Abstract
Triggering receptor expressed on myeloid cells-2 (TREM2) is an innate immune receptor that promotes phagocytosis by microglia. However, whether TREM2 is related to the stimulus-dependent phagocytic activity of microglia is unclear. In this study, the primary cultured microglia were stimulated with interferon (IFN)-γ, interleukin (IL)-4, and interleukin (IL)-10, respectively, and their phagocytic activity against microbeads and apoptotic neural stem cells (NSCs) was measured. TREM2 of microglia was detected by qPCR and western blotting. The TREM2 signal was blocked in microglia using the siRNA technique. The results showed that IL-4 or IL-10 treatment significantly increased the number of microglia gathered around the apoptotic neurosphere. IL-4 and IL-10 treatment also promoted phagocytosis of microbeads and apoptotic NSCs by primary cultured microglia. The TREM2 expression was up-regulated in IL-4- or IL-10- treated microglia. TREM2 siRNA treatment blocked the phagocytic activity of IL-4- or IL-10-treated microglia. In conclusion, these results indicated that IL-4 and IL-10 promote the phagocytic activity of microglia by the up-regulation of TREM2, which suggested a new potential therapeutic target for neurodegenerative disease.
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References
Blume ZI, Lambert JM, Lovel AG, Mitchell DM (2020) Microglia in the developing retina couple phagocytosis with the progression of apoptosis via p2ry12 signaling. Dev Dyn. https://doi.org/10.1002/dvdy.163
Brown GC, Neher JJ (2014) MicrOoglial phagocytosis of live neurons. Nat Rev Neurosci 15:209–216. https://doi.org/10.1038/nrn3710
Browne TC, McQuillan K, McManus RM, O’Reilly JA, Mills KH, Lynch MA (2013) IFN-gamma production by amyloid beta-specific th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer’s disease. J Immunol 190:2241–2251. https://doi.org/10.4049/jimmunol.1200947
Butovsky O, Bukshpan S, Kunis G, Jung S, Schwartz M (2007) Microglia can be induced by ifn-gamma or Il-4 to express neural or dendritic-like markers. Mol Cell Neurosci 35:490–500. https://doi.org/10.1016/j.mcn.2007.04.009
Cunningham CL, Martinez-Cerdeno V, Noctor SC (2013) Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J Neurosci 33:4216–4233. https://doi.org/10.1523/jneurosci.3441-12.2013
Dean HB, Roberson ED, Song Y (2019) Neurodegenerative disease-associated variants in trem2 destabilize the apical ligand-binding region of the immunoglobulin domain. Front Neurol 10:1252. https://doi.org/10.3389/fneur.2019.01252
Du L, Zhang Y, Chen Y, Zhu J, Yang Y, Zhang HL (2017) Role of microglia in neurological disorders and their potentials as a therapeutic target. Mol Neurobiol 54:7567–7584. https://doi.org/10.1007/s12035-016-0245-0
Elmore MRP et al (2018) Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice. Aging Cell 17:e12832. https://doi.org/10.1111/acel.12832
Fan Y, Ma Y, Huang W, Cheng X, Gao N, Li G, Tian S (2019) Up-regulation of trem2 accelerates the reduction of amyloid deposits and promotes neuronal regeneration in the hippocampus of amyloid beta1-42 injected mice. J Chem Neuroanat 97:71–79. https://doi.org/10.1016/j.jchemneu.2019.02.002
Figarella K, Uzcategui NL, Mogk S, Wild K, Fallier-Becker P, Neher JJ, Duszenko M (2018) Morphological changes, nitric oxide production, and phagocytosis are triggered in vitro in microglia by bloodstream forms of Trypanosoma brucei. Sci Rep 8:15002. https://doi.org/10.1038/s41598-018-33395-x
Galloway DA, Phillips AEM, Owen DRJ, Moore CS (2019) Corrigendum: phagocytosis in the brain: homeostasis and disease. Front Immunol 10:1575. https://doi.org/10.3389/fimmu.2019.01575
Gao Y, Tu D, Yang R, Chu CH (2020) Through reducing ros production, il-10 suppresses caspase-1-dependent il-1beta maturation, thereby preventing chronic neuroinflammation and neurodegeneration. Int J Mol Sci. https://doi.org/10.3390/ijms21020465
Gensel JC, Zhang B (2015) Macrophage activation and its role in repair and pathology after spinal cord injury. Brain Res 1619:1–11. https://doi.org/10.1016/j.brainres.2014.12.045
Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964. https://doi.org/10.1038/nri1733
Hanisch UK (2002) Microglia as a source and target of cytokines. Glia 40:140–155. https://doi.org/10.1002/glia.10161
Jesus EE et al (2013) Effects of ifn-gamma, tnf-alpha, il-10 and tgf-beta on neospora caninum Infection in rat glial cells. Exp Parasitol 133:269–274. https://doi.org/10.1016/j.exppara.2012.11.016
Jordan FL, Thomas WE (1987) Identification of microglia in primary cultures of mixed cerebral cortical cells. Brain Res Bull 19:153–159. https://doi.org/10.1016/0361-9230(87)90180-8
Jun BH, Kang H, Lee YS, Jeong DH (2012) Fluorescence-based multiplex protein detection using optically encoded microbeads. Molecules 17:2474–2490. https://doi.org/10.3390/molecules17032474
Kaminska B, Mota M, Pizzi M (2016) Signal transduction and epigenetic mechanisms in the control of microglia activation during neuroinflammation. Biochem Biophys Acta 1862:339–351. https://doi.org/10.1016/j.bbadis.2015.10.026
Kim SM et al (2017) Trem2 promotes abeta phagocytosis by upregulating c/ebpalpha-dependent cd36 expression in microglia. Sci Rep 7:11118. https://doi.org/10.1038/s41598-017-11634-x
Kofler J, Wiley CA (2011) Microglia: key innate immune cells of the brain. Toxicol Pathol 39:103–114. https://doi.org/10.1177/0192623310387619
Lee CY, Landreth GE (2010) The role of microglia in amyloid clearance from the ad brain. J Neural Transm (Vienna, Austria: 1996) 117:949–960. https://doi.org/10.1007/s00702-010-0433-4
Lemke G (2019) How macrophages deal with death. Nat Rev Immunol 19:539–549. https://doi.org/10.1038/s41577-019-0167-y
Lively S, Schlichter LC (2018) Microglia responses to pro-inflammatory stimuli (lps, ifngamma + tnfalpha) and reprogramming by resolving cytokines (il-4, il-10). Front Cell Neurosci 12:215. https://doi.org/10.3389/fncel.2018.00215
Loane DJ, Kumar A (2016) Microglia in the tbi brain: the good, the bad, and the dysregulated. Exp Neurol 275:316–327. https://doi.org/10.1016/j.expneurol.2015.08.018
Lobo-Silva D, Carriche GM, Castro AG, Roque S, Saraiva M (2017) Interferon-beta regulates the production of il-10 by toll-like receptor-activated microglia. Glia 65:1439–1451. https://doi.org/10.1002/glia.23172
Meilandt WJ et al (2020) Trem2 deletion reduces late-stage amyloid plaque accumulation, elevates the abeta42:abeta40 ratio, and exacerbates axonal dystrophy and dendritic spine loss in the ps2a pp Alzheimer’s mouse model. J Neurosci. https://doi.org/10.1523/jneurosci.1871-19.2019
Mizee MR et al (2017) Isolation of primary microglia from the human post-mortem brain: effects of ante- and post-mortem variables. Acta Neuropathol Commun 5:16. https://doi.org/10.1186/s40478-017-0418-8
Neher JJ, Emmrich JV, Fricker M, Mander PK, Thery C, Brown GC (2013) Phagocytosis executes delayed neuronal death after focal brain ischemia. Proc Natl Acad Sci USA 110:E4098–E4107. https://doi.org/10.1073/pnas.1308679110
Neniskyte U, Neher JJ, Brown GC (2011) Neuronal death induced by nanomolar amyloid beta is mediated by primary phagocytosis of neurons by microglia. J Biol Chem 286:39904–39913. https://doi.org/10.1074/jbc.M111.267583
Nonaka S, Nakanishi H (2019) Microglial clearance of focal apoptotic synapses. Neurosci Lett 707:134317. https://doi.org/10.1016/j.neulet.2019.134317
Nugent AA et al (2019) Trem2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge. Neuron. https://doi.org/10.1016/j.neuron.2019.12.007
Omer AM, Tamer TM, Hassan MA, Rychter P, Mohy Eldin MS, Koseva N (2016) Development of amphoteric alginate/aminated chitosan coated microbeads for oral protein delivery. Int J Biol Macromol 92:362–370. https://doi.org/10.1016/j.ijbiomac.2016.07.019
Orihuela R, McPherson CA, Harry GJ (2016) Microglial m1/m2 polarization and metabolic states. Br J Pharmacol 173:649–665. https://doi.org/10.1111/bph.13139
Schulz D, Severin Y, Zanotelli VRT, Bodenmiller B (2019) In-depth characterization of monocyte-derived macrophages using a mass cytometry-based phagocytosis assay. Sci Rep 9:1925. https://doi.org/10.1038/s41598-018-38127-9
Shao QH, Zhang XL, Yang PF, Yuan YH, Chen NH (2017) Amyloidogenic proteins associated with neurodegenerative diseases activate the nlrp3 inflammasome. Int Immunopharmacol 49:155–160. https://doi.org/10.1016/j.intimp.2017.05.027
Sierra A, Abiega O, Shahraz A, Neumann H (2013) Janus-faced microglia: beneficial and detrimental consequences of microglial phagocytosis. Front Cell Neurosci 7:6. https://doi.org/10.3389/fncel.2013.00006
Somo SI, Khanna O, Brey EM (2017) Alginate microbeads for cell and protein delivery. Methods Mol Biol 1479:217–224. https://doi.org/10.1007/978-1-4939-6364-5_17
Walker DG, Lue LF (2015) Immune phenotypes of microglia in human neurodegenerative disease: challenges to detecting microglial polarization in human brains. Alzheimer’s Res Ther 7:56. https://doi.org/10.1186/s13195-015-0139-9
Yamamiya M, Tanabe S, Muramatsu R (2019) Microglia promote the proliferation of neural precursor cells by secreting osteopontin. Biochem Biophys Res Commun 513:841–845. https://doi.org/10.1016/j.bbrc.2019.04.076
Yeh FL, Hansen DV, Sheng M (2017) Trem2, microglia, and neurodegenerative diseases. Trends Mol Med 23:512–533. https://doi.org/10.1016/j.molmed.2017.03.008
Zhong L, Chen XF (2019) The emerging roles and therapeutic potential of soluble trem2 in Alzheimer’s disease. Front Aging Neurosci 11:328. https://doi.org/10.3389/fnagi.2019.00328
Acknowledgments
The authors thank Professor Lanping Guo at the Resource Center of the Chinese Academy of Traditional Chinese Medicine for giving us guidance on the experiment and writing. The authors are grateful to Professor Jun Yu for help in revising the manuscript.
Funding
This study was funded by the Department of Science and Technology of Guizhou High-level Innovative Talents ([2018]5638), Guizhou science and technology plan project ([2019]5611) and First-class Discipline Construction Projects of Guizhou Province of China [GNYL(2017)008].
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YS, ZJ, and ZT designed the conceptual idea for this study and wrote the manuscript. YS, JX and LY performed the experiments. TX and XC analyzed these data. All the authors participated in the discussion and approved the manuscript as submitted.
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Yi, S., Jiang, X., Tang, X. et al. IL-4 and IL-10 promotes phagocytic activity of microglia by up-regulation of TREM2. Cytotechnology 72, 589–602 (2020). https://doi.org/10.1007/s10616-020-00409-4
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DOI: https://doi.org/10.1007/s10616-020-00409-4