CoChat
Sign Up
Cited by 116Neuroinflammation and Neurodegeneration MechanismsPhagocytosis and Immune RegulationInflammation biomarkers and pathways

Aminophospholipids are signal-transducing TREM2 ligands on apoptotic cells

Open access
Shirotani, Keiro, Hori, Yuma, Yoshizaki, Ryohei, Higuchi, Eri, Colonna, Marco, Saito, Takashi, Hashimoto, Shoko, Saito, Takashi +2 more·2019·Scientific Reports
DOI 10.1038/s41598-019-43535-6PMC PMC6525155
Open this paper in CoChat — free accountOpen PDF

Abstract

Variants of triggering receptor expressed on myeloid cells 2 (TREM2) are associated with an increased incidence of Alzheimer’s disease, as well as other neurodegenerative disorders. Using a newly developed, highly sensitive reporter cell model, consisting of Jurkat T cells stably overexpressing a reporter gene and a gene encoding TREM2DAP12 fusion protein, we show here that TREM2-dependent signal transduction in response to apoptotic Neuro2a cells is mediated by aminophospholipid ligands, phosphatidylserine and phosphatidylethanolamine, which are not exposed on the intact cell surface, but become exposed upon apoptosis. We also show that signal-transducing TREM2 ligands different from aminophospholipids, which appear to be derived from neurons, might be present in membrane fractions of mouse cerebral cortex. These results may suggest that TREM2 regulates microglial function by transducing intracellular signals from aminophospholipids on apoptotic cells, as well as unidentified ligands in the membranes of the cerebral cortex.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41598-019-43535-6

Cites

25 of 25 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In the CNS, TREM2 interacts with a variety of ligands, but it is most notably a receptor for lipid substrates.

    “In the CNS, TREM2 interacts with a variety of ligands, but it is most notably a receptor for lipid substrates [17, 19, 48].”

    From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [48]

    The Introduction lists several lipid ligands alongside nonlipid TREM2-binding substances, supporting the claim that TREM2 interacts with varied ligands, including lipids. But the Results and Discussion identify the signal-transducing ligands in mouse cerebral cortex only as membrane-associated and different from aminophospholipids; they do not establish that TREM2 is primarily a receptor for lipids in the CNS. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 41

  1. [1]Nimmerjahn A Kirchhoff F Helmchen F Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo Science 2005 308 1314 1319 10.1126/science.1110647 15831717 · DOI · Paper page
  2. [2]Akiyama H Inflammation and Alzheimer’s disease Neurobiol. Aging 2000 21 383 421 10.1016/S0197-4580(00)00124-X 10858586 PMC3887148 · DOI · Paper page
  3. [3]Wyss-Coray T Inflammation in Alzheimer disease: Driving force, bystander or beneficial response? Nat. Med. 2006 12 1005 1015 16960575
  4. [5]Dhawan G Floden AM Combs CK Amyloid-β oligomers stimulate microglia through a tyrosine kinase dependent mechanism Neurobiol. Aging 2012 33 2247 2261 10.1016/j.neurobiolaging.2011.10.027 22133278 PMC3294077 · DOI
  5. [8]Gold M El Khoury J β-amyloid, microglia, and the inflammasome in Alzheimer’s disease Semin Immunopathol. 2015 37 607 611 10.1007/s00281-015-0518-0 26251237 PMC4618770 · DOI · Paper page
  6. [9]Bertram L Genome-wide association analysis reveals putative Alzheimer’s disease susceptibility loci in addition to APOE Am. J. Hum. Genet. 2008 83 623 632 10.1016/j.ajhg.2008.10.008 18976728 PMC2668052 · DOI · Paper page
  7. [12]Hollingworth P Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’ s disease Nat. Genet. 2011 43 429 435 10.1038/ng.803 21460840 PMC3084173 · DOI · Paper page
  8. [13]Guerreiro R TREM2 Variants in Alzheimer’s disease N. Engl. J. Med. 2013 368 117 127 10.1056/NEJMoa1211851 23150934 PMC3631573 · DOI · Paper page
  9. [14]Jonsson T Variant of TREM2 associated with the risk of Alzheimer’s disease N. Engl. J. Med. 2013 368 107 116 10.1056/NEJMoa1211103 23150908 PMC3677583 · DOI · Paper page
  10. [15]Paloneva J Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype Am. J. Hum. Genet. 2002 71 656 662 10.1086/342259 12080485 PMC379202 · DOI · Paper page
  11. [16]Chouery E Mutations in TREM2 lead to pure early-onset dementia without bone cysts Hum. Mutat. 2008 29 194 204 10.1002/humu.20836 18546367 · DOI
  12. [19]Borroni B Heterozygous TREM2 mutations in frontotemporal dementia Neurobiol. Aging 2014 35 934.e7 934.e10 10.1016/j.neurobiolaging.2013.09.017 24139279 · DOI · Paper page
  13. [20]Cady J TREM2 variant p.R47H as a risk factor for sporadic amyotrophic lateral sclerosis JAMA Neurol. 2014 71 449 453 10.1001/jamaneurol.2013.6237 24535663 PMC4087113 · DOI · Paper page
  14. [22]Cruchaga C GWAS of cerebrospinal fluid tau levels identifies risk variants for alzheimer’s disease Neuron 2013 78 256 268 10.1016/j.neuron.2013.02.026 23562540 PMC3664945 · DOI · Paper page
  15. [23]Yuan P TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy Neuron 2016 90 724 739 10.1016/j.neuron.2016.05.003 27196974 PMC4898967 · DOI · Paper page
  16. [24]Lee CYD Elevated TREM2 gene dosage reprograms microglia responsivity and ameliorates pathological phenotypes in Alzheimer’s disease models Neuron 2018 97 1032 1048.e5 10.1016/j.neuron.2018.02.002 29518357 PMC5927822 · DOI · Paper page
  17. [26]Sudom A Molecular basis for the loss-of-function effects of the Alzheimer’s disease-associated R47H variant of the immune receptor TREM2 J. Biol. Chem. 2018 293 12634 12646 10.1074/jbc.RA118.002352 29794134 PMC6093241 · DOI · Paper page
  18. [31]Wang Y TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model Cell 2015 160 1061 1071 10.1016/j.cell.2015.01.049 25728668 PMC4477963 · DOI · Paper page
  19. [33]Jay TR Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer’s disease J. Neurosci. 2017 37 637 647 10.1523/JNEUROSCI.2110-16.2016 28100745 PMC5242410 · DOI · Paper page
  20. [34]Filipello F The microglial innate immune receptor TREM2 is required for synapse elimination and normal brain connectivity Immunity 2018 48 979 991.e8 10.1016/j.immuni.2018.04.016 29752066 · DOI · Paper page
  21. [35]Kobayashi M Konishi H Sayo A Takai T Kiyama H TREM2/DAP12 signal elicits proinflammatory response in microglia and exacerbates neuropathic pain J. Neurosci. 2016 36 11138 11150 10.1523/JNEUROSCI.1238-16.2016 27798193 PMC6705657 · DOI
  22. [36]Zhao, Y. et al. Intracellular trafficking of TREM2 is regulated by presenilin 1. Exp. Mol. Med. 49 (2017). PMC5750471 29611543
  23. [40]Hsieh CL A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia J. Neurochem. 2009 109 1144 1156 10.1111/j.1471-4159.2009.06042.x 19302484 PMC3087597 · DOI · Paper page
  24. [41]Stefano L The surface-exposed chaperone, Hsp60, is an agonist of the microglial TREM2 receptor J. Neurochem. 2009 110 284 294 10.1111/j.1471-4159.2009.06130.x 19457124 · DOI
  25. [42]Cannon JP O’Driscoll M Litman GW Specific lipid recognition is a general feature of CD300 and TREM molecules Immunogenetics 2012 64 39 47 10.1007/s00251-011-0562-4 21800138 · DOI
  26. [43]Ito H Hamerman JA TREM-2, triggering receptor expressed on myeloid cell-2, negatively regulates TLR responses in dendritic cells Eur. J. Immunol. 2012 42 176 185 10.1002/eji.201141679 21956652 PMC3444819 · DOI · Paper page
  27. [44]Phongsisay V Iizasa E Hara H Yamasaki S 3-O-sulfo-β-d-galactose moiety of endogenous sulfoglycolipids is a potential ligand for immunoglobulin-like receptor LMIR5 Mol. Immunol. 2015 63 595 599 10.1016/j.molimm.2014.07.023 25172093 · DOI
  28. [46]Atagi Y Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2) J. Biol. Chem. 2015 290 26043 26050 10.1074/jbc.M115.679043 26374899 PMC4646257 · DOI · Paper page
  29. [47]Kawabori M Triggering receptor expressed on myeloid cells 2 (TREM2) deficiency attenuates phagocytic activities of microglia and exacerbates ischemic damage in experimental stroke J. Neurosci. 2015 35 3384 3396 10.1523/JNEUROSCI.2620-14.2015 25716838 PMC4339351 · DOI · Paper page
  30. [49]Kober DL Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms Elife 2016 5 e20391 10.7554/eLife.20391 27995897 PMC5173322 · DOI · Paper page
  31. [51]Yeh FL Wang Y Tom I Gonzalez LC Sheng M TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia Neuron 2016 91 328 340 10.1016/j.neuron.2016.06.015 27477018 · DOI · Paper page
  32. [52]Zhao Y TREM2 Is a receptor for β-amyloid that mediates microglial function Neuron 2018 97 1023 1031.e7 10.1016/j.neuron.2018.01.031 29518356 PMC5889092 · DOI · Paper page
  33. [53]Zhong L Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2) Mol. Neurodegener. 2018 13 15 10.1186/s13024-018-0247-71-12 29587871 PMC5870375 · DOI
  34. [54]Lessard CB High affinity interactions and signal transduction between Aβ oligomers and TREM2 EMBO Mol. Med. 2018 10 e9027 10.15252/emmm.201809027 30341064 PMC6220267 · DOI
  35. [55]N’Diaye EN TREM-2 (triggering receptor expressed on myeloid cells 2) is a phagocytic receptor for bacteria J. Cell Biol. 2009 184 215 223 10.1083/jcb.200808080 19171755 PMC2654305 · DOI
  36. [57]Nagata S Suzuki J Segawa K Fujii T Exposure of phosphatidylserine on the cell surface Cell Death Differ. 2016 23 952 961 10.1038/cdd.2016.7 26891692 PMC4987739 · DOI
  37. [60]Masuda A Cognitive deficits in single App knock-in mouse models Neurobiol. Learn. Mem. 2016 135 73 82 10.1016/j.nlm.2016.07.001 27377630 · DOI · Paper page
  38. [61]Humphrey MB The signaling adapter protein DAP12 regulates multinucleation during osteoclast development J. Bone Miner. Res. 2004 19 224 234 10.1359/JBMR.0301234 14969392 · DOI
  39. [62]Humphrey MB TREM2, a DAP12-associated receptor, regulates osteoclast differentiation and function J. Bone Miner. Res. 2006 21 237 245 10.1359/JBMR.051016 16418779 · DOI · Paper page
  40. [63]Bader Lange ML Age-related loss of phospholipid asymmetry in APPNLh/APPNLhx PS-1P264L/PS-1P264Lhuman double mutant knock-in mice: Relevance to Alzheimer disease Neurobiol. Dis. 2010 38 104 115 10.1016/j.nbd.2010.01.004 20083199 PMC2834848 · DOI
  41. [66]Ohtsuka M NFAM1, an immunoreceptor tyrosine-based activation motif-bearing molecule that regulates B cell development and signaling Proc. Natl. Acad. Sci. USA 2004 101 8126 8131 10.1073/pnas.0401119101 15143214 PMC419568 · DOI

Cited by

Sorted by citations

Authors
Shirotani, K., Hori, Y., Yoshizaki, R., Higuchi, E., Colonna, M., Saito, T., Hashimoto, S., Saito, T., Saido, T. C., & Iwata, N.
Affiliations
  • Nagasaki University (JP)
  • Washington University in St. Louis (US)
  • RIKEN Center for Brain Science (JP)
Corresponding author
  • Shirotani, Keiro
  • Iwata, Nobuhisa
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2019-05-17
Volume
9
Issue
1
Pages
7508-7508
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-019-43535-6
PMC
PMC6525155
OpenAlex
W2945125269
Cited by
116
References
25
Citations by year
2026: 12 · 2025: 15 · 2024: 15 · 2023: 14 · 2022: 27 · 2021: 18 · 2020: 12 · 2019: 2
FWCI
6.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by)
  • Nagasaki University's Academic Output SITE (Nagasaki University) (submittedVersion, cc-by-nc-nd)
  • The Japanese Biochemical Society
Funders
  • Japan Agency for Medical Research and Development
  • Japan Society for the Promotion of Science (18K06787)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
  • Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
Keywords
TREM2, aminophospholipids, phosphatidylserine, phosphatidylethanolamine, apoptotic cells, signal transduction, microglia, Alzheimer's disease, neurodegeneration, neuroinflammation
MeSH terms
RAW 264.7 Cells, Alzheimer Disease, Animals, Cell Line, Cerebral Cortex, Humans, Ligands, Membrane Glycoproteins, Membrane Proteins, Models, Biological, Neurons, Phospholipids, Receptors, Immunologic, Recombinant Fusion Proteins, Signal Transduction, Apoptosis, Microglia, Jurkat Cells, Adaptor Proteins, Signal Transducing, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review