A Neurodegeneration-Specific Gene-Expression Signature of Acutely Isolated Microglia from an Amyotrophic Lateral Sclerosis Mouse Model
Open accessAbstract
Microglia are resident immune cells of the CNS that are activated by infection, neuronal injury, and inflammation. Here, we utilize flow cytometry and deep RNA sequencing of acutely isolated spinal cord microglia to define their activation in vivo. Analysis of resting microglia identified 29 genes that distinguish microglia from other CNS cells and peripheral macrophages/monocytes. We then analyzed molecular changes in microglia during neurodegenerative disease activation using the SOD1(G93A) mouse model of amyotrophic lateral sclerosis (ALS). We found that SOD1(G93A) microglia are not derived from infiltrating monocytes, and that both potentially neuroprotective and toxic factors, including Alzheimer's disease genes, are concurrently upregulated. Mutant microglia differed from SOD1(WT), lipopolysaccharide-activated microglia, and M1/M2 macrophages, defining an ALS-specific phenotype. Concurrent messenger RNA/fluorescence-activated cell sorting analysis revealed posttranscriptional regulation of microglia surface receptors and T cell-associated changes in the transcriptome. These results provide insights into microglia biology and establish a resource for future studies of neuroinflammation.
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?
Gene expression patterns of microglia isolated from various inflammatory contexts do not conform to a small number of transcriptional programs and are not typically analogous to profiles induced by canonical inflammatory agents such as LPS.
“It is now appreciated that gene expression patterns of microglia isolated from various inflammatory contexts do not conform to a small number of transcriptional programs and are not typically analogous to profiles induced by canonical inflammatory agents such as LPS (Chiu et al., 2013; Wang et al., 2015).”
From Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures (2017) · cites this paper as Chiu et al., 2013
The Discussion reports that activated microglia in ALS mice have a neurodegeneration-specific expression profile distinct from LPS-activated microglia and M1/M2 macrophages. It suggests that profiles in other neurological diseases are likely to be unique, but does not establish that microglia across various inflammatory contexts are typically unlike LPS-induced profiles or cannot be grouped into a small number of programs. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMiDM gene expression during the course of EAE did not correspond to the M1/M2 pattern of peripheral macrophage responses to infection or tissue injury.
“MiDM gene expression during the course of EAE did not correspond to the M1/M2 pattern of peripheral macrophage responses to infection or tissue injury.”
From Differential roles of microglia and monocytes in the inflamed central nervous system (2014) · cites this paper as Chiu et al., 2013
The Results section ('SOD1G93A microglia differ significantly from LPS induced microglia and M1 or M2 macrophages'; page unavailable) finds that microglia in an ALS mouse model did not show an M1 or M2 bias during disease progression. This supports the general M1/M2 comparison, but the paper examines resident microglia in ALS, not MiDM gene expression during EAE. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAt EAE onset, MiDMs predominantly suppressed the distinctive gene expression pattern which correlates to their unique phenotype, reflected by the observation that MiDMs down-regulated far more genes than were up-regulated.
“At EAE onset when SBF-SEM analyses were performed, MiDMs predominantly suppressed the distinctive gene expression pattern which correlates to their unique phenotype (Chiu et al., 2013), reflected by the observation that MiDMs down-regulated far more genes than were up-regulated (Table S1).”
From Differential roles of microglia and monocytes in the inflamed central nervous system (2014) · cites this paper as Chiu et al., 2013
The Results section on microglia-specific marker genes identifies a distinctive expression pattern that separates microglia from peripheral macrophages and monocytes. Chiu et al. studied an ALS mouse model, however, and do not establish that MiDMs suppress that pattern at EAE onset; the citing sentence attributes the up- versus down-regulated gene count to its own Table S1. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThere is evidence of a microglial signature in ALS SOD1G93A mice that included upregulation of some Hif1a signature genes including Tyrobp and Igf1.
“There is evidence of a microglial signature in ALS SOD1G93A mice that included upregulation of some Hif1a signature genes including Tyrobp and Igf177”
From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [77]
The Results section, “Microglia co-express potentially neuroprotective and toxic factors in ALS mice” (page unavailable), reports upregulation of both Igf1 and Tyrobp in SOD1G93A microglia. It does not identify them as Hif1a signature genes; a search for Hif1a and hypoxia-inducible factor did not establish that link in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredOlfml3 was reported recently to be a microglia-specific marker in the spinal cord.
“Consistent with this finding, Olfml3 was reported recently to be a microglia-specific marker in the spinal cord (Chiu et al., 2013).”
From An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex (2014) · cites this paper as Chiu et al., 2013
CD68 is not solely expressed in microglia, but also in other macrophages, neutrophils, and monocytes.
“As a macrophage marker it is not solely expressed in microglia, but also in other macrophages, neutrophils, and monocytes [100].”
From Beyond Activation: Characterizing Microglial Functional Phenotypes (2021) · cites this paper as [100]
In models of neurodegeneration, microglia express both neurotoxic and neuroprotective factors, as well as genes involved in oxidative phosphorylation and lysosome, ribosome, and spliceosome factors involved in responses to misfolded proteins, stress, and neuronal death or injury.
“In models of neurodegeneration, microglia express both neurotoxic and neuroprotective factors; genes involved in oxidative phosphorylation; and lysosome, ribosome, and spliceosome factors involved in responses to misfolded proteins, stress, and neuronal death or injury (36, 42) (Figure 1).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [42]
Microglia isolated from SOD1G93A transgenic mice express both neuroprotective factors such as progranulin and IGF-I and neurotoxic factors such as NADPH oxidase.
“The transcriptional profile of microglia isolated from SOD1G93A transgenic mice revealed expression of both neuroprotective factors, such as progranulin and IGF-I, and neurotoxic factors, like NADPH oxidase (42).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [42]
The DAM gene expression signature overlaps significantly with changes in microglial mRNA profiles observed in other neurodegeneration-related models including PS19 tau transgenic, SOD1-G93A transgenic, and aged mice.
“The DAM gene expression signature overlaps significantly with changes in microglial mRNA profiles observed in other neurodegeneration-related models including PS19 tau transgenic, SOD1-G93A transgenic, and aged mice (Chiu et al., 2013; Holtman et al., 2015; Friedman et al., 2017; Keren-Shaul et al., 2017).”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Chiu et al., 2013
In the healthy brain, microglia have a unique homeostatic molecular signature, comprising a distinct transcriptional profile and surface protein expression pattern, which differs from that of tissue macrophages.
“In the healthy brain, they exhibit a unique molecular homeostatic ‘signature’, consisting of a specific transcriptional profile and surface protein expression pattern, which differs from that of tissue macrophages.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [28]
Microglia, but not peripheral myeloid cells, express P2ry12, Tmem119, Siglech, Gpr34, Socs3, Hexb, Olfml3, and Fcrls.
“microglia — but not peripheral myeloid cells — were shown to express P2Y purinoceptor 12 (P2ry12), transmembrane protein 119 (Tmem119), sialic acid binding Ig-like lectin H (Siglech), probable G protein coupled receptor 34 (Gpr34), suppressor of cytokine signalling 3 (Socs3), β-hexosaminidase subunit β (Hexb), olfactomedin-like protein 3 (Olfml3) and Fc receptor-like S, scavenger receptor (Fcrls).”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [28]
In the SOD1 ALS mouse, Tau, presenilin 2, and ApoE pathways are activated in microglia, Apoe is among the most induced transcripts during progression, and loss of the homeostatic microglial signature occurs as early as 2 months before measurable disease onset.
“Tau, presenilin 2 and apolipoprotein E (ApoE) pathways were found to be activated in microglia in the SOD1 mouse, with Apoe being one of the transcripts that was the most significantly induced during disease progression.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [28]
TREM2 is an important microglial molecule involved in regulating microglial signatures in disease.
“Indeed, TREM2 is an important microglial molecule25,27,28 thought to be involved in the regulation of microglial signatures in disease1,58.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [28]
The transcriptional signature of 'primed' microglia from neurodegenerative disease brains is suggestive of increased phago-lysosome, oxidative phosphorylation, and antigen-presentation functions.
“Based on analysis of microglial transcriptomic data, the transcriptional signature of “primed” microglia from neurodegenerative disease brains is suggestive of increased phago-lysosome, oxidative phosphorylation and antigen-presentation functions [12, 13].”
From Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease (2018) · cites this paper as [12]
Homeostatic microglia gradually adopt a unique phagocytic disease-associated microglia (DAM) phenotype in neurodegenerative disease, chronic neuroinflammatory states, and advanced aging.
“Recent transcriptomics studies have shown that homeostatic microglia gradually adopt a unique phagocytic disease-associated microglia (DAM) phenotype in neurodegenerative disease, chronic neuroinflammatory states as well as advanced aging [9–12].”
From Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease (2018) · cites this paper as [12]
RNA-sequencing studies identified Olfml3 as a microglia-specific gene involved in early development patterning.
“RNA-sequencing studies have identified microglia-specific genes such as olfactomedin-like protein 3 (Olfml3), which is involved in early development patterning, and sialic acid binding Ig-like lectin H (Siglech), which is involved in innate immune cell differentiation [10].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [10]
RNA-sequencing studies identified Siglech as a microglia-specific gene involved in innate immune cell differentiation.
“RNA-sequencing studies have identified microglia-specific genes such as olfactomedin-like protein 3 (Olfml3), which is involved in early development patterning, and sialic acid binding Ig-like lectin H (Siglech), which is involved in innate immune cell differentiation [10].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [10]
Well-known and recently identified microglial-enriched genes are expressed at high levels in microglia from all analyzed regions.
“well-known and recently identified microglial-enriched genes (Chiu et al., 2013; Hickman et al., 2013; Butovsky et al., 2014; Zhang et al., 2014) were expressed at high levels in microglia from all analyzed regions”
From Local cues establish and maintain region-specific phenotypes of basal ganglia microglia (2017) · cites this paper as Chiu et al., 2013
Reactive microglia in diseased brains demonstrate a mixed phenotype with expression of pro- or anti-inflammatory and homeostatic markers, particularly showing heterogeneity at the single-cell level, rather than completely reproducing the phenotype obtained from homogenous in vitro polarization studies.
“There is increasing evidence that reactive microglia in diseased brains demonstrate a mixed phenotype with expression of pro- or anti-inflammatory and homeostatic markers, particularly showing heterogeneity at the single-cell level, rather than completely reproducing the phenotype obtained from homogenous in vitro polarization studies (58,60,61,100–103).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [102]
TMEM119 is a highly specific and well-validated marker of brain-derived microglia in both mice and humans.
“We analyzed TMEM119 in bulk human brain tissue data from the Allen Brain Institute (13) because it is a highly specific and well-validated marker of brain-derived microglia in both mice and humans.”
From The Transcriptional Landscape of Microglial Genes in Aging and Neurodegenerative Disease (2019) · cites this paper as [12]
This definition captures a mouse microglia gene signature set that is larger but mostly inclusive of previously described microglia signature sets.
“This definition captures a mouse microglia gene signature set that is larger but mostly inclusive of previously described microglia signature sets (27, 57, 58).”
From An environment-dependent transcriptional network specifies human microglia identity (2017) · cites this paper as [57]
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
Alternative activation of macrophages
Gordon, S. (2003) · Nature Reviews Immunology · doi:10.1038/nri978 · Cited by 6,189 · see citing works
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
Fate Mapping Analysis Reveals That Adult Microglia Derive from Primitive Macrophages
Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S., Mehler, M. F., Conway, S. J., Ng, L. G., Stanley, E. R., et al. (2010) · Science · doi:10.1126/science.1194637 · Cited by 5,175 · see citing works
Motor Neuron Degeneration in Mice that Express a Human Cu,Zn Superoxide Dismutase Mutation
Gurney, M. E., Pu, H., Chiu, A. Y., Dal Canto, M. C., Polchow, C. Y., Alexander, D. D., Caliendo, J., Hentati, A., Kwon, Y. W., Deng, H.-X., et al. (1994) · Science · doi:10.1126/science.8209258 · Cited by 4,143 · see citing works
Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner
Schafer, D. P., Lehrman, E. K., Kautzman, A. G., Koyama, R., Mardinly, A. R., Yamasaki, R., Ransohoff, R. M., Greenberg, M. E., Barres, B. A., & Stevens, B. (2012) · Neuron · doi:10.1016/j.neuron.2012.03.026 · Cited by 4,089 · cited 2× · see citing works
“Cx3cr1 is extensively used to characterize microglia dynamics in vivo (Cardona et al., 2006b; Nimmerjahn et al., 2005; Schafer et al., 2012).”
ATP mediates rapid microglial response to local brain injury in vivo
Davalos, D., Grutzendler, J., Yang, G., Kim, J. V., Zuo, Y., Jung, S., Littman, D. R., Dustin, M. L., & Gan, W.-B. (2005) · Nature Neuroscience · doi:10.1038/nn1472 · Cited by 3,913 · see citing works
<i>TREM2</i> Variants in Alzheimer's Disease
Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E., Cruchaga, C., Sassi, C., Kauwe, J. S. K., Younkin, S., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211851 · Cited by 3,020 · see citing works
A Lineage of Myeloid Cells Independent of Myb and Hematopoietic Stem Cells
Schulz, C., Perdiguero, E. G., Chorro, L., Szabo-Rogers, H., Cagnard, N., Kierdorf, K., Prinz, M., Wu, B., Jacobsen, S. E. W., Pollard, J. W., et al. (2012) · Science · doi:10.1126/science.1219179 · Cited by 2,578 · see citing works
Macrophage-specific PPARγ controls alternative activation and improves insulin resistance
Odegaard, J. I., Ricardo-Gonzalez, R. R., Goforth, M. H., Morel, C. R., Subramanian, V., Mukundan, L., Eagle, A. R., Vats, D., Brombacher, F., Ferrante, A. W., et al. (2007) · Nature · doi:10.1038/nature05894 · Cited by 2,107 · cited 1× · see citing works
“In inflammatory conditions, M2 macrophages are involved in wound healing and regulation of insulin resistance (Odegaard et al., 2007).”
the Immunological Genome Consortium, Gautier, E. L., Shay, T., Miller, J., Greter, M., Jakubzick, C., Ivanov, S., Helft, J., Chow, A., Elpek, K. G., et al. (2012) · Nature Immunology · doi:10.1038/ni.2419 · Cited by 1,972 · cited 1× · see citing works
“We next compared microglia microarray data with data from 22 other myeloid cell types collected by the Immunological Genome Project (ImmGen), including subsets of neutrophils, peripheral macrophages, and monocytes (Gautier et al., 2012).”
The Immunological Genome Project: networks of gene expression in immune cells
The Immunological Genome Project Consortium, Heng, T. S. P., Painter, M. W., Elpek, K., Lukacs-Kornek, V., Mauermann, N., Turley, S. J., Koller, D., Kim, F. S., Wagers, A. J., et al. (2008) · Nature Immunology · doi:10.1038/ni1008-1091 · Cited by 1,864 · 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
Local self-renewal can sustain CNS microglia maintenance and function throughout adult life
Ajami, B., Bennett, J. L., Krieger, C., Tetzlaff, W., & Rossi, F. M. V. (2007) · Nature Neuroscience · doi:10.1038/nn2014 · Cited by 1,643 · see citing works
Onset and Progression in Inherited ALS Determined by Motor Neurons and Microglia
Boillée, S., Yamanaka, K., Lobsiger, C. S., Copeland, N. G., Jenkins, N. A., Kassiotis, G., Kollias, G., & Cleveland, D. W. (2006) · Science · doi:10.1126/science.1123511 · Cited by 1,623 · see citing works
Control of microglial neurotoxicity by the fractalkine receptor
Cardona, A. E., Pioro, E. P., Sasse, M. E., Kostenko, V., Cardona, S. M., Dijkstra, I. M., Huang, D., Kidd, G., Dombrowski, S., Dutta, R., et al. (2006) · Nature Neuroscience · doi:10.1038/nn1715 · Cited by 1,531 · see citing works
Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways
Kierdorf, K., Erny, D., Goldmann, T., Sander, V., Schulz, C., Perdiguero, E. G., Wieghofer, P., Heinrich, A., Riemke, P., Hölscher, C., et al. (2013) · Nature Neuroscience · doi:10.1038/nn.3318 · Cited by 1,457 · see citing works
Microglial Dysfunction and Defective β-Amyloid Clearance Pathways in Aging Alzheimer's Disease Mice
Hickman, S. E., Allison, E. K., & El Khoury, J. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.0616-08.2008 · Cited by 1,329 · cited 3× · see citing works
“Microglia were purified by sequential Percoll gradient centrifugation andmagnetic bead isolation (Figures 1A and S1B), in a procedure modified from previous protocols (Cardona et al., 2006a; Hickman et al., 2008).”
Mutations of optineurin in amyotrophic lateral sclerosis
Maruyama, H., Morino, H., Ito, H., Izumi, Y., Kato, H., Watanabe, Y., Kinoshita, Y., Kamada, M., Nodera, H., Suzuki, H., et al. (2010) · Nature · doi:10.1038/nature08971 · Cited by 1,265 · see citing works
Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions
Mildner, A., Schmidt, H., Nitsche, M., Merkler, D., Hanisch, U.-K., Mack, M., Heikenwalder, M., Brück, W., Priller, J., & Prinz, M. (2007) · Nature Neuroscience · doi:10.1038/nn2015 · Cited by 1,089 · see citing works
ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models
Cramer, P. E., Cirrito, J. R., Wesson, D. W., Lee, C. Y. D., Karlo, J. C., Zinn, A. E., Casali, B. T., Restivo, J. L., Goebel, W. D., James, M. J., et al. (2012) · Science · doi:10.1126/science.1217697 · Cited by 1,050 · see citing works
Retrograde Viral Delivery of IGF-1 Prolongs Survival in a Mouse ALS Model
Kaspar, B. K., Lladó, J., Sherkat, N., Rothstein, J. D., & Gage, F. H. (2003) · Science · doi:10.1126/science.1086137 · Cited by 872 · see citing works
The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease
Chabas, D., Baranzini, S. E., Mitchell, D., Bernard, C. C. A., Rittling, S. R., Denhardt, D. T., Sobel, R. A., Lock, C., Karpuj, M., Pedotti, R., et al. (2001) · Science · doi:10.1126/science.1062960 · Cited by 829 · cited 2× · see citing works
“Osteopontin may be neurotoxic or neuroprotective, as it has been shown to contribute to disease progression in autoimmune encephalomyelitis (Chabas et al., 2001) and is upregulated in AD cerebral spinal fluid, but is neuroprotective in animal models of spinal cord injury (Comi et al.”
Non–cell autonomous effect of glia on motor neurons in an embryonic stem cell–based ALS model
Di Giorgio, F. P., Carrasco, M. A., Siao, M. C., Maniatis, T., & Eggan, K. (2007) · Nature Neuroscience · doi:10.1038/nn1885 · Cited by 799 · see citing works
Self-citationDoes neuroinflammation fan the flame in neurodegenerative diseases?
Frank-Cannon, T. C., Alto, L. T., McAlpine, F. E., & Tansey, M. G. (2009) · Molecular Neurodegeneration · doi:10.1186/1750-1326-4-47 · Cited by 751 · see citing works
Beers, D. R., Henkel, J. S., Xiao, Q., Zhao, W., Wang, J., Yen, A. A., Siklos, L., McKercher, S. R., & Appel, S. H. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0607423103 · Cited by 733 · see citing works
THE INFLUENCE OF THE PROINFLAMMATORY CYTOKINE, OSTEOPONTIN, ON AUTOIMMUNE DEMYELINATING DISEASE
Chabas, D., Baranzini, S. E., Mitchell, D. J., Bernard, C. C. A., Rittling, S. R., Denhardt, D. T., Sobel, R. A., Lock, C., Karpuj, M. V., Pedotti, R., et al. (2002) · International Conference on Osteopontin and SIBLING Proteins · doi:10.1100/tsw.2002.326 · Cited by 729 · see citing works
Sedgwick, J. D., Schwender, S., Imrich, H., Dörries, R., Butcher, G. W., & ter Meulen, V. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.16.7438 · Cited by 691 · see citing works
Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial
Gordon, P. H., Moore, D. H., Miller, R. G., Florence, J. M., Verheijde, J. L., Doorish, C., Hilton, J. F., Spitalny, G. M., MacArthur, R. B., Mitsumoto, H., et al. (2007) · The Lancet Neurology · doi:10.1016/s1474-4422(07)70270-3 · Cited by 649 · see citing works
Toxicity of Familial ALS-Linked SOD1 Mutants from Selective Recruitment to Spinal Mitochondria
Liu, J., Lillo, C., Jonsson, P. A., Velde, C. V., Ward, C. M., Miller, T. M., Subramaniam, J. R., Rothstein, J. D., Marklund, S. L., Andersen, P. M., et al. (2004) · Neuron · doi:10.1016/j.neuron.2004.06.016 · Cited by 506 · see citing works
Pasinelli, P., Belford, M. E., Lennon, N. J., Bacskai, B. J., Hyman, B. T., Trotti, D., & Brown, R. H. (2004) · Neuron · doi:10.1016/j.neuron.2004.06.021 · Cited by 506 · see citing works
Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS
Butovsky, O., Siddiqui, S., Gabriely, G., Lanser, A. J., Dake, B., Murugaiyan, G., Doykan, C. E., Wu, P. M., Gali, R. R., Iyer, L. K., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci62636 · Cited by 481 · see citing works
Inflammatory processes in amyotrophic lateral sclerosis
McGeer, P. L., & McGeer, E. G. (2002) · Muscle & Nerve · doi:10.1002/mus.10191 · Cited by 470 · see citing works
Beers, D. R., Henkel-Tigges, J., Zhao, W., Wang, J., & Appel, S. H. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0807419105 · Cited by 468 · see citing works
Szántó, A., Bálint, B. L., Nagy, Z. S., Barta, E., Dezsö, B., Pap, A., Széles, L., Póliska, S., Oros, M., Evans, R. M., et al. (2010) · Immunity · doi:10.1016/j.immuni.2010.11.009 · Cited by 447 · see citing works
Development of a Method for the Purification and Culture of Rodent Astrocytes
Foo, L. C., Allen, N. J., Bushong, E. A., Ventura, P. B., Chung, W.-S., Zhou, L., Cahoy, J. D., Daneman, R., Zong, H., Ellisman, M. H., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.07.022 · Cited by 433 · see citing works
Beers, D. R., Henkel-Tigges, J., Zhao, W., Wang, J., Huang, A., Wen, S., Liao, B., & Appel, S. H. (2011) · Brain · doi:10.1093/brain/awr074 · Cited by 427 · see citing works
Michelucci, A., Heurtaux, T., Grandbarbe, L., Morga, E., & Heuschling, P. (2009) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2009.02.003 · Cited by 411 · see citing works
Guerreiro, R. J., Lohmann, E., Brás, J. M., Gibbs, J. R., Rohrer, J. D., Gurunlian, N., Dursun, B., Bilgic, B., Hanagasi, H., Gurvit, H., et al. (2013) · JAMA Neurology · doi:10.1001/jamaneurol.2013.579 · Cited by 374 · cited 3× · see citing works
“Furthermore, Trem2, a microglia receptor that is upregulated during disease progression, was recently linked to AD susceptibility (Guerreiro et al., 2013a).”
T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS
Chiu, I., Chen, A., Zheng, Y., Kosaras, B., Tsiftsoglou, S., Vartanian, T., Brown, R. H., & Carroll, M. (2008) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0804610105 · Cited by 374 · see citing works
Self-citationSOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model
Harraz, M. M., Marden, J. J., Zhou, W., Zhang, Y., Williams, A. J., Sharov, V. S., Nelson, K., Luo, M., Paulson, H. L., Schöneich, C., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34060 · Cited by 357 · see citing works
Mandrekar-Colucci, S., Karlo, J. C., & Landreth, G. E. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.5268-11.2012 · Cited by 355 · cited 1× · see citing works
“Furthermore, this is likely mediated through the suppression of proinflammatory pathways and induction of anti-inflammatory pathways in microglia (Mandrekar-Colucci et al., 2012).”
Microglia in ALS: The Good, The Bad, and The Resting
Henkel, J. S., Beers, D. R., Zhao, W., & Appel, S. H. (2009) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-009-9171-5 · Cited by 353 · see citing works
Mizutani, M., Pino, P. A., Saederup, N., Charo, I. F., Ransohoff, R. M., & Cardona, A. E. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1100421 · Cited by 346 · see citing works
Developmental plasticity of CNS microglia
Santambrogio, L., Belyanskaya, S. L., Fischer, F., Cipriani, B., Brosnan, C. F., Ricciardi‐Castagnoli, P., Stern, L. J., Strominger, J. L., & Riese, R. J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.111152498 · Cited by 309 · see citing works
A Universal Framework for Regulatory Element Discovery across All Genomes and Data Types
Elemento, O., Slonim, N., & Tavazoie, S. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.09.027 · Cited by 306 · see citing works
Self-citationThe origin and differentiation of microglial cells during development
Cuadros, M. Á. (1998) · Progress in Neurobiology · doi:10.1016/s0301-0082(98)00035-5 · Cited by 305 · see citing works
Cathepsin D expression level affects alpha-synuclein processing, aggregation, and toxicity in vivo
Cullen, V., Lindfors, M., Ng, J., Paetau, A. E., Swinton, E., Kolodziej, P., Boston, H., Säftig, P., Woulfe, J., Feany, M. Β., et al. (2009) · Molecular Brain · doi:10.1186/1756-6606-2-5 · Cited by 277 · see citing works
Isolation of murine microglial cells for RNA analysis or flow cytometry
Cardona, A. E., Huang, D., Sasse, M. E., & Ransohoff, R. M. (2006) · Nature Protocols · doi:10.1038/nprot.2006.327 · Cited by 236 · see citing works
Sun, B., Zhou, Y., Halabisky, B., Lo, I., Cho, S.-H., Mueller-Steiner, S., Devidze, N., Wang, X., Grubb, A., & Gan, L. (2008) · Neuron · doi:10.1016/j.neuron.2008.10.001 · Cited by 231 · see citing works
Revealing Global Regulatory Perturbations across Human Cancers
Goodarzi, H., Elemento, O., & Tavazoie, S. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.11.016 · Cited by 201 · see citing works
Self-citationActivation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice
Chiu, I. M., Phatnani, H. P., Kuligowski, M., Tapia, J. C., Carrasco, M. A., Zhang, M., Maniatis, T., & Carroll, M. C. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0911405106 · Cited by 194 · see citing works
Self-citationThe microglial-motoneuron dialogue in ALS.
Appel, S. H., Zhao, W., Beers, D. R., & Henkel-Tigges, J. (2011) · Europe PMC (PubMed Central) · Cited by 179 · see citing works
Mutant SOD1<sup>G93A</sup> microglia are more neurotoxic relative to wild‐type microglia
Xiao, Q., Zhao, W., Beers, D. R., Yen, A. A., Xie, W., Henkel, J. S., & Appel, S. H. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04677.x · Cited by 174 · see citing works
Microglial progenitors with a high proliferative potential in the embryonic and adult mouse brain.
Alliot, F., Lecain, É., Grima, B., & Pessac, B. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.4.1541 · Cited by 174 · see citing works
Progranulin is expressed within motor neurons and promotes neuronal cell survival
Ryan, C. L., Baranowski, D. C., Chitramuthu, B. P., Malik, S., Li, Z., Cao, M., Minotti, S., Durham, H. D., Kay, D. G., Shaw, C. A., et al. (2009) · BMC Neuroscience · doi:10.1186/1471-2202-10-130 · Cited by 158 · see citing works
Role of microglial IKKβ in kainic acid-induced hippocampal neuronal cell death
Cho, I., Hong, J., Suh, E. C., Kim, J. H., Lee, H., Lee, J. E., Lee, S., Kim, C., Kim, D. W., Jo, E., et al. (2008) · Brain · doi:10.1093/brain/awn230 · Cited by 156 · see citing works
Gowing, G., Philips, T., Wijmeersch, B. V., Audet, J., Dewil, M., Bosch, L. V. D., Billiau, A., Robberecht, W., & Julien, J. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.3494-08.2008 · Cited by 150 · see citing works
Progranulin is Neurotrophic In Vivo and Protects against a Mutant TDP-43 Induced Axonopathy
Laird, A. S., Hoecke, A. V., Muynck, L. D., Timmers, M., Bosch, L. V. D., Damme, P. V., & Robberecht, W. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013368 · Cited by 147 · see citing works
Intricate interplay between astrocytes and motor neurons in ALS
Phatnani, H. P., Guarnieri, P., Friedman, B. A., Carrasco, M. A., Muratet, M. A., O’Keeffe, S., Nwakeze, C. L., Pauli, F., Newberry, K. M., Meadows, S. K., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1222361110 · Cited by 146 · see citing works
Self-citationMelchior, B., Garcia, A., Hsiung, B., Lo, K. M., Doose, J. M., Thrash, J. C., Stalder, A. K., Staufenbiel, M., Neumann, H., & Carson, M. J. (2010) · ASN NEURO · doi:10.1042/an20100010 · Cited by 133 · see citing works
Rosen, E. Y., Wexler, E. M., Versano, R., Coppola, G., Gao, F., Winden, K. D., Oldham, M. C., Martens, L. H., Zhou, P., Farese, R. V., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.07.021 · Cited by 128 · see citing works
Graber, D. J., Hickey, W. F., & Harris, B. T. (2010) · Journal of Neuroinflammation · doi:10.1186/1742-2094-7-8 · Cited by 121 · see citing works
Comi, C., Carecchio, M., Chiocchetti, A., Nicola, S., Galimberti, D., Fenoglio, C., Cappellano, G., Monaco, F., Scarpini, E., & Dianzani, U. (2010) · Journal of Alzheimer's Disease · doi:10.3233/jad-2010-1309 · Cited by 120 · see citing works
Kamei, Y., Inagaki, N., Nishizawa, M., Tsutsumi, O., Taketani, Y., & Inagaki, M. (1998) · Glia · doi:10.1002/(sici)1098-1136(199807)23:3 · Cited by 114 · see citing works
Lincecum, J. M., Vieira, F. G., Wang, M. Z., Thompson, K., Zutter, G. S. D., Kidd, J. D., Moreno, A., Sànchez, R., Carrion, I. J., Levine, B. A., et al. (2010) · Nature Genetics · doi:10.1038/ng.557 · Cited by 114 · see citing works
Loschko, J., Heink, S., Hackl, D., et al. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1102307 · Cited by 110 · see citing works
Transcriptomes of the B and T Lineages Compared by Multiplatform Microarray Profiling
Painter, M. W., Davis, S. P., Hardy, R. R., Mathis, D. J., Benoist, C. O., Zhou, Y., Shinton, S. A., Hardy, R. R., Asinovski, N., Davis, S. P., et al. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1002695 · Cited by 103 · see citing works
Thrash, J. C., Torbett, B. E., & Carson, M. J. (2008) · Neurochemical Research · doi:10.1007/s11064-008-9657-1 · Cited by 103 · see citing works
Hashimoto, M., Sun, D.-M., Rittling, S., Denhardt, D., & Young, W. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.4805-06.2007 · Cited by 101 · see citing works
Shell, S. A., Hesse, C., Morris, S. M., & Milcarek, C. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508848200 · Cited by 101 · see citing works
Calingasan, N. Y., Chen, J., Kiaei, M., & Beal, M. F. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.01.012 · Cited by 81 · see citing works
Upregulation of cathepsin S in the aging and pathological nervous system of mice
Wendt, W., Lübbert, H., & Stichel, C. C. (2008) · Brain Research · doi:10.1016/j.brainres.2008.07.067 · Cited by 73 · see citing works
The matrix metalloproteinases inhibitor Ro 26-2853 extends survival in transgenic ALS mice
Lorenzl, S., Narr, S., Angele, B., et al. (2006) · Experimental Neurology · doi:10.1016/j.expneurol.2006.01.026 · Cited by 72 · see citing works
Corcoran, K., Jabbour, M., Bhagwandin, C., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.204040 · Cited by 72 · see citing works
Dibaj, P., Steffens, H., Zschüntzsch, J., Nadrigny, F., Schomburg, E. D., Kirchhoff, F., & Neusch, C. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017910 · Cited by 63 · see citing works
Vaknin, I., Kunis, G., Miller, O., Butovsky, O., Bukshpan, S., Beers, D. R., Henkel, J. S., Yoles, E., Appel, S., & Schwartz, M. (2011) · PLoS ONE · doi:10.1371/journal.pone.0026921 · Cited by 62 · see citing works
Narai, H., Nagano, I., Ilieva, H., Shiote, M., Nagata, T., Hayashi, T., Shoji, M., & Abe, K. (2005) · Journal of Neuroscience Research · doi:10.1002/jnr.20668 · Cited by 33 · see citing works
Sakaguchi, T., Irie, T., Kawabata, R., Yoshida, A., Maruyama, H., & Kawakami, H. (2011) · Neuroscience Letters · doi:10.1016/j.neulet.2011.10.040 · Cited by 32 · see citing works
Steinacker, P., Hendrich, C., Sperfeld, A., Jesse, S., Lehnert, S., Pabst, A., Arnim, C. A. F. V., Mottaghy, F. M., Uttner, I., Tumani, H., et al. (2009) · Journal of Neural Transmission · doi:10.1007/s00702-009-0271-4 · Cited by 32 · see citing works
Sargsyan, S. A., Blackburn, D. J., Barber, S. C., Großkreutz, J., Vos, K. J. D., Monk, P. N., & Shaw, P. J. (2011) · BMC Neuroscience · doi:10.1186/1471-2202-12-91 · Cited by 28 · see citing works
Praline, J., Blasco, H., Vourc’h, P., Garrigue, M. A., Gordon, P. H., Camu, W., Corcia, P., Andres, C. R., & the French ALS Study Group (2011) · European Journal of Neurology · doi:10.1111/j.1468-1331.2010.03330.x · Cited by 20 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O'Keeffe, S., Phatnani, H. P., Guarnieri, P., Caneda, C., Ruderisch, N., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.1860-14.2014 · Cited by 4,875 · see citing works
Self-citationA 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
Host microbiota constantly control maturation and function of microglia in the CNS
Erny, D., Hrabě de Angelis, A. L., Jaitin, D., Wieghofer, P., Staszewski, O., David, E., Keren-Shaul, H., Mahlakoiv, T., Jakobshagen, K., Buch, T., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4030 · Cited by 3,569 · 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
Microglia Function in the Central Nervous System During Health and Neurodegeneration
Colonna, M., & Butovsky, O. (2017) · Annual Review of Immunology · doi:10.1146/annurev-immunol-051116-052358 · Cited by 2,894 · see citing works
Immune attack: the role of inflammation in Alzheimer disease
Heppner, F. L., Ransohoff, R. M., & Becher, B. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3880 · Cited by 2,134 · see citing works
Microglia in Alzheimer’s disease
Hansen, D. V., Hanson, J. E., & Sheng, M. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201709069 · Cited by 1,935 · see citing works
“Interestingly, whereas a reduction in plaque load was observed with Cx3cr1 knockout in amyloid models (Lee et al., 2010; Liu et al., 2010), this was reportedly accompanied by increased proinflammatory cytokines, tau pathology, and functional deficits (Cho et al., 2011; Lee et al., 2014).”
BackgroundElmore, M. R. P., Najafi, A. R., Koike, M. A., Dagher, N. N., Spangenberg, E. E., Rice, R. A., Kitazawa, M., Matusow, B., Nguyen, H., West, B. L., et al. (2014) · Neuron · doi:10.1016/j.neuron.2014.02.040 · Cited by 1,968 · see citing works
New tools for studying microglia in the mouse and human CNS
Bennett, M. L., Bennett, F. C., Liddelow, S. A., Ajami, B., Zamanian, J. L., Fernhoff, N. B., Mulinyawe, S. B., Bohlen, C. J., Adil, A., Tucker, A., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1525528113 · Cited by 1,804 · see citing works
Microglia emerge as central players in brain disease
Salter, M. W., & Stevens, B. (2017) · Nature Medicine · doi:10.1038/nm.4397 · Cited by 1,767 · see citing works
A polarizing question: do M1 and M2 microglia exist?
Ransohoff, R. M. (2016) · Nature Neuroscience · doi:10.1038/nn.4338 · Cited by 1,573 · see citing works
Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration
Deczkowska, A., Keren-Shaul, H., Weiner, A., Colonna, M., Schwartz, M., & Amit, I. (2018) · Cell · doi:10.1016/j.cell.2018.05.003 · Cited by 1,474 · 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
“42 Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell 160, 1061-1071, doi:10.1016/j.cell.2015.01.049 (2015). 43 Deczkowska, A.”
BackgroundInfluentialMicroglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease
Prinz, M., & Priller, J. (2014) · Nature Reviews Neuroscience · doi:10.1038/nrn3722 · Cited by 1,329 · see citing works
Gamma frequency entrainment attenuates amyloid load and modifies microglia
Iaccarino, H. F., Singer, A. C., Martorell, A. J., Rudenko, A., Gao, F., Gillingham, T. Z., Mathys, H., Seo, J., Kritskiy, O., Abdurrob, F., et al. (2016) · Nature · doi:10.1038/nature20587 · Cited by 1,328 · see citing works
Microglial brain region-dependent diversity and selective regional sensitivities to aging
Grabert, K., Michoel, T., Karavolos, M. H., Clohisey, S., Baillie, J. K., Stevens, M. P., Freeman, T. C., Summers, K. M., & McColl, B. W. (2016) · Nature Neuroscience · doi:10.1038/nn.4222 · Cited by 1,151 · see citing works
An environment-dependent transcriptional network specifies human microglia identity
Gosselin, D., Skola, D., Coufal, N. G., Holtman, I. R., Schlachetzki, J. C. M., Sajti, E., Jaeger, B. N., O’Connor, C., Fitzpatrick, C., Pasillas, M. P., et al. (2017) · Science · doi:10.1126/science.aal3222 · Cited by 1,220 · see citing works
“This definition captures amousemicroglia gene signature set that is larger butmostly inclusive of previously describedmicroglia signature sets (27, 57, 58).”
BackgroundMicroglial signatures and their role in health and disease
Butovsky, O., & Weiner, H. L. (2018) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0057-5 · Cited by 1,046 · see citing works
Overview of General and Discriminating Markers of Differential Microglia Phenotypes
Jurga, A. M., Paleczna, M., & Kuter, K. Z. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00198 · Cited by 1,000 · see citing works
Microglia in Alzheimer's disease
Sarlus, H., & Heneka, M. T. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90606 · Cited by 911 · see citing works
Differential roles of microglia and monocytes in the inflamed central nervous system
Yamasaki, R., Lu, H., Butovsky, O., Ohno, N., Rietsch, A. M., Cialic, R., Wu, P. M., Doykan, C. E., Lin, J., Cotleur, A. C., et al. (2014) · Journal of Experimental Medicine · doi:10.1084/jem.20132477 · Cited by 855 · see citing works
Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift
Jassam, Y. N., Izzy, S., Whalen, M., McGavern, D. B., & El Khoury, J. (2017) · Neuron · doi:10.1016/j.neuron.2017.07.010 · Cited by 799 · see citing works
Transcriptomic analysis of purified human cortical microglia reveals age-associated changes
Galatro, T. F., Holtman, I. R., Lerario, A. M., Vainchtein, I. D., Brouwer, N., Sola, P. R., Veras, M. M., Pereira, T. F., Leite, R. E. P., Möller, T., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4597 · Cited by 741 · 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
Friedman, B. A., Srinivasan, K., Ayalon, G., Meilandt, W. J., Lin, H., Huntley, M. A., Cao, Y., Lee, S.-H., Haddick, P. C. G., Ngu, H., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2017.12.066 · Cited by 662 · see citing works
Loss of ‘homeostatic’ microglia and patterns of their activation in active multiple sclerosis
Zrzavy, T., Hametner, S., Wimmer, I., Butovsky, O., Weiner, H. L., & Lassmann, H. (2017) · Brain · doi:10.1093/brain/awx113 · Cited by 684 · 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
Bohlen, C. J., Bennett, F. C., Tucker, A. F., Collins, H. Y., Mulinyawe, S. B., & Barres, B. A. (2017) · Neuron · doi:10.1016/j.neuron.2017.04.043 · Cited by 676 · see citing works
Microglia Induce Motor Neuron Death via the Classical NF-κB Pathway in Amyotrophic Lateral Sclerosis
Frakes, A. E., Ferraiuolo, L., Haidet-Phillips, A. M., Schmelzer, L., Braun, L., Miranda, C. J., Ladner, K. J., Bevan, A. K., Foust, K. D., Godbout, J. P., et al. (2014) · Neuron · doi:10.1016/j.neuron.2014.01.013 · Cited by 638 · see citing works
Holtman, I. R., Raj, D. D., Miller, J. A., Schaafsma, W., Yin, Z., Brouwer, N., Wes, P. D., Möller, T., Orre, M., Kamphuis, W., et al. (2015) · Acta Neuropathologica Communications · doi:10.1186/s40478-015-0203-5 · Cited by 619 · see citing works
Sall1 is a transcriptional regulator defining microglia identity and function
Buttgereit, A., Lelios, I., Yu, X., Vrohlings, M., Krakoski, N. R., Gautier, E. L., Nishinakamura, R., Becher, B., & Greter, M. (2016) · Nature Immunology · doi:10.1038/ni.3585 · Cited by 570 · see citing works
Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy
Muzio, L., Viotti, A., & Martino, G. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.742065 · Cited by 581 · see citing works
Tay, T. L., Savage, J. C., Hui, C. W., Bisht, K., & Tremblay, M. (2017) · The Journal of Physiology · doi:10.1113/jp272134 · Cited by 562 · see citing works
A combination of ontogeny and CNS environment establishes microglial identity
Bennett, F. C., Bennett, M. L., Yaqoob, F., Mulinyawe, S. B., Grant, G. A., Hayden Gephart, M., Plowey, E. D., & Barres, B. A. (2018) · Neuron · doi:10.1016/j.neuron.2018.05.014 · Cited by 524 · see citing works
A transcriptomic atlas of aged human microglia
Olah, M., Patrick, E., Villani, A.-C., Xu, J., White, C. C., Ryan, K. J., Piehowski, P., Kapasi, A., Nejad, P., Cimpean, M., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-02926-5 · Cited by 482 · see citing works
Rangaraju, S., Dammer, E. B., Raza, S. A., Rathakrishnan, P., Xiao, H., Gao, T., Duong, D. M., Pennington, M. W., Lah, J. J., Seyfried, N. T., et al. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0254-8 · Cited by 430 · see citing works
TREM2, microglia, and neurodegenerative diseases
Yeh, F. L., Hansen, D. V., & Sheng, M. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.03.008 · Cited by 440 · see citing works
TMEM119 marks a subset of microglia in the human brain
Satoh, J., Kino, Y., Asahina, N., Takitani, M., Miyoshi, J., Ishida, T., & Saito, Y. (2016) · Neuropathology · doi:10.1111/neup.12235 · Cited by 434 · see citing works
Origin of microglia: current concepts and past controversies
Ginhoux, F., & Prinz, M. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a020537 · Cited by 446 · see citing works
Estrogens, Neuroinflammation, and Neurodegeneration
Villa, A., Vegeto, E., Poletti, A., & Maggi, A. (2016) · Endocrine Reviews · doi:10.1210/er.2016-1007 · Cited by 423 · see citing works
Local cues establish and maintain region-specific phenotypes of basal ganglia microglia
De Biase, L. M., Schuebel, K. E., Fusfeld, Z. H., Jair, K., Hawes, I. A., Cimbro, R., Zhang, H.-Y., Liu, Q.-R., Shen, H., Xi, Z.-X., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.06.020 · Cited by 432 · see citing works
Marsh, S. E., Walker, A. J., Kamath, T., Dissing-Olesen, L., Hammond, T. R., de Soysa, T. Y., Young, A. M. H., Murphy, S., Abdulraouf, A., Nadaf, N., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01022-8 · Cited by 432 · see citing works
Cronk, J. C., Filiano, A. J., Louveau, A., Marin, I., Marsh, R., Ji, E., Goldman, D. H., Smirnov, I., Geraci, N., Acton, S., et al. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20180247 · Cited by 412 · see citing works
Microglia Function in Central Nervous System Development and Plasticity
Schafer, D. P., & Stevens, B. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a020545 · Cited by 353 · 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
Butovsky, O., Jedrychowski, M. P., Cialic, R., Krasemann, S., Murugaiyan, G., Fanek, Z., Greco, D. J., Wu, P. M., Doykan, C. E., Kiner, O., et al. (2015) · Annals of Neurology · doi:10.1002/ana.24304 · Cited by 358 · see citing works
Untangling the brain’s neuroinflammatory and neurodegenerative transcriptional responses
Srinivasan, K., Friedman, B. A., Larson, J. L., Lauffer, B. E., Goldstein, L. D., Appling, L. L., Borneo, J., Poon, C., Ho, T., Cai, F., et al. (2016) · Nature Communications · doi:10.1038/ncomms11295 · Cited by 336 · see citing works
Transcriptional signature in microglia associated with Aβ plaque phagocytosis
Grubman, A., Choo, X. Y., Chew, G., Ouyang, J. F., Sun, G., Croft, N. P., Rossello, F. J., Simmons, R., Buckberry, S., Landin, D. V., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23111-1 · Cited by 357 · see citing works
Microglial Physiology and Pathophysiology: Insights from Genome-wide Transcriptional Profiling
Crotti, A., & Ransohoff, R. M. (2016) · Immunity · doi:10.1016/j.immuni.2016.02.013 · Cited by 323 · see citing works
Sankowski, R., Mader, S., & Valdés-Ferrer, S. I. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00028 · Cited by 351 · see citing works
Tam, O. H., Rozhkov, N. V., Shaw, R., Kim, D., Hubbard, I., Fennessey, S., Propp, N., Phatnani, H., Kwan, J., Sareen, D., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.09.066 · Cited by 327 · see citing works
Self-citationInitiative, F. T. A. D. N., Suárez-Calvet, M., Morenas-Rodríguez, E., Kleinberger, G., Schlepckow, K., Araque Caballero, M. Á., Franzmeier, N., Capell, A., Fellerer, K., Nuscher, B., et al. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0301-5 · Cited by 347 · see citing works
Microglia Phenotypes in Aging and Neurodegenerative Diseases
Wendimu, M. Y., & Hooks, S. B. (2022) · Cells · doi:10.3390/cells11132091 · Cited by 336 · see citing works
Microglia in Health and Disease
Ransohoff, R. M., & Khoury, J. E. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a020560 · Cited by 303 · see citing works
The identity and function of microglia in neurodegeneration
Song, W. M., & Colonna, M. (2018) · Nature Immunology · doi:10.1038/s41590-018-0212-1 · Cited by 308 · see citing works
Spiller, K. J., Restrepo, C. R., Khan, T., Dominique, M. A., Fang, T. C., Canter, R. G., Roberts, C. J., Miller, K. R., Ransohoff, R. M., Trojanowski, J. Q., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0083-7 · Cited by 301 · see citing works
Microglia Versus Myeloid Cell Nomenclature during Brain Inflammation
Greter, M., Lelios, I., & Croxford, A. L. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00249 · Cited by 273 · see citing works
Sobue, A., Komine, O., Hara, Y., Endo, F., Mizoguchi, H., Watanabe, S., Murayama, S., Saito, T., Saido, T. C., Sahara, N., et al. (2021) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-01099-x · Cited by 253 · see citing works
Beyond Activation: Characterizing Microglial Functional Phenotypes
Lier, J., Streit, W. J., & Bechmann, I. (2021) · Cells · doi:10.3390/cells10092236 · Cited by 274 · see citing works
<i>TREM2</i>Variant p.R47H as a Risk Factor for Sporadic Amyotrophic Lateral Sclerosis
Cady, J., Koval, E. D., Benitez, B. A., Zaidman, C., Jockel-Balsarotti, J., Allred, P., Baloh, R. H., Ravits, J., Simpson, E., Appel, S. H., et al. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2013.6237 · Cited by 262 · see citing works
Lund, H., Pieber, M., Parsa, R., Han, J., Grommisch, D., Ewing, E., Kular, L., Needhamsen, M., Espinosa, A., Nilsson, E., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-07295-7 · Cited by 249 · see citing works
Microglia in Brain Development, Homeostasis, and Neurodegeneration
Bohlen, C. J., Friedman, B. A., Dejanovic, B., & Sheng, M. (2019) · Annual Review of Genetics · doi:10.1146/annurev-genet-112618-043515 · Cited by 212 · see citing works
Call off the dog(ma): M1/M2 polarization is concurrent following traumatic brain injury
Morganti, J. M., Riparip, L.-K., & Rosi, S. (2016) · PLoS ONE · doi:10.1371/journal.pone.0148001 · Cited by 229 · see citing works
Ishimura, R., Nagy, G., Dotu, I., Chuang, J. H., & Ackerman, S. L. (2016) · eLife · doi:10.7554/elife.14295 · Cited by 221 · see citing works
Liu, W., Taso, O., Wang, R., Bayram, S., Graham, A. C., Garcia-Reitboeck, P., Mallach, A., Andrews, W. D., Piers, T. M., Botia, J. A., et al. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa209 · Cited by 214 · see citing works
Bordt, E. A., & Polster, B. M. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.07.033 · Cited by 202 · see citing works
Wes, P. D., Holtman, I. R., Boddeke, E. W. G. M., Möller, T., & Eggen, B. J. L. (2016) · Glia · doi:10.1002/glia.22866 · Cited by 167 · see citing works
Rudnick, N. D., Griffey, C. J., Guarnieri, P., Gerbino, V., Wang, X., Piersaint, J. A., Tapia, J. C., Rich, M. M., & Maniatis, T. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1704294114 · Cited by 189 · see citing works
Self-citationTREM2 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
Garofalo, S., Cocozza, G., Porzia, A., Inghilleri, M., Raspa, M., Scavizzi, F., Aronica, E., Bernardini, G., Peng, L., Ransohoff, R. M., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15644-8 · Cited by 170 · see citing works
Peripheral monocytes are functionally altered and invade the CNS in ALS patients
Zondler, L., Müller, K., Khalaji, S., Bliederhäuser, C., Ruf, W. P., Grozdanov, V., Thiemann, M., Fundel-Clemes, K., Freischmidt, A., Holzmann, K., et al. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1548-y · Cited by 154 · see citing works
Microglial activation in the pathogenesis of Huntington's disease
Yang, H.-M., Yang, S., Huang, S.-S., Tang, B.-S., & Guo, J.-F. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00193 · Cited by 151 · see citing works
Anti-Inflammatory Effects of GLP-1 Receptor Activation in the Brain in Neurodegenerative Diseases
Diz-Chaves, Y., Mastoor, Z., Spuch, C., González-Matías, L. C., & Mallo, F. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23179583 · Cited by 148 · see citing works
Humphrey, J., Venkatesh, S., Hasan, R., Herb, J. T., de Paiva Lopes, K., Küçükali, F., Byrska-Bishop, M., Evani, U. S., Narzisi, G., Fagegaltier, D., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-022-01205-3 · Cited by 138 · see citing works
Self-citationTranscriptional profiling of microglia; current state of the art and future perspectives
Gerrits, E., Heng, Y., Boddeke, E. W. G. M., & Eggen, B. J. L. (2020) · Glia · doi:10.1002/glia.23767 · Cited by 140 · see citing works
Transcriptional and Epigenetic Regulation of Microglia in Health and Disease
Yeh, H., & Ikezu, T. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2018.11.004 · Cited by 135 · see citing works
Hypoxia compromises the mitochondrial metabolism of Alzheimer’s disease microglia via HIF1
March-Diaz, R., Lara-Ureña, N., Romero-Molina, C., Heras-Garvin, A., Ortega-de San Luis, C., Alvarez-Vergara, M. I., Sanchez-Garcia, M. A., Sanchez-Mejias, E., Davila, J. C., Rosales-Nieves, A. E., et al. (2021) · Nature Aging · doi:10.1038/s43587-021-00054-2 · Cited by 125 · see citing works
Rangaraju, S., Raza, S. A., Li, N. X., Betarbet, R., Dammer, E. B., Duong, D., Lah, J. J., Seyfried, N. T., & Levey, A. I. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00405 · Cited by 126 · see citing works
Béland, L.-C., Markovinovic, A., Jakovac, H., De Marchi, F., Bilic, E., Mazzini, L., Kriz, J., & Munitic, I. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa124 · Cited by 125 · see citing works
Chiot, A., Zaïdi, S., Iltis, C., Ribon, M., Berriat, F., Schiaffino, L., Jolly, A., de la Grange, P., Mallat, M., Bohl, D., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-00718-z · Cited by 122 · see citing works
Martins-Ferreira, R., Calafell-Segura, J., Leal, B., Rodríguez-Ubreva, J., Martínez-Saez, E., Mereu, E., Pinho E Costa, P., Laguna, A., & Ballestar, E. (2025) · Nature Communications · doi:10.1038/s41467-025-56124-1 · Cited by 123 · see citing works
A limited capacity for microglial repopulation in the adult brain
Najafi, A. R., Crapser, J., Jiang, S., Ng, W., Mortazavi, A., West, B. L., & Green, K. N. (2018) · Glia · doi:10.1002/glia.23477 · Cited by 99 · see citing works
Time-Dependent Changes in Microglia Transcriptional Networks Following Traumatic Brain Injury
Izzy, S., Liu, Q., Fang, Z., Lule, S., Wu, L., Chung, J. Y., Sarro-Schwartz, A., Brown-Whalen, A., Perner, C., Hickman, S. E., et al. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00307 · Cited by 110 · see citing works
Shibuya, Y., Chang, C. C. Y., Huang, L.-H., Bryleva, E. Y., & Chang, T.-Y. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.2567-14.2014 · Cited by 108 · see citing works
“Microglia isolated by using this method are thought to recapitulate their in vivo features, such as gene expressions (Nikodemova and Watters, 2012; Chiu et al., 2013).”
MethodNeuronal integrity and complement control synaptic material clearance by microglia after CNS injury
Norris, G. T., Smirnov, I., Filiano, A. J., Shadowen, H. M., Cody, K. R., Thompson, J. A., Harris, T. H., Gaultier, A., Overall, C. C., & Kipnis, J. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20172244 · Cited by 109 · see citing works
<i>Cx3cr1-</i> deficient microglia exhibit a premature aging transcriptome
Gyoneva, S., Hosur, R., Gosselin, D., Zhang, B., Ouyang, Z., Cotleur, A. C., Peterson, M., Allaire, N., Challa, R., Cullen, P., et al. (2019) · Life Science Alliance · doi:10.26508/lsa.201900453 · Cited by 103 · see citing works
“In multiple conditions, mouse microglia demonstrate a core conserved reactive-state transcriptome, which is extensively modi fi ed to yield disease-speci fi c transcriptomes (Chiu et al, 2013; Keren-Shaul et al, 2017; Friedman et al, 2018).”
Carroll, J. A., Striebel, J. F., Rangel, A., Woods, T., Phillips, K., Peterson, K. E., Race, B., & Chesebro, B. (2016) · PLOS Pathogens · doi:10.1371/journal.ppat.1005551 · Cited by 92 · see citing works
Wang, H., Li, Y., Ryder, J. W., Hole, J. T., Ebert, P. J., Airey, D. C., Qian, H.-R., Logsdon, B., Fisher, A., Ahmed, Z., et al. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0296-y · Cited by 83 · see citing works
Acute microglia ablation induces neurodegeneration in the somatosensory system
Rubino, S. J., Mayo, L., Wimmer, I., Siedler, V., Brunner, F., Hametner, S., Madi, A., Lanser, A., Moreira, T., Donnelly, D., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05929-4 · Cited by 91 · see citing works
Patir, A., Shih, B., McColl, B. W., & Freeman, T. C. (2019) · Glia · doi:10.1002/glia.23572 · Cited by 90 · see citing works
The contribution of the peripheral immune system to neurodegeneration
Berriat, F., Lobsiger, C. S., & Boillée, S. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01323-6 · Cited by 87 · see citing works
Senescent Microglia: The Key to the Ageing Brain?
Greenwood, E. K., & Brown, D. R. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094402 · Cited by 84 · see citing works
Burm, S. M., Zuiderwijk-Sick, E. A., ‘t Jong, A. E. J., van der Putten, C., Veth, J., Kondova, I., & Bajramovic, J. J. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.2510-14.2015 · Cited by 82 · see citing works
Oligodendroglial α‐synucleinopathy‐driven neuroinflammation in multiple system atrophy
Hoffmann, A., Ettle, B., Battis, K., Reiprich, S., Schlachetzki, J. C. M., Masliah, E., Wegner, M., Kuhlmann, T., Riemenschneider, M. J., & Winkler, J. (2019) · Brain Pathology · doi:10.1111/bpa.12678 · Cited by 83 · see citing works
The Transcriptional Landscape of Microglial Genes in Aging and Neurodegenerative Disease
Bonham, L. W., Sirkis, D. W., & Yokoyama, J. S. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01170 · Cited by 83 · see citing works
Rossi, C., Cusimano, M., Zambito, M., Finardi, A., Capotondo, A., Garcia-Manteiga, J. M., Comi, G., Furlan, R., Martino, G., & Muzio, L. (2018) · Cell Death & Disease · doi:10.1038/s41419-018-0288-4 · Cited by 77 · see citing works
What are activated and reactive glia and what is their role in neurodegeneration?
Bennett, M. L., & Viaene, A. N. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.105172 · Cited by 77 · see citing works
Cadiz, M. P., Jensen, T. D., Sens, J. P., Zhu, K., Song, W.-M., Zhang, B., Ebbert, M., Chang, R., & Fryer, J. D. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00531-1 · Cited by 73 · see citing works
Rayaprolu, S., Gao, T., Xiao, H., Ramesha, S., Weinstock, L. D., Shah, J., Duong, D. M., Dammer, E. B., Webster, J. A., Lah, J. J., et al. (2019) · doi:10.1101/802694 · Cited by 71 · see citing works
Shen, X., Qiu, Y., Wight, A. E., Kim, H.-J., & Cantor, H. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2116241119 · Cited by 58 · see citing works
- Authors
- Chiu, I. M., Morimoto, E. T. A., Goodarzi, H., Liao, J. T., O’Keeffe, S., Phatnani, H. P., Muratet, M., Carroll, M. C., Levy, S., Tavazoie, S., Myers, R. M., & Maniatis, T.
- Affiliations
- Boston Children's Hospital (US)
- Columbia University Irving Medical Center (US)
- Rockefeller University (US)
- HudsonAlpha Institute for Biotechnology (US)
- Corresponding author
- Maniatis, Tom
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2013-07
- Volume
- 4
- Issue
- 2
- Pages
- 385-401
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4272581
- OpenAlex
- W2135768865
- Cited by
- 651
- References
- 81
- Citations by year
- 2026: 25 · 2025: 32 · 2024: 60 · 2023: 44 · 2022: 58 · 2021: 60 · 2020: 69 · 2019: 47 · 2018: 73 · 2017: 63 · 2016: 49 · 2015: 40 · 2014: 29 · 2013: 1
- FWCI
- 22.27
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- ALS Therapy Alliance
- National Institutes of Health (DP1OD003930)
- National Human Genome Research Institute (R01HG003219)
- National Institute of Neurological Disorders and Stroke (DP1NS082099)
- National Center for Chronic Disease Prevention and Health Promotion (5DP10D003930)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Keywords
- microglia, amyotrophic lateral sclerosis, SOD1 G93A mouse model, microglial activation, gene expression signatures, resting microglia, neuroinflammation, neurodegeneration, microglial phenotype, post-transcriptional regulation, cell surface receptors, lipopolysaccharide stimulation, M1/M2 macrophages, spinal cord
- MeSH terms
- Amyotrophic Lateral Sclerosis, Animals, Disease Models, Animal, Female, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Microglia, Mice, Transcriptome
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
