The microglial sensome revealed by direct RNA sequencing

Hickman, Suzanne E; Kingery, Nathan D; Ohsumi, Toshiro K; Borowsky, Mark L; Wang, Li-chong; Means, Terry K; El Khoury, Joseph

doi:10.1038/nn.3554

Cited by 1,511Neuroinflammation and Neurodegeneration MechanismsSingle-cell and spatial transcriptomicsInflammasome and immune disorders

The microglial sensome revealed by direct RNA sequencing

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Hickman, Suzanne E, Kingery, Nathan D, Ohsumi, Toshiro K, Borowsky, Mark L, Wang, Li-chong, Means, Terry K, El Khoury, Joseph·2013·Nature Neuroscience

DOI 10.1038/nn.3554PMC PMC3840123

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Abstract

Microglia, the principal neuroimmune sentinels of the brain, continuously sense changes in their environment and respond to invading pathogens, toxins and cellular debris. Microglia exhibit plasticity and can assume neurotoxic or neuroprotective priming states that determine their responses to danger. We used direct RNA sequencing, without amplification or cDNA synthesis, to determine the quantitative transcriptomes of microglia of healthy adult and aged mice. We validated our findings using fluorescence dual in situ hybridization, unbiased proteomic analysis and quantitative PCR. We found that microglia have a distinct transcriptomic signature and express a unique cluster of transcripts encoding proteins for sensing endogenous ligands and microbes that we refer to as the sensome. With aging, sensome transcripts for endogenous ligand recognition were downregulated, whereas those involved in microbe recognition and host defense were upregulated. In addition, aging was associated with an overall increase in the expression of microglial genes involved in neuroprotection.

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TMEM119 and P2RY12 have been shown to be expressed solely by microglial cells and not by infiltrating macrophages.
“TMEM119 and P2RY12 are especially useful, since they have been shown to be expressed solely by microglial cells and not by infiltrating macrophages [41,42,43].”
From Beyond Activation: Characterizing Microglial Functional Phenotypes (2021) · cites this paper as [43]
The Results (Microglia vs. Macrophages; page not provided) list Tmem119 and P2ry12 among transcripts unique to microglia in a comparison with peritoneal macrophages. The study did not test infiltrating macrophages, so it does not establish that these markers are absent from that population. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Aged or stressed microglia present a buildup of intracellular LDs, deterioration of mitochondrial efficiency, and downregulation of oxidative phosphorylation-related genes.
“aged or stressed microglia present a buildup of intracellular LDs, deterioration of mitochondrial efficiency, and downregulation of oxidative phosphorylation-related genes [59, 60].”
From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [59]
The Results section, “Effects of aging on the microglial biological pathways” (page unavailable), reports that oxidative phosphorylation–related genes are downregulated in microglia from aged mice. The cited paper does not establish intracellular lipid-droplet buildup or deteriorating mitochondrial efficiency, and this result concerns aging rather than stressed microglia. (LLM, conf=0.88)
Experimental — accuracy not yet measured
CX3CR1 is a chemokine receptor expressed on microglia and a subset of monocytes.
“CX3CR1 is a chemokine receptor expressed on microglia and a subset of monocytes (8, 9).”
From Heterozygous CX3CR1 Deficiency in Microglia Restores Neuronal β-Amyloid Clearance Pathways and Slows Progression of Alzheimer's Like-Disease in PS1-APP Mice (2019) · cites this paper as [9]
The Results section, “Microglia vs. Macrophages” (page not specified), identifies Cx3cr1 among chemokine-receptor genes expressed at higher levels in microglia than in peritoneal macrophages. The paper does not establish expression in a subset of monocytes; its comparison is with macrophages, not monocytes. (LLM, conf=0.88)
Experimental — accuracy not yet measured
63% of microglial sensome genes were DEGs in XO4+ microglia (p = 6.1 × 10−11).
“A significant proportion (63%, p = 6.1 × 10−11, hypergeometric test) of microglial sensome genes30 were DEGs in XO4+ microglia”
From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [30]
There are several hypermorphic variants in PLCG2 that have been associated with autoimmune disease and cancer.
“There are several hypermorphic variants in PLCG2 that have been associated with autoimmune disease and cancer [58–61, 66].”
From The protective PLCγ2-P522R variant mitigates Alzheimer’s disease-associated pathologies by enhancing beneficial microglial functions (2025) · cites this paper as [59]
The Discussion passages concern microglial gene expression and disease, not PLCG2 variants. Searches of our full-text copy for PLCG2, hypermorphic variants, and phospholipase C gamma 2 with autoimmunity or cancer found no passage addressing the claimed association. (LLM, conf=0.76)
Experimental — accuracy not yet measured

During normal CNS function, microglia have a resting or homeostatic transcriptome profile that reflects a surveilling activity.
“During normal CNS function, microglia have a “resting,” or homeostatic, transcriptome profile that reflects a surveilling activity (36–41) (Figure 1).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [40]
Microglia use nearly 100 genes, their sensome, to detect microenvironment changes; this includes P2yr12, AXL, and MER.
“They use the products of nearly 100 genes to sense changes in their microenvironment (their sensome) including P2yr12, AXL, and MER4,7,19”
From Microglia in neurodegeneration (2018) · cites this paper as [7]
RNA-seq identified microglia-specific markers in healthy brain including HexB, P2ry12, S100A8, S100A9, Tmem119, Gpr34, SiglecH, TREM2, and Olfml3.
“RNA-seq analysis identified a new set of microglia-specific markers in the healthy brain that include HexB, P2ry12, S100A8, S100A9, Tmem119, Gpr34, SiglecH, TREM2, and Olfml37.”
From Microglia in neurodegeneration (2018) · cites this paper as [7]
Aβ interaction with microglial pattern recognition receptors including TLRs, SRs, and CR3 is required for these effects.
“This requires Aβ interaction with microglial pattern recognition receptors (PRRs) including TLRs, SRs, and complement receptor 3 (CR3)7,43.”
From Microglia in neurodegeneration (2018) · cites this paper as [7]
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 [27]
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 [27]
Microglia from MFP2-deficient mice, which model ageing peroxisomal β-oxidation deficiency, express inflammatory surface markers and downregulate P2RY12 like aged microglia, and Tgfbr1 is downregulated in these mice.
“Microglia from transgenic mice that lack multifunctional protein 2 (MFP2) and thus model the peroxisomal β-oxidation deficiency common to ageing express inflammatory surface markers and downregulate the homeostatic purinergic receptor P2RY12 (REF.121) in the same manner as aged microglia27.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [27]
Aged microglia display a dystrophic phenotype, ageing induces a hypersensitive pro-inflammatory primed phenotype, sensome genes are downregulated, and aged microglia express LGALS3, AXL, CLEC7A, MHC class II, and CXCR4 while appearing activated but not polarized.
“Aged microglia display a dystrophic phenotype118–120. It is also known that ageing, similar to neurodegeneration, induces a hypersensitive, pro-inflammatory microglial phenotype that some have referred to as ‘primed microglia’26.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [27]
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 [27]
Microglia express a unique gene set called the sensome that enables them to sense endogenous ligands and interact with their environment.
“Transcriptomic analysis of isolated mouse microglia revealed that microglia express a unique genes sets called the “sensome” that enable them to sense endogenous ligands and interact with their environment [12].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [12]
NanoString-based gene expression analysis revealed APOE and TGFβ as major upstream regulators of MGnD microglia.
“Customized NanoString-based gene expression analysis, which uses molecular barcodes and microscopic imaging to detect and count unique transcripts in hybridization reactions, revealed APOE and TGFβ as the major upstream regulators of MGnD microglia.”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [12]
Genetic ablation of miR-155 can reverse abnormal microglia signature and ameliorate disease in SOD1 ALS mice.
“which if genetically ablated, can reverse abnormal microglia signature and ameliorate disease in SOD1 mice, a mouse model for ALS [12, 45].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [12]
APOE upregulation suppresses expression of homeostatic microglial transcription factors Spi1, Mef2a, Mafb, and Smad3.
“Upregulation of APOE suppresses gene expression of microglial homeostatic transcriptional factors including Spi1, Mef2a, Mafb, Smad3”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [12]
APOE upregulation induces inflammatory response via Bhlhe40, Tfec, Atf, and miR-155.
“and induces inflammatory response via induction of transcription factors Bhlhe40, Tfec, Atf, and inflammatory miRNA miR-155”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [12]
In aging mice, microbe recognition and host defense genes such as Tlr2, Cd74, Ltf, Clec7a, and Cxcl16 are upregulated.
“Microbe recognition and host defense genes such as Tlr2, Cd74, Ltf, Clec7a, Cxcl16, are also upregulated [12].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [12]
In aging mice, microglial sensome transcripts for sensing endogenous ligands including Trem2, Gpr34, P2ry12, Fcrl1, and Dap12 are downregulated.
“In aging mice, the microglial sensome transcripts for sensing endogenous ligands including Trem2, Gpr34, P2ry12, Fcrl1, and Dap12, are downregulated.”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [12]
Olah et al. suggested a protective effect of the APOE2 haplotype against increased expression of the aged human microglia gene set in human microglia.
“More recently, Olah et al. suggested a protective effect of APOE2 haplotype against increased expression of aged human microglia gene set in human microglia [12, 56].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [12]
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 Hickman et al., 2013
Microglia-like cells matching acutely isolated microglial signatures and following non-monocytic yolk sac ontogeny had not been reported from human pluripotent cells.
“However, generation of microglia-like cells matching the recently identified signatures of acutely isolated microglia 10,11, and following their non-monocytic yolk sac ontogeny 4, has not been reported from pluripotent human cells.”
From Efficient derivation of microglia-like cells from human pluripotent stem cells (2016) · cites this paper as [11]
Mature pMGLs stained positive for markers of murine and human microglia, with TMEM119 and P2RY12 displaying broad membrane and punctate vesicular expression.
“Mature pMGLs stained positive for markers of murine and human microglia 10,11,29,30, with both TMEM119 and P2RY12 displaying a broad membrane and punctate vesicular expression pattern”
From Efficient derivation of microglia-like cells from human pluripotent stem cells (2016) · cites this paper as [11]
Genes expected to be highly expressed in peripheral macrophages and low in microglia, such as SLPI, SAA1/2, PRG4, CFP, CD5l and CRIP1, are in the lower expression quartile of the dataset.
“genes such SLPI, SAA1/2, PRG4, CFP, CD5l, CRIP1 are expected to be highly expressed in peripheral macrophages, and low in microglia 11: these genes are in the lower expression quartile of our dataset.”
From Efficient derivation of microglia-like cells from human pluripotent stem cells (2016) · cites this paper as [11]
Addition of CD200 and CX3CL1 to iMGLs increased expression of select genes like COMT, CD52, and HLADRB5 while maintaining similar expression levels of core-microglial genes and AD-risk genes.
“The addition of CD200 and CX3CL1 to iMGLs increased the expression of select genes like COMT (Bennett et al., 2016)(Figure S5B), CD52, a cell surface receptor that binds Siglec-10 and interacts with DAP12 as part of the microglia sensome (Hickman et al., 2013) and HLADRB5, a member of the MHC II complex implicated in AD, while maintaining similar expression levels of core-microglial genes (e.g. P2”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Hickman et al., 2013
This expression profile concurs with other studies of DAM.
“This expression profile concurs with other studies of DAM [10,37,78,124,194].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [124]
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 [58]
These receptors and their downstream signaling are implicated in chemotaxis and are part of the microglial sensome.
“These receptors and their downstream signaling are implicated in chemotaxis and are part of the microglial sensome 4 .”
From Transcriptomic analysis of purified human cortical microglia reveals age-associated changes (2017) · cites this paper as [4]
P2RY12 is an established microglial marker.
“P2RY12, an established microglial marker 3,4 ,”
From Transcriptomic analysis of purified human cortical microglia reveals age-associated changes (2017) · cites this paper as [4]

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Liao, B., Zhao, W., Beers, D. R., Henkel-Tigges, J., & Appel, S. H. (2012) · Experimental Neurology · doi:10.1016/j.expneurol.2012.06.011 · Cited by 438 · see citing works
Direct RNA sequencing
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RNA‐Seq: A Method for Comprehensive Transcriptome Analysis
Nagalakshmi, U., Waern, K., & Snyder, M. P. (2010) · Current Protocols in Molecular Biology · doi:10.1002/0471142727.mb0411s89 · Cited by 319 · see citing works
Role of Signal Transducer and Activator of Transcription 3 in Neuronal Survival and Regeneration
Dziennis, S., & Alkayed, N. J. (2008) · Reviews in the Neurosciences · doi:10.1515/revneuro.2008.19.4-5.341 · Cited by 158 · see citing works
MESOGLIA & MICROGLIA – A Historical Review of the Concept of Mononuclear Phagocytes Within the Central Nervous System
Rezaie, P., & Male, D. K. (2002) · Journal of the History of the Neurosciences · doi:10.1076/jhin.11.4.325.8531 · Cited by 145 · see citing works
Aging enhances classical activation but mitigates alternative activation in the central nervous system
Lee, D. C., Ruiz, C. R., Lebson, L. A., Selenica, M. B., Rizer, J., Hunt, J. B., Rojiani, R., Reid, P., Kammath, S., Nash, K. R., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.12.014 · Cited by 119 · see citing works
Microglial physiopathology: how to explain the dual role of microglia after acute neural disorders?
Gomes‐Leal, W. (2012) · Brain and Behavior · doi:10.1002/brb3.51 · Cited by 115 · see citing works
Neuroprotection by neuregulin-1 following focal stroke is associated with the attenuation of ischemia-induced pro-inflammatory and stress gene expression
Xu, Z., Ford, G. D., Croslan, D. R., et al. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.01.027 · Cited by 114 · see citing works
Developmental Regulation of TREM2 and DAP12 Expression in the Murine CNS: Implications for Nasu-Hakola Disease
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
Multifaceted aspects of inflammation in multiple sclerosis: The role of microglia
Muzio, L., Martino, G., & Furlan, R. (2007) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2007.09.016 · Cited by 90 · see citing works
Digital transcriptome profiling from attomole-level RNA samplesPreprint
Ozsolak, F., Goren, A., Gymrek, M., Guttman, M., Regev, A., Bernstein, B., & Milos, P. M. (2010) · Genome Research · doi:10.1101/gr.102129.109 · Cited by 60 · see citing works
Amplification-free digital gene expression profiling from minute cell quantities
Ozsolak, F., Ting, D. T., Wittner, B. S., Brannigan, B. W., Paul, S., Bardeesy, N. M., Ramaswamy, S., Milos, P. M., & Haber, D. A. (2010) · Nature Methods · doi:10.1038/nmeth.1480 · Cited by 59 · see citing works
Neurodegeneration and the neuroimmune system
El Khoury, J. (2010) · Nature Medicine · doi:10.1038/nm1210-1369 · Cited by 46 · see citing works
Self-citation
Corrigendum to “Neuroprotection by neuregulin-1 following focal stroke is associated with the attenuation of ischemia-induced pro-inflammatory and stress gene expression” [Neurobiol. Dis. 19 (2005) 461–470]
Xu, Z., Ford, G. D., Croslan, D. R., et al. (2008) · Neurobiology of Disease · doi:10.1016/j.nbd.2008.05.002 · Cited by 17 · see citing works
MolBioLib: a C++11 framework for rapid development and deployment of bioinformatics tasks
Ohsumi, T. K., & Borowsky, M. L. (2012) · Bioinformatics · doi:10.1093/bioinformatics/bts458 · Cited by 9 · see citing works
Self-citation
Age-changes in gene expression in primary mixed glia cultures from young vs. old rat cerebral cortex are modified by interactions with neurons
Kremsky, I., Morgan, T. E., Hou, X., Li, L., & Finch, C. E. (2011) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2011.12.008 · Cited by 8 · see citing works

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Neuroinflammation in Alzheimer's disease
Heneka, M. T., Carson, M. J., Khoury, J. E., Landreth, G. E., Brosseron, F., Feinstein, D. L., Jacobs, A. H., Wyss-Coray, T., Vitorica, J., Ransohoff, R. M., et al. (2015) · The Lancet Neurology · doi:10.1016/s1474-4422(15)70016-5 · Cited by 6,226 · see citing works
Self-citation
A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease
Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-Szternfeld, R., Ulland, T. K., David, E., Baruch, K., Lara-Astaiso, D., Toth, B., et al. (2017) · Cell · doi:10.1016/j.cell.2017.05.018 · Cited by 5,493 · see citing works
The Microbiota-Gut-Brain Axis
Cryan, J. F., O'Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F. S., Boehme, M., Codagnone, M. G., Cussotto, S., Fulling, C., Golubeva, A. V., et al. (2019) · Physiological Reviews · doi:10.1152/physrev.00018.2018 · Cited by 5,286 · 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
The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases
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
Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes
Kwon, H. S., & Koh, S.-H. (2020) · Translational Neurodegeneration · doi:10.1186/s40035-020-00221-2 · Cited by 2,595 · see citing works
Inflammation as a central mechanism in Alzheimer's disease
Kinney, J. W., Bemiller, S. M., Murtishaw, A. S., Leisgang, A. M., Salazar, A. M., & Lamb, B. T. (2018) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2018.06.014 · Cited by 2,253 · see citing works
Complex cell-state changes revealed by single cell RNA sequencing of 76,149 microglia throughout the mouse lifespan and in the injured brain
Hammond, T. R., Dufort, C., Dissing-Olesen, L., Giera, S., Young, A., Wysoker, A., Walker, A. J., Segel, M., Nemesh, J., Saunders, A., et al. (2018) · doi:10.1101/406140 · Cited by 2,225 · 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
Microglial <scp>M1/M2</scp> polarization and metabolic states
Orihuela, R., McPherson, C. A., & Harry, G. J. (2016) · British Journal of Pharmacology · doi:10.1111/bph.13139 · Cited by 2,070 · see citing works
Microglia in neurodegeneration
Hickman, S., Izzy, S., Sen, P., Morsett, L., & El Khoury, J. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0242-x · Cited by 1,710 · see citing works
Self-citation
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
Single-cell profiling of the developing mouse brain and spinal cord with split-pool barcoding
Rosenberg, A. B., Roco, C. M., Muscat, R. A., Kuchina, A., Sample, P., Yao, Z., Graybuck, L. T., Peeler, D. J., Mukherjee, S., Chen, W., et al. (2018) · Science · doi:10.1126/science.aam8999 · Cited by 1,422 · see citing works
Microglia Biology: One Century of Evolving Concepts
Prinz, M., Jung, S., & Priller, J. (2019) · Cell · doi:10.1016/j.cell.2019.08.053 · Cited by 1,525 · see citing works
Normal aging induces A1-like astrocyte reactivity
Clarke, L. E., Liddelow, S. A., Chakraborty, C., Münch, A. E., Heiman, M., & Barres, B. A. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1800165115 · Cited by 1,237 · see citing works
Microglia 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
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).”
Background
Origin, fate and dynamics of macrophages at central nervous system interfaces
Goldmann, T., Wieghofer, P., Jordão, M. J. C., Prutek, F., Hagemeyer, N., Frenzel, K., Amann, L., Staszewski, O., Kierdorf, K., Krueger, M., et al. (2016) · Nature Immunology · doi:10.1038/ni.3423 · Cited by 1,209 · see citing works
Microglial 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
A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment
Van Hove, H., Martens, L., Scheyltjens, I., De Vlaminck, K., Pombo Antunes, A. R., De Prijck, S., Vandamme, N., De Schepper, S., Van Isterdael, G., Scott, C. L., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0393-4 · Cited by 1,160 · see citing works
iPSC-derived human microglia-like cells to study neurological diseases
Abud, E. M., Ramirez, R. N., Martinez, E. S., Healy, L. M., Nguyen, C. H. H., Newman, S. A., Yeromin, A. V., Scarfone, V. M., Marsh, S. E., Fimbres, C., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.03.042 · Cited by 1,154 · see citing works
A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease
Wightman, D. P., Jansen, I. E., Savage, J. E., Shadrin, A. A., Bahrami, S., Holland, D., Rongve, A., Børte, S., Winsvold, B. S., Drange, O. K., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00921-z · Cited by 1,011 · see citing works
ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease
Simpson, D. S. A., & Oliver, P. L. (2020) · Antioxidants · doi:10.3390/antiox9080743 · Cited by 1,044 · see citing works
Cell type- and brain region-resolved mouse brain proteome
Sharma, K., Schmitt, S., Bergner, C. G., Tyanova, S., Kannaiyan, N., Manrique-Hoyos, N., Kongi, K., Cantuti, L., Hanisch, U.-K., Philips, M.-A., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4160 · Cited by 871 · see citing works
“Q4 7,940 1 (112) 2 (9) 2 (3) 10 (3) 370 124 29 Q3 Q2 Q1 Neurons total”
Inflammation and neuroprotection in traumatic brain injury.
Corps, K. N., Roth, T. L., & McGavern, D. B. (2015) · JAMA Neurology · doi:10.1001/jamaneurol.2014.3558 · Cited by 853 · see citing works
Microbiome Influences Prenatal and Adult Microglia in a Sex-Specific Manner
Thion, M. S., Low, D., Silvin, A., Chen, J., Grisel, P., Schulte-Schrepping, J., Blecher, R., Ulas, T., Squarzoni, P., Hoeffel, G., et al. (2018) · Cell · doi:10.1016/j.cell.2017.11.042 · Cited by 779 · 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
Self-citation
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
Diverse Brain Myeloid Expression Profiles Reveal Distinct Microglial Activation States and Aspects of Alzheimer’s Disease Not Evident in Mouse Models
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
TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models
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
Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures
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
A complement–microglial axis drives synapse loss during virus-induced memory impairment
Vasek, M. J., Garber, C., Dorsey, D., Durrant, D. M., Bollman, B., Soung, A., Yu, J., Perez-Torres, C., Frouin, A., Wilton, D. K., et al. (2016) · Nature · doi:10.1038/nature18283 · Cited by 671 · see citing works
Microglia: Dynamic Mediators of Synapse Development and Plasticity
Wu, Y., Dissing-Olesen, L., MacVicar, B. A., & Stevens, B. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.08.008 · Cited by 661 · see citing works
Efficient derivation of microglia-like cells from human pluripotent stem cells
Muffat, J., Li, Y., Yuan, B., Mitalipova, M., Omer, A., Corcoran, S., Bakiasi, G., Tsai, L.-H., Aubourg, P., Ransohoff, R. M., et al. (2016) · Nature Medicine · doi:10.1038/nm.4189 · Cited by 651 · see citing works
Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)
Atagi, Y., Liu, C.-C., Painter, M. M., Chen, X.-F., Verbeeck, C., Zheng, H., Li, X., Rademakers, R., Kang, S. S., Xu, H., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.679043 · Cited by 587 · see citing works
Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease
Gjoneska, E., Pfenning, A. R., Mathys, H., Quon, G., Kundaje, A., Tsai, L.-H., & Kellis, M. (2015) · Nature · doi:10.1038/nature14252 · Cited by 576 · see citing works
Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis
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
New insights on the role of microglia in synaptic pruning in health and disease
Hong, S., Dissing-Olesen, L., & Stevens, B. (2016) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2015.12.004 · Cited by 557 · see citing works
Neuroimmune mechanisms of depression
Hodes, G. E., Kana, V., Menard, C., Merad, M., & Russo, S. J. (2015) · Nature Neuroscience · doi:10.1038/nn.4113 · Cited by 585 · see citing works
Age-related myelin degradation burdens the clearance function of microglia during aging
Safaiyan, S., Kannaiyan, N., Snaidero, N., Brioschi, S., Biber, K., Yona, S., Edinger, A. L., Jung, S., Rossner, M. J., & Simons, M. (2016) · Nature Neuroscience · doi:10.1038/nn.4325 · Cited by 604 · see citing works
Microglia contribute to normal myelinogenesis and to oligodendrocyte progenitor maintenance during adulthood
Hagemeyer, N., Hanft, K.-M., Akriditou, M.-A., Unger, N., Park, E. S., Stanley, E. R., Staszewski, O., Dimou, L., & Prinz, M. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1747-1 · Cited by 558 · 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
Microglia across the lifespan: from origin to function in brain development, plasticity and cognition
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
TREM2 sustains microglial expansion during aging and response to demyelination
Poliani, P. L., Wang, Y., Fontana, E., Robinette, M. L., Yamanishi, Y., Gilfillan, S., & Colonna, M. (2015) · Journal of Clinical Investigation · doi:10.1172/jci77983 · Cited by 525 · see citing works
Complement C3aR Inactivation Attenuates Tau Pathology and Reverses an Immune Network Deregulated in Tauopathy Models and Alzheimer’s Disease
Litvinchuk, A., Wan, Y.-W., Swartzlander, D. B., Chen, F., Cole, A., Propson, N. E., Wang, Q., Zhang, B., Liu, Z., & Zheng, H. (2018) · Neuron · doi:10.1016/j.neuron.2018.10.031 · Cited by 523 · see citing works
Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex
Sipe, G. O., Lowery, Tremblay, M.-È., Kelly, E. A., Lamantia, C. E., & Majewska, A. K. (2016) · Nature Communications · doi:10.1038/ncomms10905 · Cited by 512 · see citing works
Microglial Ramification, Surveillance, and Interleukin-1β Release Are Regulated by the Two-Pore Domain K+ Channel THIK-1
Madry, C., Kyrargyri, V., Arancibia-Cárcamo, I. L., Jolivet, R., Kohsaka, S., Bryan, R. M., & Attwell, D. (2018) · Neuron · doi:10.1016/j.neuron.2017.12.002 · Cited by 464 · see citing works
Microglia in Central Nervous System Inflammation and Multiple Sclerosis Pathology
Voet, S., Prinz, M., & van Loo, G. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2018.11.005 · Cited by 503 · see citing works
Microbiome–microglia connections via the gut–brain axis
Abdel-Haq, R., Schlachetzki, J. C. M., Glass, C. K., & Mazmanian, S. K. (2019) · Journal of Experimental Medicine · doi:10.1084/jem.20180794 · Cited by 471 · see citing works
“The adult microglia transcriptome overlaps with, but is distinct from, other tissue-resident macrophages and is characterized by expression of microglial-specific markers, including Sall1, P2ry12, Gpr84, and Tmem119 (Hickman et al., 2013; Butovsky et al., 2014; Gosselin et al., 2014; Matcovitch-Natan et al., 2016).”
Background
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
CD22 blockade restores homeostatic microglial phagocytosis in ageing brains
Pluvinage, J. V., Haney, M. S., Smith, B. A. H., Sun, J., Iram, T., Bonanno, L., Li, L., Lee, D. P., Morgens, D. W., Yang, A. C., et al. (2019) · Nature · doi:10.1038/s41586-019-1088-4 · Cited by 459 · 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
Mapping microglia states in the human brain through the integration of high-dimensional techniques
Sankowski, R., Böttcher, C., Masuda, T., Geirsdottir, L., Sagar, Sindram, E., Seredenina, T., Muhs, A., Scheiwe, C., Shah, M. J., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0532-y · Cited by 449 · see citing works
TREM2 variants: new keys to decipher Alzheimer disease pathogenesis
Colonna, M., & Wang, Y. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2016.7 · Cited by 418 · 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
Microglial priming and enhanced reactivity to secondary insult in aging, and traumatic CNS injury, and neurodegenerative disease
Norden, D. M., Muccigrosso, M. M., & Godbout, J. P. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.10.028 · Cited by 413 · see citing works
Anti-inflammatory effects of omega-3 fatty acids in the brain: physiological mechanisms and relevance to pharmacology
Layé, S., Nadjar, A., Joffre, C., & Bazinet, R. P. (2018) · Pharmacological Reviews · doi:10.1124/pr.117.014092 · Cited by 420 · see citing works
TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer's Disease
Griciuc, A., Patel, S., Federico, A. N., Choi, S. H., Innes, B. J., Oram, M. K., Cereghetti, G., McGinty, D., Anselmo, A., Sadreyev, R. I., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.06.010 · Cited by 378 · see citing works
Self-citation
Directed differentiation of human pluripotent stem cells to microglia
Douvaras, P., Sun, B., Wang, M., Kruglikov, I., Lallos, G., Zimmer, M., Terrenoire, C., Zhang, B., Gandy, S., Schadt, E., et al. (2017) · Stem Cell Reports · doi:10.1016/j.stemcr.2017.04.023 · Cited by 381 · see citing works
The pro-remyelination properties of microglia in the central nervous system
Lloyd, A. F., & Miron, V. E. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0184-2 · Cited by 381 · see citing works
NLRP3 inflammasome-driven pathways in depression: clinical and preclinical findings
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Microglia: Agents of the CNS Pro-Inflammatory Response
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Authors: Hickman, S. E., Kingery, N. D., Ohsumi, T. K., Borowsky, M. L., Wang, L.-C., Means, T. K., & El Khoury, J.
Affiliations: Massachusetts General Hospital (US)
Harvard University (US)
Advanced Cell Diagnostics (United States) (US)
Corresponding author: Hickman, Suzanne E
ORCID: Hickman, Suzanne E
Ohsumi, Toshiro K
Means, Terry K
Venue: Nature Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2013-10-27
Volume: 16
Issue: 12
Pages: 1896-1905
ISSN: 1097-6256 (ISSN-L)
1546-1726
DOI: 10.1038/nn.3554
PMC: PMC3840123
OpenAlex: W2163410184
Cited by: 1,511
References: 59
Citations by year: 2026: 88 · 2025: 98 · 2024: 135 · 2023: 113 · 2022: 139 · 2021: 164 · 2020: 142 · 2019: 152 · 2018: 137 · 2017: 121 · 2016: 95 · 2015: 88 · 2014: 36 · 2013: 2
FWCI: 40.72
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Neuroscience (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
Funders: National Institute on Aging (AG032349, R01AG032349)
National Institute of Allergy and Infectious Diseases (R01AI084884)
National Institute of Neurological Disorders and Stroke (NS059005, R01NS059005)
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords: microglia, microglial transcriptome, pathogen recognition, aging, neuroprotection, peripheral macrophages, host defense, neuroinflammation
MeSH terms: Age Factors, Animals, Flow Cytometry, Ligands, Mice, Inbred C57BL, Mass Spectrometry, Sequence Analysis, RNA, Leukocyte Common Antigens, Microglia, Macrophages, Peritoneal, Computational Biology, CD11b Antigen, Mice, Transcriptome

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