Inhibition of Microglial Phagocytosis Is Sufficient To Prevent Inflammatory Neuronal Death
Open accessAbstract
It is well-known that dead and dying neurons are quickly removed through phagocytosis by the brain’s macrophages, the microglia. Therefore, neuronal loss during brain inflammation has always been assumed to be due to phagocytosis of neurons subsequent to their apoptotic or necrotic death. However, we report in this article that under inflammatory conditions in primary rat cultures of neurons and glia, phagocytosis actively induces neuronal death. Specifically, two inflammatory bacterial ligands, lipoteichoic acid or LPS (agonists of glial TLR2 and TLR4, respectively), stimulated microglial proliferation, phagocytic activity, and engulfment of ∼30% of neurons within 3 d. Phagocytosis of neurons was dependent on the microglial release of soluble mediators (and peroxynitrite in particular), which induced neuronal exposure of the eat-me signal phosphatidylserine (PS). Surprisingly, however, eat-me signaling was reversible, so that blocking any step in a phagocytic pathway consisting of PS exposure, the PS-binding protein milk fat globule epidermal growth factor-8, and its microglial vitronectin receptor was sufficient to rescue up to 90% of neurons without reducing inflammation. Hence, our data indicate a novel form of inflammatory neurodegeneration, where inflammation can cause eat-me signal exposure by otherwise viable neurons, leading to their death through phagocytosis. Thus, blocking phagocytosis may prevent some forms of inflammatory neurodegeneration, and therefore might be beneficial during brain infection, trauma, ischemia, neurodegeneration, and aging.
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?
Endotoxin directly and indirectly activates microglia that damage neurons via nitric oxide, oxidants and cytokines, and by phagocytosis of synapses and neurons.
“Endotoxin directly and indirectly activates microglia that damage neurons via nitric oxide, oxidants and cytokines, and by phagocytosis of synapses and neurons.”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [59]
Treatment of glial-neuronal cultures with LPS alone results in little or no neuronal apoptosis or necrosis, but rather progressive loss of neurons over several days due to microglial phagocytosis of stressed-but-viable neurons, and blocking the phagocytosis saves the neurons.
“However, treatment of glial-neuronal cultures with LPS alone results in little or no neuronal apoptosis or necrosis, but rather progressive loss of neurons over several days due to microglial phagocytosis of stressed-but-viable neurons and blocking the phagocytosis saves the neurons [59].”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [59]
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
Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo
Nimmerjahn, A., Kirchhoff, F., & Helmchen, F. (2005) · Science · doi:10.1126/science.1110647 · Cited by 5,827 · see citing works
Microglia-mediated neurotoxicity: uncovering the molecular mechanisms
Block, M. L., Zecca, L., & Hong, J.-S. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2038 · Cited by 4,110 · see citing works
Mechanisms underlying inflammation in neurodegeneration
Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C., & Gage, F. H. (2010) · Cell · doi:10.1016/j.cell.2010.02.016 · Cited by 3,580 · see citing works
Alternative Activation of Macrophages: An Immunologic Functional Perspective
Martinez, F. O., Helming, L., & Gordon, S. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132532 · Cited by 2,745 · see citing works
Lipton, S. A., Choi, Y.-B., Pan, Z.-H., Lei, S. Z., Chen, H.-S. V., Sucher, N. J., Loscalzo, J., Singel, D. J., & Stamler, J. S. (1993) · Nature · doi:10.1038/364626a0 · Cited by 2,433 · see citing works
Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration
Qin, L., Wu, X., Block, M. L., Liu, Y., Breese, G. R., Hong, J., Knapp, D. J., & Crews, F. T. (2007) · Glia · doi:10.1002/glia.20467 · Cited by 2,144 · see citing works
Microglial physiology: unique stimuli, specialized responses
Ransohoff, R. M., & Perry, V. H. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132528 · Cited by 1,858 · see citing works
A blast from the past: clearance of apoptotic cells regulates immune responses
Savill, J., Dransfield, I., Gregory, C. D., & Haslett, C. (2002) · Nature reviews. Immunology · doi:10.1038/nri957 · Cited by 1,574 · see citing works
Park, J. S., Svetkauskaite, D., He, Q., Kim, J., Strassheim, D., Ishizaka, A., & Abraham, E. H. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m306793200 · Cited by 1,560 · see citing works
Microglia and inflammation-mediated neurodegeneration: Multiple triggers with a common mechanism
Block, M. L., & Hong, J.-S. (2005) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2005.06.004 · Cited by 1,557 · see citing works
Identification of a factor that links apoptotic cells to phagocytes
Hanayama, R., Tanaka, M., Miwa, K., Shinohara, A., Iwamatsu, A., & Nagata, S. (2002) · Nature · doi:10.1038/417182a · Cited by 1,401 · see citing works
Lehnardt, S., Massillon, L., Follett, P., Jensen, F. E., Ratan, R., Rosenberg, P. A., Volpe, J. J., & Vartanian, T. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1432609100 · Cited by 1,052 · see citing works
The myeloid cells of the central nervous system parenchyma
Ransohoff, R. M., & Cardona, A. E. (2010) · Nature · doi:10.1038/nature09615 · Cited by 804 · see citing works
Microglia Promote the Death of Developing Purkinje Cells
Marı́n-Teva, J. L., Dusart, I., Colin, C., Gervais, A., van Rooijen, N., & Mallat, M. (2004) · Neuron · doi:10.1016/s0896-6273(04)00069-8 · Cited by 757 · see citing works
Combs, C. K., Karlo, J. C., Kao, S.-C., & Landreth, G. E. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-04-01179.2001 · Cited by 721 · see citing works
Gao, H., Jiang, J., Wilson, B. C., Zhang, W., Hong, J., & Liu, B. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.00928.x · Cited by 690 · see citing works
Immune activation in brain aging and neurodegeneration: too much or too little?
Lucin, K. M., & Wyss-Coray, T. (2009) · Neuron · doi:10.1016/j.neuron.2009.08.039 · Cited by 679 · see citing works
Toll-Like Receptor 4 Is Involved in Brain Damage and Inflammation After Experimental Stroke
Caso, J. R., Pradillo, J. M., Hurtado, O., Lorenzo, P. L., Moro, M. Á., & Lizasoaín, I. (2007) · Circulation · doi:10.1161/circulationaha.106.603431 · Cited by 606 · see citing works
Lehnardt, S. (2009) · Glia · doi:10.1002/glia.20928 · Cited by 596 · see citing works
CD14 and Toll-Like Receptors 2 and 4 Are Required for Fibrillar Aβ-Stimulated Microglial Activation
Reed-Geaghan, E. G., Savage, J. C., Hise, A. G., & Landreth, G. E. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.3158-09.2009 · Cited by 591 · see citing works
Haubner, R., Gratias, R., Diefenbach, B., Goodman, S. L., Jonczyk, A., & Kessler, H. (1996) · Journal of the American Chemical Society · doi:10.1021/ja9603721 · Cited by 585 · see citing works
Decoding Cell Death Signals in Inflammation and Immunity
Zitvogel, L., Kepp, O., & Kroemer, G. (2010) · Cell · doi:10.1016/j.cell.2010.02.015 · Cited by 558 · see citing works
Role of the Toll-Like Receptor 4 in Neuroinflammation in Alzheimer’s Disease
Walter, S., Letiembre, M., Liu, Y., Heine, H., Penke, B., Hao, W., Bode, B., Manietta, N., Walter, J., Schulz-Schüffer, W., et al. (2007) · Cellular Physiology and Biochemistry · doi:10.1159/000110455 · Cited by 543 · see citing works
Li, Z., Jo, J., Jia, J., Lo, S., Whitcomb, D. J., Jiao, S., Cho, K., & Sheng, M. (2010) · Cell · doi:10.1016/j.cell.2010.03.053 · Cited by 533 · see citing works
Inflammatory Neurodegeneration and Mechanisms of Microglial Killing of Neurons
Brown, G. C., & Neher, J. J. (2010) · Molecular Neurobiology · doi:10.1007/s12035-010-8105-9 · Cited by 526 · see citing works
Self-citationBal-Price, A., & Brown, G. C. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-17-06480.2001 · Cited by 489 · see citing works
Self-citationGlial cells as intrinsic components of non-cell-autonomous neurodegenerative disease
Lobsiger, C. S., & Cleveland, D. W. (2007) · Nature Neuroscience · doi:10.1038/nn1988 · Cited by 438 · see citing works
Brain glia release factors with opposing actions upon neuronal survival
Giulian, D., Vaca, K., & Corpuz, M. (1993) · Journal of Neuroscience · doi:10.1523/jneurosci.13-01-00029.1993 · Cited by 433 · see citing works
Glial pathology but absence of apoptotic nigral neurons in long‐standing Parkinson's disease
Banati, R. B., Daniel, S. E., & Blunt, S. B. (1998) · Movement Disorders · doi:10.1002/mds.870130205 · Cited by 430 · see citing works
Phosphatidylserine Receptor Is Required for Clearance of Apoptotic Cells
Li, M. O., Sarkisian, M. R., Mehal, W. Z., RAKIC, P. T., & Flavell, R. A. (2003) · Science · doi:10.1126/science.1087621 · Cited by 403 · see citing works
Molecular mechanisms of late apoptotic/necrotic cell clearance
Poon, I. K. H., Hulett, M. D., & Parish, C. R. (2009) · Cell Death and Differentiation · doi:10.1038/cdd.2009.195 · Cited by 353 · see citing works
Wakselman, S., Béchade, C., Roumier, A., Bernard, D., Triller, A., & Bessis, A. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.1006-08.2008 · Cited by 351 · see citing works
Combs, C. K., Johnson, D. E., Cannady, S. B., Lehman, T. M., & Landreth, G. E. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-03-00928.1999 · Cited by 349 · see citing works
Phagocytosis promotes programmed cell death in C. elegans
Reddien, P. W., Cameron, S., & Horvitz, H. R. (2001) · Nature · doi:10.1038/35084096 · Cited by 348 · see citing works
Phosphatidylserine recognition by phagocytes: a view to a kill
Wu, Y., Tibrewal, N., & Birge, R. B. (2006) · Trends in Cell Biology · doi:10.1016/j.tcb.2006.02.003 · Cited by 341 · see citing works
Colony-stimulating factors as promoters of ameboid microglia
Giulian, D., & Ingeman, J. (1988) · Journal of Neuroscience · doi:10.1523/jneurosci.08-12-04707.1988 · Cited by 323 · see citing works
Microglial clearance function in health and disease
Napoli, I., & Neumann, H. (2008) · Neuroscience · doi:10.1016/j.neuroscience.2008.06.046 · Cited by 312 · see citing works
Engulfment genes cooperate with ced-3 to promote cell death in Caenorhabditis elegans
Hoeppner, D. J., Hengartner, M. O., & Schnabel, R. (2001) · Nature · doi:10.1038/35084103 · Cited by 295 · see citing works
Lehnardt, S., Schott, E., Trimbuch, T., Laubisch, D., Krueger, C., Wulczyn, G., Nitsch, R., & Weber, J. R. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.4760-07.2008 · Cited by 287 · see citing works
Toll-like receptor 2 mediates CNS injury in focal cerebral ischemia
Lehnardt, S., Lehmann, S., Kaul, D., Tschimmel, K., Hoffmann, O. M., Cho, S., Krueger, C., Nitsch, R., Meisel, A., & Weber, J. R. (2007) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2007.07.023 · Cited by 252 · see citing works
Akakura, S., Singh, S., Spataro, M., Akakura, R., Kim, J., Albert, M. L., & Birge, R. B. (2003) · Experimental Cell Research · doi:10.1016/j.yexcr.2003.09.011 · Cited by 229 · see citing works
Annexin A1: A Central Player in the Anti-Inflammatory and Neuroprotective Role of Microglia
McArthur, S., Cristante, E., Paterno, M., Christian, H., Roncaroli, F., Gillies, G. E., & Solito, E. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1001095 · Cited by 209 · see citing works
Muta, T., & Takeshige, K. (2001) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2001.02385.x · Cited by 205 · see citing works
Regulated Externalization of Phosphatidylserine at the Cell Surface
Balasubramanian, K., Mirnikjoo, B., & Schroit, A. J. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m700202200 · Cited by 199 · see citing works
Toll-Like Receptor 2 Signaling in Response to Brain Injury: An Innate Bridge to Neuroinflammation
Babcock, A. A., Wirenfeldt, M., Holm, T. H., Nielsen, H. H., Dissing‐Olesen, L., Toft‐Hansen, H., Millward, J. M., Landmann, R. M., Rivest, S., Finsen, B. R., et al. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.4937-05.2006 · Cited by 186 · see citing works
The Extracellular Matrix and Cytokines Regulate Microglial Integrin Expression and Activation
Milner, R., & Campbell, I. L. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.7.3850 · Cited by 179 · see citing works
Nicholls, D. G. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m510916200 · Cited by 175 · see citing works
Choi, H. B., Ryu, J. K., Kim, S. U., & McLarnon, J. G. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.5417-06.2007 · Cited by 173 · see citing works
Secretion of a peripheral membrane protein, MFG‐E8, as a complex with membrane vesicles
Oshima, K., Aoki, N., Kato, T., Kitajima, K., & Matsuda, T. (2002) · European Journal of Biochemistry · doi:10.1046/j.1432-1033.2002.02758.x · Cited by 166 · see citing works
MFG-E8 Regulates Microglial Phagocytosis of Apoptotic Neurons
Fuller, A. D., & Eldik, L. J. V. (2008) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-008-9118-2 · Cited by 155 · see citing works
Borisenko, G. G., Matsura, T., Liu, S., Tyurin, V. A., Jiang, J., Serinkan, F. B., & Kagan, V. E. (2003) · Archives of Biochemistry and Biophysics · doi:10.1016/s0003-9861(03)00083-3 · Cited by 125 · see citing works
Fractalkine-Induced MFG-E8 Leads to Enhanced Apoptotic Cell Clearance by Macrophages
Miksa, M., Amin, D., Wu, R., Dong, W., Ravikumar, T. S., & Wang, P. (2007) · Molecular Medicine · doi:10.2119/2007-00019.miksa · Cited by 118 · see citing works
Re, F., Belyanskaya, S. L., Riese, R. J., Cipriani, B., Fischer, F. R., Granucci, F., Ricciardi-Castagnoli, P., Brosnan, C., Stern, L. J., Strominger, J. L., et al. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.5.2264 · Cited by 109 · see citing works
Kinsner, A., Pilotto, V., Deininger, S., Brown, G. C., Coecke, S., Härtung, T., & Bal‐Price, A. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03422.x · Cited by 88 · see citing works
Self-citationGavilán, M. P., Revilla, E., Pintado, C., Castaño, A., Vizuete, M., Moreno‐González, I., Baglietto‐Vargas, D., Sanchez-Varo, R. M., Vitórica, J., Gutiérrez, A., et al. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04787.x · Cited by 77 · see citing works
Detection of Apoptosis Using the C2A Domain of Synaptotagmin I
Jung, H., Kettunen, M. I., Davletov, B. A., & Brindle, K. M. (2004) · Bioconjugate Chemistry · doi:10.1021/bc049899q · Cited by 76 · see citing works
Chan, A., Seguin, R. M., Magnus, T., Papadimitriou, C., Toyka, K. V., Antel, J. P., & Gold, R. (2003) · Glia · doi:10.1002/glia.10258 · Cited by 74 · see citing works
Kinsner, A., Boveri, M., Hareng, L., Brown, G. C., Coecke, S., Hartung, T., & Bal‐Price, A. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04085.x · Cited by 59 · see citing works
Self-citationSuzumura, A., Sawada, M., & Marunouchi, T. (1996) · Brain Research · doi:10.1016/0006-8993(95)01535-3 · Cited by 56 · see citing works
Schrammel, A., Pfeiffer, S., Schmidt, K., Koesling, D., & Mayer, B. (1998) · Molecular Pharmacology · doi:10.1124/mol.54.1.207 · Cited by 52 · see citing works
Fabisiak, J. P., Tyurin, V. A., Tyurina, Y. Y., Sedlov, A., Lazo, J. S., & Kagan, V. E. (1999) · Biochemistry · doi:10.1021/bi9912544 · Cited by 40 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Immunopathology of multiple sclerosis
Dendrou, C. A., Fugger, L., & Friese, M. A. (2015) · Nature Reviews Immunology · doi:10.1038/nri3871 · Cited by 2,215 · see citing works
Fricker, M., Tolkovsky, A. M., Borutaitė, V., Coleman, M. P., & Brown, G. C. (2018) · Physiological Reviews · doi:10.1152/physrev.00011.2017 · Cited by 1,122 · see citing works
Self-citationMicroglia Regulate the Number of Neural Precursor Cells in the Developing Cerebral Cortex
Cunningham, C. L., Martínez-Cerdeño, V., & Noctor, S. C. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.3441-12.2013 · Cited by 976 · see citing works
The Role of Microglia in the Healthy Brain: Figure 1.
Tremblay, M.-È., Stevens, B., Sierra, A., Wake, H., Bessis, A., & Nimmerjahn, A. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.4158-11.2011 · Cited by 992 · see citing works
Microglial Phagocytosis of Live Neurons
Brown, G. C., & Neher, J. J. (2014) · Nature Reviews Neuroscience · doi:10.1038/nrn3710 · Cited by 853 · see citing works
Self-citationMicroglia and neurodegeneration: The role of systemic inflammation
Cunningham, C. (2013) · Glia · doi:10.1002/glia.22350 · Cited by 769 · see citing works
The biphasic function of microglia in ischemic stroke
Ma, Y., Wang, J., Wang, Y., & Yang, G. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.01.005 · Cited by 724 · see citing works
Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications
Tuo, Q., Zhang, S., & Lei, P. (2021) · Medicinal Research Reviews · doi:10.1002/med.21817 · Cited by 747 · see citing works
Glial Cells: Role of the Immune Response in Ischemic Stroke
Xu, S., Lü, J., Shao, A., Zhang, J. H., & Zhang, J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00294 · Cited by 604 · see citing works
Janus-faced microglia: beneficial and detrimental consequences of microglial phagocytosis
Sierra, A., Abiega, O., Shahraz, A., & Neumann, H. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00006 · Cited by 574 · see citing works
Retinal microglia: Just bystander or target for therapy?
Karlstetter, M., Scholz, R., Rutar, M., Wong, W. T., Provis, J. M., & Langmann, T. (2014) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2014.11.004 · Cited by 550 · see citing works
The endotoxin hypothesis of neurodegeneration
Brown, G. C. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1564-7 · Cited by 457 · see citing works
Self-citationMicroglial phagocytosis of living photoreceptors contributes to inherited retinal degeneration
Zhao, L., Zabel, M. K., Wang, X., Ma, W., Shah, P., Fariss, R. N., Qian, H., Parkhurst, C. N., Gan, W., & Wong, W. T. (2015) · EMBO Molecular Medicine · doi:10.15252/emmm.201505298 · Cited by 445 · see citing works
IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline
Fu, A. K. Y., Hung, K.-W., Yuen, M. Y. F., Zhou, X., Mak, D. S. Y., Chan, I. C. W., Cheung, T. H., Zhang, B., Fu, W.-Y., Liew, F. Y., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1604032113 · Cited by 369 · see citing works
Microglia: Agents of the CNS Pro-Inflammatory Response
Rodríguez-Gómez, J. A., Kavanagh, E., Engskog-Vlachos, P., Engskog, M. K. R., Herrera, A. J., Espinosa-Oliva, A. M., Joseph, B., Hajji, N., Venero, J. L., & Burguillos, M. A. (2020) · Cells · doi:10.3390/cells9071717 · Cited by 365 · see citing works
Microglia and ischemic stroke: a double-edged sword.
Patel, A. R., Ritzel, R. M., McCullough, L. D., & Liu, F. (2013) · Europe PMC (PubMed Central) · Cited by 355 · see citing works
Phagocytosis executes delayed neuronal death after focal brain ischemia
Neher, J. J., Emmrich, J., Fricker, M., Mander, P. K., Théry, C., & Brown, G. C. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1308679110 · Cited by 350 · see citing works
Self-citationMicroglia Function in Alzheimer’s Disease
Solito, E., & Sastre, M. (2012) · Frontiers in Pharmacology · doi:10.3389/fphar.2012.00014 · Cited by 347 · see citing works
Microglial Dynamics and Role in the Healthy and Diseased Brain: A Paradigm of Functional Plasticity
Gomez-Nicola, D., & Perry, V. H. (2015) · The Neuroscientist · doi:10.1177/1073858414530512 · Cited by 340 · see citing works
Eaten alive! Cell death by primary phagocytosis: ‘phagoptosis’
Brown, G. C., & Neher, J. J. (2012) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2012.05.002 · Cited by 320 · see citing works
Self-citationBrown, G. C., & Vilalta, A. (2015) · Brain Research · doi:10.1016/j.brainres.2015.08.031 · Cited by 306 · see citing works
Self-citationMicroglial phagocytosis of neurons in neurodegeneration, and its regulation
Butler, C. A., Popescu, A. S., Kitchener, E. J. A., Allendorf, D. H., Puigdellívol, M., & Brown, G. C. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15327 · Cited by 293 · see citing works
Self-citationMicroglia in Alzheimer’s disease: pathogenesis, mechanisms, and therapeutic potentials
Miao, J., Ma, H., Yang, Y., Liao, Y., Lin, C., Zheng, J., Yu, M., & Lan, J. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1201982 · Cited by 293 · see citing works
Neuronal Death Mechanisms and Therapeutic Strategy in Ischemic Stroke
Mao, R., Zong, N., Hu, Y., Chen, Y., & Xu, Y. (2022) · Neuroscience Bulletin · doi:10.1007/s12264-022-00859-0 · Cited by 289 · see citing works
Hsiao, I., Hsieh, Y., Wang, C., Chen, I.-C., & Huang, Y.-J. (2015) · Environmental Science & Technology · doi:10.1021/es504705p · Cited by 263 · see citing works
Microglial cell loss after ischemic stroke favors brain neutrophil accumulation
Otxoa-de-Amezaga, A., Miró-Mur, F., Pedragosa, J., Gallizioli, M., Justicia, C., Gaja-Capdevila, N., Ruíz-Jaen, F., Salas-Perdomo, A., Bosch, A., Calvo, M., et al. (2019) · Acta Neuropathologica · doi:10.1007/s00401-018-1954-4 · Cited by 258 · see citing works
Structural and functional consequences of reversible lipid asymmetry in living membranes
Doktorova, M., Symons, J. L., & Levental, I. (2020) · Nature Chemical Biology · doi:10.1038/s41589-020-00688-0 · Cited by 232 · see citing works
Microglial activation and progressive brain changes in schizophrenia
Laskaris, L., Biase, M. A. D., Everall, I., Chana, G., Christopoulos, A., Skafidas, E. S., Cropley, V., & Pantelis, C. (2015) · British Journal of Pharmacology · doi:10.1111/bph.13364 · Cited by 227 · see citing works
MFG-E8 Mediates Primary Phagocytosis of Viable Neurons during Neuroinflammation
Fricker, M., Neher, J. J., Zhao, J.-W., Théry, C., Tolkovsky, A. M., & Brown, G. C. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.4837-11.2012 · Cited by 218 · see citing works
Self-citationModulating neurotoxicity through CX3CL1/CX3CR1 signaling
Limatola, C., & Ransohoff, R. M. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00229 · Cited by 210 · see citing works
Microglial Activation – Tuning and Pruning Adult Neurogenesis
Ekdahl, C. T. (2012) · Frontiers in Pharmacology · doi:10.3389/fphar.2012.00041 · Cited by 211 · see citing works
Svoboda, D. S., Barrasa, M. I., Shu, J., Rietjens, R. G. J., Zhang, S., Mitalipova, M., Berube, P., Fu, D., Shultz, L. D., Bell, G. W., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1913541116 · Cited by 203 · see citing works
Neniškytė, U., Neher, J. J., & Brown, G. C. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.267583 · Cited by 208 · see citing works
Self-citationPhagocytic microglia and macrophages in brain injury and repair
Yu, F., Wang, Y., Stetler, R. A., Leak, R. K., Hu, X., & Chen, J. (2022) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13899 · Cited by 209 · see citing works
Versatility of the complement system in neuroinflammation, neurodegeneration and brain homeostasis
Orsini, F., Blasio, D. D., Zangari, R., Zanier, E. R., & Simoni, M. G. D. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00380 · Cited by 202 · see citing works
Targeting toll-like receptor 4 to modulate neuroinflammation in central nervous system disorders
Leitner, G. R., Wenzel, T., Marshall, N., Gates, E. J., & Klegeris, A. (2019) · Expert opinion on therapeutic targets · doi:10.1080/14728222.2019.1676416 · Cited by 187 · see citing works
Microglia: Multitasking Specialists of the Brain
Casano, A. M., & Peri, F. (2015) · Developmental Cell · doi:10.1016/j.devcel.2015.01.018 · Cited by 192 · see citing works
Brelstaff, J., Tolkovsky, A. M., Ghetti, B., Goedert, M., & Spillantini, M. G. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.07.072 · Cited by 195 · see citing works
Self-citationBlankman, J. L., Long, J. Z., Trauger, S. A., Siuzdak, G. E., & Cravatt, B. F. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1217121110 · Cited by 193 · see citing works
CX3CL1 Is Neuroprotective in Permanent Focal Cerebral Ischemia in Rodents
Cipriani, R., Villa, P., Chece, G., Lauro, C., Paladini, A., Micotti, E., Perego, C., Simoni, M. G. D., Fredholm, B. B., Eusebi, F., et al. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.3611-11.2011 · Cited by 189 · see citing works
Glutamate and GABA in Microglia-Neuron Cross-Talk in Alzheimer’s Disease
Czapski, G. A., & Strosznajder, J. B. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111677 · Cited by 194 · see citing works
Oxidative stress and neurodegeneration: the involvement of iron
Carocci, A., Catalano, A. A., Sinicropi, M. S., & Genchi, G. (2018) · BioMetals · doi:10.1007/s10534-018-0126-2 · Cited by 180 · see citing works
PU.1 regulates Alzheimer’s disease-associated genes in primary human microglia
Rustenhoven, J., Smith, A. M., Smyth, L. C., Jansson, D., Scotter, E. L., Swanson, M. E. V., Aalderink, M., Coppieters, N., Narayan, P., Handley, R., et al. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0277-1 · Cited by 155 · see citing works
Vilalta, A., & Brown, G. C. (2017) · FEBS Journal · doi:10.1111/febs.14323 · Cited by 174 · see citing works
Self-citationNeurotransmitter signaling in the pathophysiology of microglia
Domercq, M., Vázquez‐Villoldo, N., & Matute, C. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00049 · Cited by 170 · see citing works
Anti-inflammatory Effects of Curcumin in Microglial Cells
Yu, Y., Shen, Q., Lai, Y., Park, S. Y., Ou, X., Lin, D., Jin, M., & Zhang, W. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00386 · Cited by 166 · see citing works
Microglia and neuronal cell death
Marín‐Teva, J. L., Cuadros, M. Á., Martín‐Oliva, D., & Navascués, J. (2011) · Neuron Glia Biology · doi:10.1017/s1740925x12000014 · Cited by 152 · see citing works
Bone Marrow Mesenchymal Stromal Cells Drive Protective M2 Microglia Polarization After Brain Trauma
Zanier, E. R., Pischiutta, F., Riganti, L., Marchesi, F., Turola, E., Fumagalli, S., Perego, C., Parotto, E., Vinci, P., Veglianese, P., et al. (2014) · Neurotherapeutics · doi:10.1007/s13311-014-0277-y · Cited by 155 · see citing works
Barcia, C., Ros, C. M., Annese, V., Carrillo-de Sauvage, M. A., Ros-Bernal, F., Gómez, A., Yuste, J. E., Campuzano, C. M., de Pablos, V., Fernandez-Villalba, E., et al. (2012) · Scientific Reports · doi:10.1038/srep00809 · Cited by 150 · see citing works
Fricker, M., Oliva-Martín, M. J., & Brown, G. C. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-196 · Cited by 153 · see citing works
Self-citationAndersen, H. H., Johnsen, K. B., & Moos, T. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1509-8 · Cited by 151 · see citing works
Tumour necrosis factor alpha‐induced neuronal loss is mediated by microglial phagocytosis
Neniškytė, U., Vilalta, A., & Brown, G. C. (2014) · FEBS Letters · doi:10.1016/j.febslet.2014.05.046 · Cited by 151 · see citing works
Self-citationPrimary Phagocytosis of Neurons by Inflamed Microglia: Potential Roles in Neurodegeneration
Neher, J. J., Neniškytė, U., & Brown, G. C. (2012) · Frontiers in Pharmacology · doi:10.3389/fphar.2012.00027 · Cited by 151 · see citing works
Self-citationInflammatory Activation of Microglia and Astrocytes in Manganese Neurotoxicity
Tjalkens, R. B., Popichak, K. A., & Kirkley, K. A. (2017) · Advances in neurobiology · doi:10.1007/978-3-319-60189-2_8 · Cited by 146 · see citing works
Neher, J. J., Neniškytė, U., Hornik, T. C., & Brown, G. C. (2014) · Glia · doi:10.1002/glia.22693 · Cited by 143 · see citing works
Self-citationRole of microglia in ischemic focal stroke and recovery: focus on Toll-like receptors
Anttila, J. E., Whitaker, K. W., Wires, E. S., Harvey, B. K., & Airavaara, M. (2016) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2016.07.003 · Cited by 144 · see citing works
The transcription factor PU.1 is critical for viability and function of human brain microglia
Smith, A. M., Gibbons, H. M., Oldfield, R. L., Bergin, P. M., Mee, E. W., Faull, R. L. M., & Dragunow, M. (2013) · Glia · doi:10.1002/glia.22486 · Cited by 141 · see citing works
Molecular Communication of a Dying Neuron in Stroke
Puig, B., Brenna, S., & Magnus, T. U. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19092834 · Cited by 138 · see citing works
Brelstaff, J. H., Mason, M., Katsinelos, T., McEwan, W. A., Ghetti, B., Tolkovsky, A. M., & Spillantini, M. G. (2021) · Science Advances · doi:10.1126/sciadv.abg4980 · Cited by 135 · see citing works
Self-citationThe Role of Microglial Phagocytosis in Ischemic Stroke
Jia, J., Yang, L., Chen, Y., Zheng, L., Chen, Y., Xu, Y., & Zhang, M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2021.790201 · Cited by 136 · see citing works
The endotoxin hypothesis of Alzheimer’s disease
Brown, G. C., & Heneka, M. T. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00722-y · Cited by 140 · see citing works
Self-citationNazmi, A., Field, R. H., Griffin, É. W., Haugh, O., Hennessy, E., Cox, D. J., dos Reis, R. R., Tortorelli, L. S., Murray, C., López-Rodríguez, A. B., et al. (2019) · Glia · doi:10.1002/glia.23592 · Cited by 133 · see citing works
Planas, A. M. (2024) · Glia · doi:10.1002/glia.24501 · Cited by 133 · see citing works
Margeta, M. A., Yin, Z., Madore, C., Pitts, K. M., Letcher, S. M., Tang, J., Jiang, S., Gauthier, C. D., Silveira, S. R., Schroeder, C. M., et al. (2022) · Immunity · doi:10.1016/j.immuni.2022.07.014 · Cited by 130 · see citing works
Brown, G. C. (2024) · Nature Reviews Immunology · doi:10.1038/s41577-023-00921-6 · Cited by 129 · see citing works
Self-citationMicroglial phagocytosis in aging and Alzheimer's disease
Gabandé‐Rodríguez, E., Keane, L., & Capasso, M. (2020) · Journal of Neuroscience Research · doi:10.1002/jnr.24419 · Cited by 127 · see citing works
Zhou, T. G., Li, Y., Li, X., Zeng, F., Rao, Y., He, Y., Wang, Y., Liu, M., Li, D., Xu, Z., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33932-3 · Cited by 122 · see citing works
Eles, J. R., Vazquez, A. L., Snyder, N. R., Lagenaur, C. F., Murphy, M. C., Kozai, T. D. Y., & Cui, X. T. (2016) · Biomaterials · doi:10.1016/j.biomaterials.2016.10.054 · Cited by 116 · see citing works
Microglial Corpse Clearance: Lessons From Macrophages
Márquez-Ropero, M., Benito, E., Plaza‐Zabala, A., & Sierra, A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00506 · Cited by 112 · see citing works
The Phagocytic Code Regulating Phagocytosis of Mammalian Cells
Cockram, T. O. J., Dundee, J. M., Popescu, A. S., & Brown, G. C. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.629979 · Cited by 111 · see citing works
Self-citationChuang, D. Y., Simonyi, Á., Kotzbauer, P. T., Gu, Z., & Sun, G. Y. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0419-0 · Cited by 110 · see citing works
Nomura, K., Vilalta, A., Allendorf, D. H., Hornik, T. C., & Brown, G. C. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1502532 · Cited by 111 · see citing works
Self-citationSong, S., Zhou, F., & Chen, W. R. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-219 · Cited by 110 · see citing works
Trudler, D., Weinreb, O., Mandel, S. A., Youdim, M. B. H., & Frenkel, D. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12633 · Cited by 108 · see citing works
Complement Targets Newborn Retinal Ganglion Cells for Phagocytic Elimination by Microglia
Anderson, S., Zhang, J., Steele, M. R., Romero, C. O., Kautzman, A. G., Schafer, D. P., & Vetter, M. L. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.1854-18.2018 · Cited by 106 · see citing works
Lead roles for supporting actors: Critical functions of inner ear supporting cells
Monzack, E. L., & Cunningham, L. L. (2013) · Hearing Research · doi:10.1016/j.heares.2013.01.008 · Cited by 104 · see citing works
Herzog, C., Pons Garcia, L., Keatinge, M., Greenald, D., Moritz, C., Peri, F., & Herrgen, L. (2019) · Development · doi:10.1242/dev.174698 · Cited by 106 · see citing works
Targeting Keap1/Nrf2/ARE signaling pathway in multiple sclerosis
Michaličková, D., Hrnčíř, T., Canová, N. K., & Slanař, O. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.172973 · Cited by 103 · see citing works
Hippocampal adult neurogenesis: Does the immune system matter?
de Miranda, A. S., Zhang, C., Katsumoto, A., & Teixeira, A. L. (2016) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2016.10.052 · Cited by 100 · see citing works
The role of microglia in brain maintenance: implications for Rett syndrome
Derecki, N. C., Cronk, J. C., & Kipnis, J. (2012) · Trends in Immunology · doi:10.1016/j.it.2012.10.002 · Cited by 99 · see citing works
Blockage of CR1 prevents activation of rodent microglia
Crehan, H., Hardy, J., & Pocock, J. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.02.003 · Cited by 98 · see citing works
Roodveldt, C., Labrador‐Garrido, A., González‐Rey, E., Lachaud, C. C., Guilliams, T., Fernández-Montesinos, R., Benitez-Rondan, A., Robledo, G., Hmadcha, A., Delgado, M., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0079160 · Cited by 96 · see citing works
The role of phosphatidylserine on the membrane in immunity and blood coagulation
Wang, J., Yu, C., Zhuang, J., Qi, W., Jiang, J., Liu, X., Zhao, W., Cao, Y., Wu, H., Qi, J., et al. (2022) · Biomarker Research · doi:10.1186/s40364-021-00346-0 · Cited by 99 · see citing works
Thomsen, M. S., Andersen, M. V., Christoffersen, P., Jensen, M. D., Lichota, J., & Moos, T. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.03.013 · Cited by 96 · see citing works
Microglia engulf viable newborn cells in the epileptic dentate gyrus
Luo, C., Koyama, R., & Ikegaya, Y. (2016) · Glia · doi:10.1002/glia.23018 · Cited by 94 · see citing works
Caspase Inhibitors Protect Neurons by Enabling Selective Necroptosis of Inflamed Microglia
Fricker, M., Vilalta, A., Tolkovsky, A. M., & Brown, G. C. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.427880 · Cited by 92 · see citing works
Self-citationEtchegaray, J. I., Timmons, A. K., Klein, A. P., Pritchett, T. L., Welch, E., Meehan, T. L., Li, C., & McCall, K. (2012) · Development · doi:10.1242/dev.082776 · Cited by 92 · see citing works
Rotenone induces neuronal death by microglial phagocytosis of neurons
Emmrich, J., Hornik, T. C., Neher, J. J., & Brown, G. C. (2013) · FEBS Journal · doi:10.1111/febs.12401 · Cited by 93 · see citing works
Self-citationPhagocytic astrocytes: Emerging from the shadows of microglia
Konishi, H., Koizumi, S., & Kiyama, H. (2022) · Glia · doi:10.1002/glia.24145 · Cited by 88 · see citing works
Marker, D. F., Puccini, J. M., Mockus, T. E., Barbieri, J., Lu, S.-M., & Gelbard, H. A. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-261 · Cited by 90 · see citing works
Meng, F. W., Slivka, P. F., Dearth, C. L., & Badylak, S. F. (2015) · Biomaterials · doi:10.1016/j.biomaterials.2014.12.044 · Cited by 87 · see citing works
Metabolic regulation of microglial phagocytosis: Implications for Alzheimer's disease therapeutics
Lepiarz-Raba, I., Gbadamosi, I., Florea, R., Paolicelli, R. C., & Jawaid, A. (2023) · Translational Neurodegeneration · doi:10.1186/s40035-023-00382-w · Cited by 90 · see citing works
Role of Leptin in Mood Disorder and Neurodegenerative Disease
Zou, X., Zhong, L., Zhu, C., Zhao, H., Zhao, F., Cui, R., Gao, S., & Li, B. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00378 · Cited by 85 · see citing works
Microglia and Macrophages in the Pathological Central and Peripheral Nervous Systems
Abe, N., Nishihara, T., Yorozuya, T., & Tanaka, J. (2020) · Cells · doi:10.3390/cells9092132 · Cited by 85 · see citing works
The Endotoxin Hypothesis of Parkinson's Disease
Brown, G. C., Camacho, M., & Williams‐Gray, C. H. (2023) · Movement Disorders · doi:10.1002/mds.29432 · Cited by 81 · see citing works
Self-citationYanuck, S. F. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00712 · Cited by 80 · see citing works
Xu, H., Wang, Y., Song, N., Wang, J., Jiang, H. F., & Xie, J. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00455 · Cited by 80 · see citing works
The microglial P2Y6 receptor mediates neuronal loss and memory deficits in neurodegeneration
Puigdellívol, M., Milde, S., Vilalta, A., Cockram, T. O. J., Allendorf, D. H., Lee, Y. S., Dundee, J. M., Pampuščenko, K., Borutaitė, V., Nuthall, H. N., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.110148 · Cited by 74 · see citing works
Self-citationEffect of Systemic Inflammation in the CNS: A Silent History of Neuronal Damage
Solano, M. V. M., Lara, C. S., Sánchez-Garibay, C., Soto-Rojas, L. O., Escobedo-Ávila, I., Tena‐Suck, M. L., Ortiz-Butrón, R., Choreño-Parra, J. A., Romero‐López, J. P., & Meléndez-Camargo, M. E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241511902 · Cited by 77 · see citing works
Neniškytė, U., & Brown, G. C. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12288 · Cited by 77 · see citing works
Self-citation
- Authors
- Neher, J. J., Neniskyte, U., Zhao, J.-W., Bal-Price, A., Tolkovsky, A. M., & Brown, G. C.
- Affiliations
- University of Cambridge (GB)
- Department of Biochemistry, University of Cambridge , Cambridge CB2 1QW ,
- Cambridge Centre for Brain Repair, University of Cambridge , Cambridge CB2 OPY ,
- In Vitro Toxicology Unit, European Centre for the Validation of Alternative Methods, Institute of Health and Consumer Protection, European Commission Joint Research Centre , 21027 Ispra ,
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-04
- Volume
- 186
- Issue
- 8
- Pages
- 4973-4983
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2120950413
- Cited by
- 373
- References
- 61
- Citations by year
- 2026: 8 · 2025: 20 · 2024: 27 · 2023: 30 · 2022: 30 · 2021: 36 · 2020: 30 · 2019: 24 · 2018: 25 · 2017: 21 · 2016: 30 · 2015: 21 · 2014: 18 · 2013: 30 · 2012: 16
- FWCI
- 12.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Joint Research Centre (European Commission) (submittedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (RG50995)
- Cambridge Trust
- Gates Cambridge Trust
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- microglial phagocytosis, neuronal cell death, phosphatidylserine exposure, milk fat globule epidermal growth factor 8, integrin αvβ3, peroxynitrite, lipoteichoic acid, lipopolysaccharide, TLR2, TLR4, microglial proliferation, neuroinflammation
- MeSH terms
- Animals, Antigens, Surface, Cells, Cultured, Cerebellum, Inflammation, Lipopolysaccharides, Milk Proteins, Neurons, Peptide Fragments, Phagocytosis, Phosphatidylserines, Teichoic Acids, Time Factors, Tumor Necrosis Factor-alpha, Amyloid beta-Peptides, Apoptosis, Microglia, Inflammation Mediators, Coculture Techniques, Toll-Like Receptor 2, Toll-Like Receptor 4, Rats, Interleukin-1beta
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
