"Structural reorganization of the dentate gyrus following entorhinal denervation: species differences between rat and mouse","volume":"163","author":"Deller","year":"2007","journal-title":"Prog. Brain Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1080\/14728222.2018.1486823","article-title":"Triggering receptor expressed on myeloid cells 2 (TREM2): a potential therapeutic target for Alzheimer disease?","volume":"22","author":"Deming","year":"2018","journal-title":"Expert Opin. Ther. Targets"},{"key":"B17","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1007\/BF00293378","article-title":"Lesion of the rat entorhinal cortex leads to a rapid microglial reaction in the dentate gyrus. A light and electron microscopical study","volume":"82","author":"Gehrmann","year":"1991","journal-title":"Acta Neuropathol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1668","DOI":"10.3389\/fimmu.2019.01668","article-title":"The emerging role of triggering receptor expressed on myeloid cells 2 as a target for immunomodulation in ischemic stroke","volume":"10","author":"Gervois","year":"2019","journal-title":"Front. Immunol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s13024-018-0298-9","article-title":"New insights into the role of TREM2 in Alzheimer\u2019s disease","volume":"13","author":"Gratuze","year":"2018","journal-title":"Mol. Neurodegener."},{"key":"B20","doi-asserted-by":"publisher","first-page":"e2005264","DOI":"10.1371\/journal.pbio.2005264","article-title":"Peripherally derived macrophages modulate microglial function to reduce inflammation after CNS injury","volume":"16","author":"Greenhalgh","year":"2018","journal-title":"PLoS Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1038\/nn.4189","article-title":"Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain","volume":"19","author":"Guan","year":"2016","journal-title":"Nat. Neurosci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1144","DOI":"10.1111\/j.1471-4159.2009.06042.x","article-title":"A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia","volume":"109","author":"Hsieh","year":"2009","journal-title":"J. Neurochem."},{"key":"B23","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1523\/JNEUROSCI.2110-16.2016","article-title":"Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer\u2019s disease","volume":"37","author":"Jay","year":"","journal-title":"J. Neurosci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1186\/s13024-017-0197-5","article-title":"TREM2 in neurodegenerative diseases","volume":"12","author":"Jay","year":"","journal-title":"Mol. Neurodegener."},{"key":"B25","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1016\/s0306-4522(99)00139-6","article-title":"Microglial reactivity correlates to the density and the myelination of the anterogradely degenerating axons and terminals following perforant path denervation of the mouse fascia dentata","volume":"93","author":"Jensen","year":"1999","journal-title":"Neuroscience"},{"key":"B26","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.neurobiolaging.2019.09.004","article-title":"The role of TREM2 in Alzheimer\u2019s disease; evidence from transgenic mouse models","volume":"86","author":"Karanfilian","year":"2020","journal-title":"Neurobiol. Aging"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1276.e17","DOI":"10.1016\/j.cell.2017.05.018","article-title":"A unique microglia type associated with restricting development of Alzheimer\u2019s disease","volume":"169","author":"Keren-Shaul","year":"2017","journal-title":"Cell"},{"key":"B28","doi-asserted-by":"publisher","first-page":"11138","DOI":"10.1523\/JNEUROSCI.1238-16.2016","article-title":"TREM2\/DAP12 signal elicits proinflammatory response in microglia and exacerbates neuropathic pain","volume":"36","author":"Kobayashi","year":"2016","journal-title":"J. Neurosci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1002\/glia.22802","article-title":"A DAP12-dependent signal promotes pro-inflammatory polarization in microglia following nerve injury and exacerbates degeneration of injured neurons","volume":"63","author":"Kobayashi","year":"2015","journal-title":"Glia"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1607","DOI":"10.1016\/j.jmb.2017.04.004","article-title":"TREM2-ligand interactions in health and disease","volume":"429","author":"Kober","year":"2017","journal-title":"J. Mol. Biol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"566.e9","DOI":"10.1016\/j.immuni.2017.08.008","article-title":"The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases","volume":"47","author":"Krasemann","year":"2017","journal-title":"Immunity"},{"key":"B32","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.brainresrev.2004.12.009","article-title":"Microglial cell population dynamics in the injured adult central nervous system","volume":"48","author":"Ladeby","year":"2005","journal-title":"Brain Res. Brain Res. Rev."},{"key":"B33","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1002\/glia.23563","article-title":"TREM2 triggers microglial density and age-related neuronal loss","volume":"67","author":"Linnartz-Gerlach","year":"2019","journal-title":"Glia"},{"key":"B34","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/0006-8993(72)90533-1","article-title":"Induced acetylcholinesterase-rich layer in rat dentate gyrus following entorhinal lesions","volume":"42","author":"Lynch","year":"1972","journal-title":"Brain Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1956","DOI":"10.1523\/JNEUROSCI.1871-19.2019","article-title":"Trem2 deletion reduces late-stage amyloid plaque accumulation, elevates the A\u03b242:A\u03b240 ratio, and exacerbates axonal dystrophy and dendritic spine loss in the PS2APP Alzheimer\u2019s mouse model","volume":"40","author":"Meilandt","year":"2020","journal-title":"J. Neurosci."},{"key":"B36","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1016\/j.brainresrev.2003.11.004","article-title":"The facial nerve axotomy model","volume":"44","author":"Moran","year":"2004","journal-title":"Brain Res. Brain Res. Rev."},{"key":"B37","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1093\/brain\/awn109","article-title":"Debris clearance by microglia: an essential link between degeneration and regeneration","volume":"132","author":"Neumann","year":"2009","journal-title":"Brain"},{"key":"B38","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1097\/NEN.0b013e3181ae0236","article-title":"Enhanced microglial clearance of myelin debris in T cell-infiltrated central nervous system","volume":"68","author":"Nielsen","year":"2009","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"4792","DOI":"10.4049\/jimmunol.1502532","article-title":"Activated microglia desialylate and phagocytose cells via neuraminidase, galectin-3, and mer tyrosine kinase","volume":"198","author":"Nomura","year":"2017","journal-title":"J. Immunol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1111\/j.1460-9568.2010.07152.x","article-title":"In vitro differentiation of lineage-negative bone marrow cells into microglia-like cells","volume":"31","author":"Noto","year":"2010","journal-title":"Eur. J. Neurosci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"837.e9","DOI":"10.1016\/j.neuron.2019.12.007","article-title":"TREM2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge","volume":"105","author":"Nugent","year":"2020","journal-title":"Neuron"},{"key":"B42","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1186\/s13024-015-0040-9","article-title":"TREM2 in CNS homeostasis and neurodegenerative disease","volume":"10","author":"Painter","year":"2015","journal-title":"Mol. Neurodegener."},{"key":"B43","doi-asserted-by":"publisher","first-page":"2104","DOI":"10.1002\/glia.23043","article-title":"Astrocyte-targeted production of interleukin-6 reduces astroglial and microglial activation in the cuprizone demyelination model: implications for myelin clearance and oligodendrocyte maturation","volume":"64","author":"Petkovi\u0107","year":"2016","journal-title":"Glia"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.1002\/eji.200636837","article-title":"Blockade of TREM-2 exacerbates experimental autoimmune encephalomyelitis","volume":"37","author":"Piccio","year":"2007","journal-title":"Eur. J. Immunol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"2161","DOI":"10.1172\/JCI77983","article-title":"TREM2 sustains microglial expansion during aging and response to demyelination","volume":"125","author":"Poliani","year":"2015","journal-title":"J. Clin. Invest."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.1016\/j.neuroscience.2006.03.058","article-title":"Triggering receptor expressed in myeloid cells 2 (TREM2) trafficking in microglial cells: continuous shuttling to and from the plasma membrane regulated by cell stimulation","volume":"140","author":"Prada","year":"2006","journal-title":"Neuroscience"},{"key":"B47","doi-asserted-by":"publisher","first-page":"162","DOI":"10.3389\/fncel.2020.00162","article-title":"Sialylation and Galectin-3 in microglia-mediated neuroinflammation and neurodegeneration","volume":"14","author":"Puigdellivol","year":"2020","journal-title":"Front. Cell. Neurosci."},{"key":"B48","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1002\/glia.23573","article-title":"Astrocyte-targeted IL-10 production decreases proliferation and induces a downregulation of activated microglia\/macrophages after PPT","volume":"67","author":"Recasens","year":"2019","journal-title":"Glia"},{"key":"B49","doi-asserted-by":"publisher","first-page":"56322","DOI":"10.3791\/56322","article-title":"In vitro phagocytosis of myelin debris by bone marrow-derived macrophages","volume":"130","author":"Rolfe","year":"2017","journal-title":"J. Vis. Exp."},{"key":"B50","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1089\/neu.2016.4401","article-title":"Triggering receptor expressed on myeloid cells 2 deficiency alters acute macrophage distribution and improves recovery after traumatic brain injury","volume":"34","author":"Saber","year":"2017","journal-title":"J. Neurotrauma"},{"key":"B51","doi-asserted-by":"publisher","first-page":"10172","DOI":"10.1073\/pnas.1811411115","article-title":"Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy","volume":"115","author":"Sayed","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"B52","doi-asserted-by":"publisher","first-page":"2825","DOI":"10.1093\/hmg\/ddx153","article-title":"Heterozygote galactocerebrosidase (GALC) mutants have reduced remyelination and impaired myelin debris clearance following demyelinating injury","volume":"26","author":"Scott-Hewitt","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"B53","doi-asserted-by":"publisher","first-page":"1309","DOI":"10.1046\/j.1471-4159.2002.01243.x","article-title":"Heterogeneous expression of the triggering receptor expressed on myeloid cells-2 on adult murine microglia","volume":"83","author":"Schmid","year":"2002","journal-title":"J. Neurochem."},{"key":"B610","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1177\/002215549904700601","article-title":"Reduction of lipofuscin-like autofluorescence in fluorescently labeled tissue","volume":"47","author":"Schnell","year":"1999","journal-title":"J. Histochem. Cytochem."},{"key":"B54","doi-asserted-by":"publisher","first-page":"e124","DOI":"10.1371\/journal.pmed.0040124","article-title":"TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis","volume":"4","author":"Takahashi","year":"2007","journal-title":"PLoS Med."},{"key":"B55","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1084\/jem.20041611","article-title":"Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2","volume":"201","author":"Takahashi","year":"2005","journal-title":"J. Exp. Med."},{"key":"B56","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1186\/s40478-018-0584-3","article-title":"Unique microglia recovery population revealed by single-cell RNAseq following neurodegeneration","volume":"6","author":"Tay","year":"2018","journal-title":"Acta Neuropathol. Commun."},{"key":"B57","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1186\/s40478-019-0850-z","article-title":"Regulation of microglial TMEM119 and P2RY12 immunoreactivity in multiple sclerosis white and gray matter lesions is dependent on their inflammatory environment","volume":"7","author":"van Wageningen","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"B58","doi-asserted-by":"publisher","first-page":"1166","DOI":"10.1002\/glia.22807","article-title":"Astrocyte-targeted production of IL-10 induces changes in microglial reactivity and reduces motor neuron death after facial nerve axotomy","volume":"63","author":"Villacampa","year":"2015","journal-title":"Glia"},{"key":"B59","doi-asserted-by":"publisher","first-page":"678","DOI":"10.3390\/ijms21020678","article-title":"Patterns of expression of purinergic receptor P2RY12, a putative marker for non-activated microglia, in aged and Alzheimer\u2019s disease brains","volume":"21","author":"Walker","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B60","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1016\/j.cell.2015.01.049","article-title":"TREM2 lipid sensing sustains the microglial response in an Alzheimer\u2019s disease model","volume":"160","author":"Wang","year":"2015","journal-title":"Cell"},{"key":"B61","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1146\/annurev-physiol-022516-034406","article-title":"Microglia in physiology and disease","volume":"79","author":"Wolf","year":"2017","journal-title":"Annu. Rev. Physiol."},{"key":"B62","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/s13041-017-0296-9","article-title":"TREM2 protects against cerebral ischemia\/reperfusion injury","volume":"10","author":"Wu","year":"2017","journal-title":"Mol. Brain"},{"key":"B63","doi-asserted-by":"publisher","first-page":"457","DOI":"10.3389\/fncel.2019.00457","article-title":"Distinct signaling pathways regulate TREM2 phagocytic and NF\u03baB antagonistic activities","volume":"13","author":"Yao","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"B64","doi-asserted-by":"publisher","first-page":"41689","DOI":"10.1038\/srep41689","article-title":"Galectin-3 released in response to traumatic brain injury acts as an alarmin orchestrating brain immune response and promoting neurodegeneration","volume":"7","author":"Yip","year":"2017","journal-title":"Sci. Rep."},{"key":"B65","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1097\/ALN.0000000000001628","article-title":"Triggering receptor expressed on myeloid cells 2, a novel regulator of immunocyte phenotypes, confers neuroprotection by relieving neuroinflammation","volume":"127","author":"Zhai","year":"2017","journal-title":"Anesthesiology"},{"key":"B66","doi-asserted-by":"publisher","first-page":"1772","DOI":"10.1523\/JNEUROSCI.2459-16.2017","article-title":"TREM2 promotes microglial survival by activating Wnt\/\u03b2-catenin pathway","volume":"37","author":"Zheng","year":"2017","journal-title":"J. Neurosci."},{"key":"B67","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1084\/jem.20160844","article-title":"Soluble TREM2 induces inflammatory responses and enhances microglial survival","volume":"214","author":"Zhong","year":"2017","journal-title":"J. Exp. Med."},{"key":"B68","doi-asserted-by":"publisher","first-page":"1365","DOI":"10.1038\/s41467-019-09118-9","article-title":"Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer\u2019s disease model","volume":"10","author":"Zhong","year":"2019","journal-title":"Nat. Commun."}],"container-title":["Frontiers in Cellular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2020.567404\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,11,20]],"date-time":"2020-11-20T06:19:38Z","timestamp":1605853178000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2020.567404\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,20]]},"references-count":69,"alternative-id":["10.3389\/fncel.2020.567404"],"URL":"https:\/\/doi.org\/10.3389\/fncel.2020.567404","relation":{},"ISSN":["1662-5102"],"issn-type":[{"value":"1662-5102","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,20]]},"article-number":"567404"}}