TREM2 regulates microglial lipid droplet formation and represses post-ischemic brain injury
Open accessAbstract
Triggering 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-β1/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-β1 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-β1/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.
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.
Integrity signals
Registry
Cites
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.
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 ischemic brain injury, lipid droplets mitigate the microglial pro-inflammatory response, decrease infarct volume, and improve neurobehavioral performance.
“In ischemic brain injury, for instance, LDs mitigate the microglial pro-inflammatory response, decrease infarct volume, and improve their neurobehavioral performance (63, 64).”
From Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model (2025) · cites this paper as [63]
The Discussion (page unavailable) says that lipid-droplet accumulation after ischemia may promote neuronal death and inflammatory responses—the opposite of the claimed anti-inflammatory effect. It also links lipid-rich microglia after TREM2 knockdown to severe neurological deficits. The paper attributes protection to TREM2, not to lipid droplets. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredDepletion of either TREM2 or PLCγ2 has previously been shown to increase lipid accumulation and impair mitochondrial respiration via suppression of lipid regulatory genes, including FABP5.
“depletion of either TREM2 or PLCγ2 has previously been shown to increase lipid accumulation and impair mitochondrial respiration via the suppression of lipid regulatory genes, including FABP5 [6, 8, 61].”
From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [61]
Section 3.3 reports that TREM2 knockdown increased cholesterol accumulation and downregulated several genes involved in cholesterol clearance and lipid hydrolysis. The passages do not establish the same effects for PLCγ2, impaired mitochondrial respiration, or suppression of FABP5; they also report upregulation of some lipid-synthesis genes. Page numbers were not provided in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAged and diseased microglia have more gangliosides, while macroglia in ischemic stroke are characterized by high cholesterol levels.
“In relation to LD content, we and others have revealed the presence of more GLs in aged and diseased microglia (11), while the macroglia encountered in ischemic stroke are characterized by high cholesterol levels (63).”
From Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model (2025) · cites this paper as [63]
The Discussion reports increased cholesterol in mouse brains after ischemia with TREM2 knockdown and impaired cholesterol clearance in microglia. Citation (63) is attached only to the cholesterol clause, not the earlier ganglioside claim. The source studies microglia, not macroglia, and does not establish high cholesterol as a general characteristic of macroglia in ischemic stroke. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThere are several hypermorphic variants in PLCG2 that have been associated with autoimmune disease and cancer.
“There are several hypermorphic variants in PLCG2 that have been associated with autoimmune disease and cancer [58–61, 66].”
From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [61]
The Introduction discusses TREM2 and TGF-β1 signaling, including cancer-related lipid metabolism, but does not address PLCG2 variants. Searches for PLCG2, hypermorphic variants, and gain-of-function variants found no passage in our copy linking them to autoimmune disease or cancer. (LLM, conf=0.75)
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
A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease
Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-Szternfeld, R., Ulland, T. K., David, E., Baruch, K., Lara-Astaiso, D., Toth, B., et al. (2017) · Cell · doi:10.1016/j.cell.2017.05.018 · Cited by 5,493 · see citing works
Krasemann, S., Madore, C., Cialic, R., Baufeld, C., Calcagno, N., El Fatimy, R., Beckers, L., O’Loughlin, E., Xu, Y., Fanek, Z., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.08.008 · Cited by 2,979 · see citing works
Marschallinger, J., Iram, T., Zardeneta, M., Lee, S. E., Lehallier, B., Haney, M. S., Pluvinage, J. V., Mathur, V., Hahn, O., Morgens, D. W., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-019-0566-1 · Cited by 1,384 · see citing works
TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease
Ulland, T. K., Song, W. M., Huang, S. C.-C., Ulrich, J. D., Sergushichev, A., Beatty, W. L., Loboda, A. A., Zhou, Y., Cairns, N. J., Kambal, A., et al. (2017) · Cell · doi:10.1016/j.cell.2017.07.023 · Cited by 1,263 · see citing works
TREM2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge
Nugent, A. A., Lin, K., van Lengerich, B., Lianoglou, S., Przybyla, L., Davis, S. S., Llapashtica, C., Wang, J., Kim, D. J., Xia, D., et al. (2020) · Neuron · doi:10.1016/j.neuron.2019.12.007 · Cited by 745 · see citing works
TREM2 — a key player in microglial biology and Alzheimer disease
Ulland, T. K., & Colonna, M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0072-1 · Cited by 735 · see citing works
Jay, T. R., Miller, C. M., Cheng, P. J., Graham, L. C., Bemiller, S., Broihier, M. L., Xu, G., Margevicius, D., Karlo, J. C., Sousa, G. L., et al. (2015) · Journal of Experimental Medicine · doi:10.1084/jem.20142322 · Cited by 682 · see citing works
Takahashi, K., Prinz, M., Stagi, M., Chechneva, O., & Neumann, H. (2007) · PLoS Medicine · doi:10.1371/journal.pmed.0040124 · Cited by 414 · see citing works
Rayaprolu, S., Mullen, B., Baker, M., Lynch, T., Finger, E., Seeley, W. W., Hatanpaa, K. J., Lomen-Hoerth, C., Kertesz, A., Bigio, E. H., et al. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-19 · Cited by 404 · see citing works
Cignarella, F., Filipello, F., Bollman, B., Cantoni, C., Locca, A., Mikesell, R., Manis, M., Ibrahim, A., Deng, L., Benitez, B. A., et al. (2020) · Acta Neuropathologica · doi:10.1007/s00401-020-02193-z · Cited by 392 · see citing works
TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury
Mazaheri, F., Snaidero, N., Kleinberger, G., Madore, C., Daria, A., Werner, G., Krasemann, S., Capell, A., Trümbach, D., Wurst, W., et al. (2017) · The EMBO Reports · doi:10.15252/embr.201743922 · Cited by 351 · see citing works
TREM2 regulates microglial cell activation in response to demyelination in vivo
Cantoni, C., Bollman, B., Licastro, D., Xie, M., Mikesell, R., Schmidt, R., Yuede, C. M., Galimberti, D., Olivecrona, G., Klein, R. S., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1388-1 · Cited by 296 · see citing works
Li, R.-Y., Qin, Q., Yang, H.-C., Wang, Y.-Y., Mi, Y.-X., Yin, Y.-S., Wang, M., Yu, C.-J., & Tang, Y. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00542-y · Cited by 204 · see citing works
Claes, C., Danhash, E. P., Hasselmann, J., Chadarevian, J. P., Shabestari, S. K., England, W. E., Lim, T. E., Hidalgo, J. L. S., Spitale, R. C., Davtyan, H., et al. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00473-0 · Cited by 197 · see citing works
Wang, Y., Lin, Y., Wang, L., Zhan, H., Luo, X., Zeng, Y., Wu, W., Zhang, X., & Wang, F. (2020) · Aging · doi:10.18632/aging.104104 · Cited by 196 · see citing works
TREM2 dependent and independent functions of microglia in Alzheimer’s disease
Hou, J., Chen, Y., Grajales-Reyes, G., & Colonna, M. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00588-y · Cited by 191 · see citing works
TREM2 deficiency reduces the efficacy of immunotherapeutic amyloid clearance
Xiang, X., Werner, G., Bohrmann, B., Liesz, A., Mazaheri, F., Capell, A., Feederle, R., Knuesel, I., Kleinberger, G., & Haass, C. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201606370 · Cited by 183 · see citing works
TREM2 macrophages induced by human lipids drive inflammation in acne lesions
Do, T. H., Ma, F., Andrade, P. R., Teles, R., de Andrade Silva, B. J., Hu, C., Espinoza, A., Hsu, J.-E., Cho, C.-S., Kim, M., et al. (2022) · Science Immunology · doi:10.1126/sciimmunol.abo2787 · Cited by 139 · see citing works
Guo, Y., Wei, X., Yan, H., Qin, Y., Yan, S., Liu, J., Zhao, Y., Jiang, F., & Lou, H. (2019) · The FASEB Journal · doi:10.1096/fj.201900992r · Cited by 101 · see citing works
Microglia gone awry: linking immunometabolism to neurodegeneration
Afridi, R., Lee, W.-H., & Suk, K. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00246 · Cited by 64 · see citing works
Flagged first, then by citations
Research works printed but not linked: 9
- J. Jia, L. Yang, Y. Chen, L. Zheng, Y. Chen, Y. Xu, M. Zhang, The role of microglial phagocytosis in ischemic stroke, Front Immunol. 12 (2021), 790201.
- H. Wang, X. Li, Q. Wang, J. Ma, X. Gao, M. Wang, TREM2, microglial and ischemic stroke, J. Neuroimmunol. 381 (2023), 578108.
- S. Liu, X. Cao, Z. Wu, S. Deng, H. Fu, Y. Wang, F. Liu, TREM2 improves neurological dysfunction and attenuates neuroinflammation, TLR signaling and neuronal apoptosis in the acute phase of intracerebral hemorrhage, Front Aging Neurosci. 14 (2022), 967825.
- X. Zhuang, Y. Yu, Y. Jiang, S. Zhao, Y. Wang, L. Su, K. Xie, Y. Yu, Y. Lu, G. Lv, Molecular hydrogen attenuates sepsis-induced neuroinflammation through regulation of microglia polarization through an mTOR-autophagy-dependent pathway, Int. Immunopharmacol. 81 (2020), 106287.
- S.D. Skaper, L. Facci, Central nervous system neuron-glia co-culture models and application to neuroprotective agents. Neurotrophic Factors, Springer, 2018, pp. 63-80.
- S. Yang, C. Qin, Z.-W. Hu, L.-Q. Zhou, H.-H. Yu, M. Chen, D.B. Bosco, W. Wang, L.-J. Wu, D. Tian, Micro reprogram Metab, Profiles phenotype Funct. Chang. Cent. Nerv. Syst. 152 (2021), 105290.
- Q. Luo, D. Deng, Y. Li, H. Shi, J. Zhao, Q. Qian, W. Wang, J. Cai, W. Yu, J. Liu, TREM2 insufficiency protects against pulmonary fibrosis by inhibiting m2 macrophage polarization, Int Immunopharmacol. 118 (2023), 110070.
- Y. Hu, C. Li, X. Wang, W. Chen, Y. Qian, X. Dai, TREM2, driving the microglial polarization, Has a TLR4 sensitivity profile after subarachnoid hemorrhage, Front Cell Dev. Biol. 9 (2021), 693342.
- H. Zheng, B. Cheng, Y. Li, X. Li, X. Chen, Y.W. Zhang, TREM2 in Alzheimer's disease: microglial survival and energy metabolism, Front. Aging Neurosci. 10 (2018), 395.
Cited by
Sorted by citations
Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model
Wu, X., Miller, J. A., Lee, B. T. K., Wang, Y., & Ruedl, C. (2025) · Science Advances · doi:10.1126/sciadv.adq6038 · Cited by 67 · see citing works
“In ischemic brain injury, for instance, LDs mitigate the microglial pro-inflammatory response, decrease infarct volume, and improve their neurobehavioral performance ( 63 , 64 ).”
TGF-β Signaling in Microglia: A Key Regulator of Development, Homeostasis and Reactivity
Li, L., Sun, B., Harris, O. A., & Luo, J. (2024) · Biomedicines · doi:10.3390/biomedicines12112468 · Cited by 38 · see citing works
Takalo, M., Jeskanen, H., Rolova, T., Kervinen, I., Hellén, M., Heikkinen, S., Koivisto, H., Jokivarsi, K., Müller, S. A., Koivumäki, E.-M., et al. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03387-6 · Cited by 15 · see citing works
“There are several hypermorphic variants in PLCG2 that have been associated with autoimmune disease and cancer [58–61 , 66].”
- Authors
- Wei, W., Zhang, L., Xin, W., Pan, Y., Tatenhorst, L., Hao, Z., Gerner, S. T., Huber, S., Juenemann, M., Butz, M., Huttner, H. B., Bähr, M., Fitzner, D., Jia, F., & Doeppner, T. R.
- Affiliations
- Universitätsmedizin Göttingen (DE)
- Shanghai Jiao Tong University (CN)
- Justus-Liebig-Universität Gießen (DE)
- Kerckhoff Klinik (DE)
- Medical University of Varna (BG)
- Corresponding author
- Fitzner, Dirk
- Jia, Feng
- Doeppner, Thorsten R.
- ORCID
- Venue
- Biomedicine & Pharmacotherapy
- Publisher
- Elsevier BV
- Published
- 2024-01
- Volume
- 170
- Pages
- 115962
- ISSN
- 0753-3322 (ISSN-L)
- OpenAlex
- W4389235660
- Cited by
- 122
- References
- 20
- Citations by year
- 2026: 51 · 2025: 51 · 2024: 20
- FWCI
- 12.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Biomedicine & Pharmacotherapy (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by-nc-nd)
- Funders
- China Scholarship Council (202008080082)
- National Natural Science Foundation of China (82271310)
- Science and Technology Commission of Shanghai Municipality (21ZR1439000)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- TREM2, microglia, ischemic stroke, lipid droplet formation, cholesteryl ester accumulation, PLIN2, TGF-β1/Smad2/3 signaling, neuroinflammation, M2 microglia, neuronal apoptosis, hypoxia
- MeSH terms
- Ischemic Stroke, Animals, Brain Injuries, Cholesterol Esters, Inflammation, Membrane Glycoproteins, Receptors, Immunologic, Microglia, Stroke, Mice, Transforming Growth Factor beta1, Lipid Droplets
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
