Microglial repopulation resolves inflammation and promotes brain recovery after injury: RICE et al.
Open accessAbstract
Microglia mediate chronic neuroinflammation following central nervous system (CNS) disease or injury, and in doing so, damage the local brain environment by impairing recovery and contributing to disease processes. Microglia are critically dependent on signaling through the colony-stimulating factor 1 receptor (CSF1R) and can be eliminated via administration of CSF1R inhibitors. Resolving chronic neuroinflammation represents a universal goal for CNS disorders, but long-term microglial elimination may not be amenable to clinical use. Notably, withdrawal of CSF1R inhibitors stimulates new microglia to fully repopulate the CNS, affording an opportunity to renew this cellular compartment. To that end, we have explored the effects of acute microglial elimination, followed by microglial repopulation, in a mouse model of extensive neuronal loss. Neuronal loss leads to a prolonged neuroinflammatory response, characterized by the presence of swollen microglia expressing CD68 and CD45, as well as elevated levels of cytokines, chemokines, complement, and other inflammatory signals. These collective responses are largely resolved by microglial repopulation. Furthermore, microglial repopulation promotes functional recovery in mice, with elevated plus maze performance matching that of uninjured mice, despite the loss of 80% of hippocampal neurons. Analyses of synaptic surrogates revealed increases in PSD95 and synaptophysin puncta with microglial repopulation, suggesting that these cells sculpt and regulate the synaptic landscape. Thus, our results show that short-term microglial elimination followed by repopulation may represent a clinically feasible and novel approach to resolve neuroinflammatory events and promote brain recovery.
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Post-injury microglial depletion followed by microglial repopulation improves behavioral recovery, attenuates the lesion-induced neuroinflammatory response, and increases dendritic spin densities despite extensive neuronal loss in the hippocampus.
“Recent studies using the same injury model confirmed that post-injury microglial depletion followed by microglial repopulation improves behavioral recovery, attenuates the lesion-induced neuroinflammatory response, and increases dendritic spin densities despite extensive neuronal loss in the hippocampus (240).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [240]
The Results sections report behavioral recovery and reduced inflammatory markers after microglial repopulation despite extensive hippocampal neuronal loss. However, the dendritic-spine Results report no significant difference in spine density between lesioned mice with and without repopulation; the reported increase was relative to uninjured controls. Page numbers are unavailable in our copy. (LLM, conf=0.90)
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Cites
Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo
Nimmerjahn, A., Kirchhoff, F., & Helmchen, F. (2005) · Science · doi:10.1126/science.1110647 · Cited by 5,827 · see citing works
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 · cited 2× · see citing works
“…are critically dependent upon CSF1R signaling; CSF1R knockout mice do not develop microglia (Erblich, Zhu, Etgen, Dobrenis, & Pollard, 2011; Ginhoux et al., 2010), while pharmacologic inhibition of the CSF1R rapidly eliminates most microglia from the brain (Elmore et al., 2014), including…”
BackgroundImaging Neuronal Subsets in Transgenic Mice Expressing Multiple Spectral Variants of GFP
Feng, G., Mellor, R. H., Bernstein, M., Keller-Peck, C., Nguyen, Q. T., Wallace, M., Nerbonne, J. M., Lichtman, J. W., & Sanes, J. R. (2000) · Neuron · doi:10.1016/s0896-6273(00)00084-2 · Cited by 3,042 · cited 1× · see citing works
“…are critically dependent upon CSF1R signaling; CSF1R knockout mice do not develop microglia (Erblich, Zhu, Etgen, Dobrenis, & Pollard, 2011; Ginhoux et al., 2010), while pharmacologic inhibition of the CSF1R rapidly eliminates most microglia from the brain (Elmore et al., 2014), including…”
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 · cited 9× · see citing works
“Fluorescent immunolabeling followed a standard indirect technique (primary antibody followed by fluorescent secondary antibody), as previously described (Elmore et al., 2014).”
BackgroundMethodResultInfluentialSelf-citationWray, S. (2003) · Between Auschwitz and Tradition · doi:10.1002/0471142301.ns0200s23 · Cited by 1,703 · cited 2×
“…of inducible neuronal loss was employed for functional studies, and has been previously described (Yamasaki et al., 2007), and was crossed with the Thy1-GFP-M mouse to enable visualization of neuronal structures (Feng et al., 2000), as previously shown (Castello et al., 2014; Rice et al., 2015).”
MethodWake, H., Moorhouse, A. J., Jinno, S., Kohsaka, S., & Nabekura, J. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.4363-08.2009 · Cited by 1,619 · see citing works
Microglial priming in neurodegenerative disease
Perry, V. H., & Holmes, C. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2014.38 · Cited by 1,127 · cited 1× · see citing works
“Microglia become primed with age, disease, and injury, wherein they fail to resolve insults and instead remain chronically activated (Holtman et al., 2015; Perry & Holmes, 2014; Wes, Holtman, Boddeke, Moller, & Eggen, 2016).”
BackgroundInflammation after trauma: Microglial activation and traumatic brain injury
Ramlackhansingh, A. F., Brooks, D. J., Greenwood, R. J., Bose, S. K., Turkheimer, F. E., Kinnunen, K. M., Gentleman, S., Heckemann, R. A., Gunanayagam, K., Gelosa, G., et al. (2011) · Annals of Neurology · doi:10.1002/ana.22455 · Cited by 999 · see citing works
Saijo, K., Winner, B., Carson, C. T., Collier, J. G., Boyer, L., Rosenfeld, M. G., Gage, F. H., & Glass, C. K. (2009) · Cell · doi:10.1016/j.cell.2009.01.038 · Cited by 859 · cited 12× · see citing works
“Resolving chronic neuroinflammation represents a universal goal for CNS disorders, but long-term microglial elimination may not be amenable to clinical use.”
BackgroundInfluentialSpangenberg, E. E., Lee, R. J., Najafi, A. R., Rice, R. A., Elmore, M. R. P., Blurton-Jones, M., West, B. L., & Green, K. N. (2016) · Brain · doi:10.1093/brain/aww016 · Cited by 695 · cited 2× · see citing works
“As chronic microglial responses are negatively implicated in neurodegenerative diseases and severe brain injuries, inhibition of the CSF1R may offer therapeutic promise (Rice et al., 2015; Spangenberg et al., 2016).”
BackgroundSelf-citationErblich, B., Zhu, L., Etgen, A. M., Dobrenis, K., & Pollard, J. W. (2011) · PLoS ONE · doi:10.1371/journal.pone.0026317 · Cited by 649 · see citing works
Bruttger, J., Karram, K., Wörtge, S., Regen, T., Marini, F., Hoppmann, N., Klein, M., Blank, T., Yona, S., Wolf, Y., et al. (2015) · Immunity · doi:10.1016/j.immuni.2015.06.012 · Cited by 634 · cited 1× · see citing works
“Repopulation occurs both from the proliferation of surviving microglia and from progenitors that differentiate into microglia (Bruttger et al., 2015; Elmore et al., 2014).”
BackgroundValdearcos, M., Robblee, M. M., Benjamin, D. I., Nomura, D. K., Xu, A. W., & Koliwad, S. K. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.11.018 · Cited by 629 · cited 12× · see citing works
“…elimination and repopulation with the selective CSF1R antagonist PLX5622 (Acharya et al., 2016; Dagher et al., 2015; Klein et al., 2015; Schreiner et al., 2015; Valdearcos et al., 2014), a more brainpenetrant and specific sister molecule of the clinically utilized PLX3397 (Tap et al., 2015).”
BackgroundInfluentialStructure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor
Tap, W. D., Wainberg, Z. A., Anthony, S. P., Ibrahim, P. N., Zhang, C., Healey, J. H., Chmielowski, B., Staddon, A. P., Cohn, A. L., Shapiro, G. I., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1411366 · Cited by 582 · cited 4× · see citing works
“As CSF1R inhibitors are currently used in the clinic, and more are being developed (Tap et al., 2015), these molecules offer a powerful tool against neuroinflammation.”
BackgroundInfluentialSelf-citationMolecular cloning of CD68, a human macrophage marker related to lysosomal glycoproteins.
Holness, C. L. L., & Simmons, D. (1993) · Blood · doi:10.1182/blood.v81.6.1607.bloodjournal8161607 · Cited by 548 · cited 4× · see citing works
“Primary antibodies used include NeuN (1:1000; Abcam, Cambridge, MA), IBA1 (1:1000; Wako, Richmond, VA), GFAP (1:10,000; Abcam), S100b (1:1000, Abcam), CD45 (1:1000, AbD Serotec, Raleigh, NC) CD68 (1:2000, AbD Serotec), synaptophysin (1:500; Sigma Aldrich), and PSD95 (1:1000; Cell Signaling, Danvers, MA).”
BackgroundInfluentialDagher, N. N., Najafi, A. R., Kayala, K. M. N., Elmore, M. R. P., White, T. E., Medeiros, R., West, B. L., & Green, K. N. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0366-9 · Cited by 505 · cited 14× · see citing works
“We first wanted to establish an appropriate treatment paradigm for microglial elimination and repopulation with the selective CSF1R antagonist PLX5622 (Acharya et al., 2016; Dagher et al., 2015; Klein et al., 2015; Schreiner et al., 2015; Valdearcos et al., 2014), a more brainpenetrant and specific sister molecule of…”
BackgroundInfluentialSelf-citationLoane, D. J., Kumar, A., Stoica, B. A., Cabatbat, R., & Faden, A. I. (2014) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0000000000000021 · Cited by 498 · see citing works
Progressive atrophy and neuron death for one year following brain trauma in the rat
Smith, D. H., Chen, X.-H., Pierce, J. E. S., Wolf, J. A., Trojanowski, J. Q., Graham, D. I., & McIntosh, T. K. (1997) · Journal of Neurotrauma · doi:10.1089/neu.1997.14.715 · Cited by 440 · cited 1× · see citing works
“2017;65:931–944. wileyonlinelibrary.com/journal/glia VC 2017Wiley Periodicals, Inc. | 931 Morecraft, & Combs, 2007; Smith et al., 1997).”
Assessing Activation States in Microglia
Colton, C. A., & Wilcock, D. M. (2010) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152710791012053 · Cited by 421 · cited 1× · see citing works
“Despite the protective roles that microglia play in the brain, they are negatively implicated in many CNS disorders and injuries (Clark et al., 2016; Colton & Wilcock, 2010).”
BackgroundRenno, T., Krakowski, M., Piccirillo, C., Lin, J. Y., & Owens, T. (1995) · The Journal of Immunology · doi:10.4049/jimmunol.154.2.944 · Cited by 401 · see citing works
Evidence for synaptic stripping by cortical microglia
Trapp, B. D., Wujek, J. R., Criste, G. A., Jalabi, W., Yin, X., Kidd, G. J., Stohlman, S. A., & Ransohoff, R. M. (2006) · Glia · doi:10.1002/glia.20462 · Cited by 318 · see citing works
Matarin, M., Salih, D. A., Yasvoina, M., Cummings, D. M., Guelfi, S., Liu, W., Nahaboo Solim, M. A., Moens, T. G., Paublete, R. M., Ali, S. S., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2014.12.041 · Cited by 290 · cited 1× · see citing works
“Thus, neuronal loss itself recapitulates many of the pathway changes seen in the AD brain (Matarin et al., 2015).”
BackgroundRice, R. A., Spangenberg, E. E., Yamate-Morgan, H., Lee, R. J., Arora, R. P. S., Hernandez, M. X., Tenner, A. J., West, B. L., & Green, K. N. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.0336-15.2015 · Cited by 270 · cited 10× · see citing works
“Importantly, chronically activated microglia induced by this neuronal lesion model are eliminated with CSF1R inhibitors to the same extent as in control mice (Rice et al., 2015).”
BackgroundMethodInfluentialSelf-citationMin, K.-J., Yang, M.-S., Kim, S.-U., Jou, I., & Joe, E. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.3696-05.2006 · Cited by 269 · see citing works
Microglial neuroinflammation contributes to tau accumulation in chronic traumatic encephalopathy
Cherry, J. D., Tripodis, Y., Alvarez, V. E., Huber, B., Kiernan, P. T., Daneshvar, D., Mez, J., Montenigro, P., Solomon, T. M., Alosco, M., et al. (2016) · Acta Neuropathologica Communications · doi:10.1186/s40478-016-0382-8 · Cited by 267 · cited 3× · see citing works
“, 2011), and for decades after repetitive head injuries in American football athletes, correlating with dementia and chronic traumatic encephalopathy (Cherry et al., 2016).”
BackgroundInfluentialElimination of microglia improves cognitive function following cranial irradiation
Acharya, M. M., Green, K. N., Allen, B. D., Najafi, A. R., Syage, A., Minasyan, H., Le, M. T., Kawashita, T., Giedzinski, E., Parihar, V. K., et al. (2016) · Scientific Reports · doi:10.1038/srep31545 · Cited by 259 · cited 4× · see citing works
“Small-molecule inhibitors of the CSF1R that cross the blood brain barrier (BBB) rapidly eliminate microglia within days (Acharya et al., 2016; Elmore et al., 2014).”
BackgroundInfluentialSelf-citationElmore, M. R. P., Lee, R. J., West, B. L., & Green, K. N. (2015) · PLoS ONE · doi:10.1371/journal.pone.0122912 · Cited by 228 · cited 1× · see citing works
“Microglia remain eliminated for the duration of treatment, but withdrawal of CSF1R inhibition stimulates robust and rapid repopulation of the entire CNS with new cells that becomemicroglia (Elmore et al., 2015; Elmore et al., 2014), effectively replacing the entire microglial compartment.”
BackgroundSelf-citationWes, 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
Neural Stem Cells Improve Memory in an Inducible Mouse Model of Neuronal Loss
Yamasaki, T. R., Blurton-Jones, M. M., Morrissette, D. A., Kitazawa, M., Oddo, S., & LaFerla, F. M. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.1627-07.2007 · Cited by 158 · cited 3× · see citing works
“The CaM/Tet-diphtheria toxin A (DTA) mouse model of inducible neuronal loss was employed for functional studies, and has been previously described (Yamasaki et al., 2007), and was crossed with the Thy1-GFP-M mouse to enable visualization of neuronal structures (Feng et al., 2000), as previously…”
MethodProlonged Microgliosis in the Rhesus Monkey Central Nervous System after Traumatic Brain Injury
Nagamoto-Combs, K., McNeal, D. W., Morecraft, R. J., & Combs, C. K. (2007) · Journal of Neurotrauma · doi:10.1089/neu.2007.0377 · Cited by 156 · see citing works
Astrocyte Depletion Impairs Redox Homeostasis and Triggers Neuronal Loss in the Adult CNS
Schreiner, B., Romanelli, E., Liberski, P. P., Ingold‐Heppner, B., Sobottka, B., Hartwig, T., Chandrasekar, V., Johannssen, H. C., Zeilhofer, H. U., Aguzzi, A., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.07.051 · Cited by 129 · cited 12× · see citing works
“We first wanted to establish an appropriate treatment paradigm for microglial elimination and repopulation with the selective CSF1R antagonist PLX5622 (Acharya et al., 2016; Dagher et al., 2015; Klein et al., 2015; Schreiner et al., 2015; Valdearcos et al., 2014), a more brainpenetrant and specific sister molecule of…”
BackgroundInfluentialImmunoreactivity of CD45, a protein phosphotyrosine phosphatase, in Alzheimer's disease
Masliah, E., Mallory, M., Hansen, L., Alford, M., Albright, T., Terry, R., Shapiro, P., Sundsmo, M., & Saitoh, T. (1991) · Acta Neuropathologica · doi:10.1007/bf00294425 · Cited by 112 · cited 4× · see citing works
“Primary antibodies used include NeuN (1:1000; Abcam, Cambridge, MA), IBA1 (1:1000; Wako, Richmond, VA), GFAP (1:10,000; Abcam), S100b (1:1000, Abcam), CD45 (1:1000, AbD Serotec, Raleigh, NC) CD68 (1:2000, AbD Serotec), synaptophysin (1:500; Sigma Aldrich), and PSD95 (1:1000; Cell Signaling, Danvers, MA).”
BackgroundInfluentialCastello, N. A., Nguyen, M. H. K., Tran, J. D., Cheng, D., Green, K. N., & LaFerla, F. M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0091453 · Cited by 112 · cited 2× · see citing works
“…of inducible neuronal loss was employed for functional studies, and has been previously described (Yamasaki et al., 2007), and was crossed with the Thy1-GFP-M mouse to enable visualization of neuronal structures (Feng et al., 2000), as previously shown (Castello et al., 2014; Rice et al., 2015).”
MethodSelf-citationBaglietto‐Vargas, D., Medeiros, R., Martínez‐Coria, H., LaFerla, F. M., & Green, K. N. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.12.003 · Cited by 98 · see citing works
Self-citationClarke, W. E., Berry, M., Smith, C. S., Kent, A., & Logan, A. (2001) · Molecular and cellular neurosciences · doi:10.1006/mcne.2000.0920 · Cited by 87
IFNs are critical regulators of IL-1 receptor antagonist and IL-1 expression in human microglia.
Liu, J. S. H., Amaral, T., Brosnan, C., & Lee, S. C. (1998) · Journal of Immunology · doi:10.4049/jimmunol.161.4.1989 · Cited by 84 · see citing works
Cik, M., Masure, S., Lesage, A., van der Linden, I., Gompel, P. V. V., Pangalos, M., Gordon, R., & Leysen, J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m000306200 · Cited by 82 · cited 1× · see citing works
“Of these, only two lesion-associated increases are rescued by microglial repopulation—FGF2 (fibroblast growth factor 2), which is upregulated by astrocytes with brain lesion (Clarke, Berry, Smith, Kent, & Logan, 2001), and GFRA1, which is a receptor for GDNF (Cik et al., 2000).”
BackgroundReactive microgIia in Creutzfeldt‐Jakob disease
Mühleisen, H., Gehrmann, J., & Meyermann, R. (1995) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.1995.tb01097.x · Cited by 63 · see citing works
Holtman, I. R., Noback, M. A., Bijlsma, M., Duong, K. N., van der Geest, M. A., Ketelaars, P. T., Brouwer, N., Vainchtein, I. D., Eggen, B. J. L., & Boddeke, H. W. G. M. (2015) · Glia · doi:10.1002/glia.22810 · Cited by 57 · cited 1× · see citing works
“Microglia become primed with age, disease, and injury, wherein they fail to resolve insults and instead remain chronically activated (Holtman et al., 2015; Perry & Holmes, 2014; Wes, Holtman, Boddeke, Moller, & Eggen, 2016).”
BackgroundCompromised axon initial segment integrity in EAE is preceded by microglial reactivity and contact
Clark, K. C., Josephson, A., Benusa, S. D., Hartley, R. K., Baer, M. L., Thummala, S. K., Joslyn, M., Sword, B. A., Elford, H. L., Oh, U., et al. (2016) · Glia · doi:10.1002/glia.22991 · Cited by 55 · cited 1× · see citing works
“Despite the protective roles that microglia play in the brain, they are negatively implicated in many CNS disorders and injuries (Clark et al., 2016; Colton & Wilcock, 2010).”
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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
“…et al., 2016), although caution must be taken because CD45 expression increases in microglia upon inflammation and Frontiers in Cellular Neuroscience | www.frontiersin.org 6 August 2020 | Volume 14 | Article 198 with aging (Roesch et al., 2018; Haage et al., 2019; BenmamarBadel et al., 2020).”
BackgroundSpangenberg, E., Severson, P. L., Hohsfield, L. A., Crapser, J., Zhang, J., Burton, E. A., Zhang, Y., Spevak, W., Lin, J., Phan, N. Y., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11674-z · Cited by 939 · see citing works
Self-citationInflammation: the link between comorbidities, genetics, and Alzheimer’s disease
Newcombe, E. A., Camats-Perna, J., Silva, M. L., Valmas, N., Huat, T. J., & Medeiros, R. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1313-3 · Cited by 532 · see citing works
Repopulating Microglia Promote Brain Repair in an IL-6-Dependent Manner
Willis, E. F., MacDonald, K. P. A., Nguyen, Q. H., Garrido, A. L., Gillespie, E. R., Harley, S. B. R., Bartlett, P. F., Schroder, W. A., Yates, A. G., Anthony, D. C., et al. (2020) · Cell · doi:10.1016/j.cell.2020.02.013 · Cited by 520 · see citing works
Elmore, M. R. P., Hohsfield, L. A., Kramár, E. A., Soreq, L., Lee, R. J., Pham, S. T., Najafi, A. R., Spangenberg, E. E., Wood, M. A., West, B. L., et al. (2018) · Aging Cell · doi:10.1111/acel.12832 · Cited by 380 · see citing works
Self-citationWitcher, K. G., Bray, C. E., Chunchai, T., Zhao, F., O'Neil, S. M., Gordillo, A. J., Campbell, W. A., McKim, D. B., Liu, X., Dziabis, J. E., et al. (2021) · The Journal of Neuroscience · doi:10.1523/jneurosci.2469-20.2020 · Cited by 387 · see citing works
“This dose and time was validated in our lab to deplete;96% of microglia in C57BL/6 mice (McKim et al., 2018). mFPI Mice received a midline diffuse TBI using a FPI apparatus (Custom Design & Fabrication) as we previously described (Fenn et al., 2014, 2015; Rowe et al., 2016; Witcher et al., 2018).”
MethodInfluentialThe 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
Central nervous system regeneration is driven by microglia necroptosis and repopulation
Lloyd, A. F., Davies, C. L., Holloway, R. K., Labrak, Y., Ireland, G., Carradori, D., Dillenburg, A., Borger, E., Soong, D., Richardson, J. C., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0418-z · Cited by 316 · see citing works
Henry, R. J., Ritzel, R. M., Barrett, J. P., Doran, S. J., Jiao, Y., Leach, J. B., Szeto, G. L., Wu, J., Stoica, B. A., Faden, A. I., et al. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.2402-19.2020 · Cited by 333 · see citing works
“However, withdrawal of CSF1R inhibitors in microglia-depleted mice resulted in rapid repopulation of microglia (Elmore et al., 2014; Elmore et al., 2015), which correlated with improved functional recovery in a hippocampal lesion model in mice (Rice et al., 2017).”
BackgroundFernández-Calle, R., Konings, S. C., Frontiñán-Rubio, J., García-Revilla, J., Camprubí-Ferrer, L., Svensson, M., Martinson, I., Boza-Serrano, A., Venero, J. L., Nielsen, H. M., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00566-4 · Cited by 278 · see citing works
Sexual dimorphism in the inflammatory response to traumatic brain injury
Villapol, S., Loane, D. J., & Burns, M. P. (2017) · Glia · doi:10.1002/glia.23171 · Cited by 310 · see citing works
Activated microglia mitigate Aβ-associated tau seeding and spreading
Gratuze, M., Chen, Y., Parhizkar, S., Jain, N., Strickland, M. R., Serrano, J. R., Colonna, M., Ulrich, J. D., & Holtzman, D. M. (2021) · Journal of Experimental Medicine · doi:10.1084/jem.20210542 · Cited by 215 · see citing works
“It has been shown that microglial repopulation could increase synaptic number and dampen inflammation in a neuronal lesion model and facilitate neuroprotective effects during the acute phase of traumatic brain injury (Willis et al., 2020; Rice et al., 2017).”
BackgroundTo Kill a Microglia: A Case for CSF1R Inhibitors
Green, K. N., Crapser, J. D., & Hohsfield, L. A. (2020) · Trends in Immunology · doi:10.1016/j.it.2020.07.001 · Cited by 259 · see citing works
“Furthermore, some of the primary effects of microglial elimination in mice that we have consistently found are increases in PSD95 and synaptophysin synaptic staining [70], enhanced dendritic spine densities [70,115], and unimpaired or improved performance in memory-related tasks relative to controls, even after 6 mont…”
BackgroundInfluentialSelf-citationQin, J., Ma, Z., Chen, X., & Shu, S. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1103416 · Cited by 229 · see citing works
Casali, B. T., MacPherson, K. P., Reed-Geaghan, E. G., & Landreth, G. E. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104956 · Cited by 186 · see citing works
Microglia as hackers of the matrix: sculpting synapses and the extracellular space
Crapser, J. D., Arreola, M. A., Tsourmas, K. I., & Green, K. N. (2021) · Cellular & Molecular Immunology · doi:10.1038/s41423-021-00751-3 · Cited by 178 · see citing works
“This aspect of microglial biology has been utilized to promote brain recovery after traumatic brain injury (TBI) [75], neuronal lesion [76], and aging [77] by resolving chronically activated or otherwise dyshomeostatic microglia in vivo.”
BackgroundSelf-citationMicroglial/Macrophage polarization and function in brain injury and repair after stroke
Lyu, J., Xie, D., Bhatia, T. N., Leak, R. K., Hu, X., & Jiang, X. (2021) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13620 · Cited by 171 · see citing works
CSF1R antagonism limits local restimulation of antiviral CD8+ T cells during viral encephalitis
Funk, K. E., & Klein, R. S. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1397-4 · Cited by 156 · see citing works
Lupus antibodies induce behavioral changes mediated by microglia and blocked by ACE inhibitors
Nestor, J., Arinuma, Y., Huerta, T. S., Kowal, C., Nasiri, E., Kello, N., Fujieda, Y., Bialas, A., Hammond, T., Sriram, U., et al. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20180776 · Cited by 146 · see citing works
Huang, C., Wang, P., Xu, X., Zhang, Y., Gong, Y. L., Hu, W., Gao, M., Wu, Y. H., Ling, Y., Zhao, X., et al. (2017) · Glia · doi:10.1002/glia.23241 · Cited by 149 · see citing works
“Through production of modest inflammatory cytokines, they participate in the process of hippocampal neurogenesis and synaptic elimination or formation (Luo, Koyama, & Ikegaya, 2016; Rice et al., 2017), while the over-activated microglia could exacerbate neurodegeneration (Blank & Prinz, 2017).”
BackgroundAn updated assessment of microglia depletion: current concepts and future directions
Han, J., Harris, R. A., & Zhang, X.-M. (2017) · Molecular Brain · doi:10.1186/s13041-017-0307-x · Cited by 141 · see citing works
“CSF-1R inhibitor (PLX5622) ~90% 7 days ameliorates inflammation induced by neuronal lesion [64]”
BackgroundResultMicroglia Elimination Increases Neural Circuit Connectivity and Activity in Adult Mouse Cortex
Liu, Y., Spangenberg, E. E., Tang, B., Holmes, T. C., Green, K. N., & Xu, X. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.2140-20.2020 · Cited by 163 · see citing works
Self-citationWitcher, K. G., Bray, C. E., Dziabis, J. E., McKim, D. B., Benner, B. N., Rowe, R. K., Kokiko‐Cochran, O. N., Popovich, P. G., Lifshitz, J., Eiferman, D. S., et al. (2018) · Glia · doi:10.1002/glia.23523 · Cited by 153 · see citing works
“Notably, Rice et al. (2015) showed that microglia have both neuroprotective and maladaptive roles following hippocampal lesion.”
InfluentialCSF1R signaling is a regulator of pathogenesis in progressive MS
Hagan, N., Kane, J. L. J., Grover, D., Woodworth, L. A., Madore, C., Saleh, J., Sancho, J., Liu, J., Li, Y., Proto, J. D., et al. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-03084-7 · Cited by 162 · see citing works
The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease
Kokiko-Cochran, O. N., & Godbout, J. P. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00672 · Cited by 128 · see citing works
“Recent studies using the same injury model confirmed that post-injury microglial depletion followed by microglial repopulation improves behavioral recovery, attenuates the lesion-induced neuroinflammatory response, and increases dendritic spin densities despite extensive neuronal loss in the hippocampus (240).”
BackgroundO’Neil, S. M., Witcher, K. G., McKim, D. B., & Godbout, J. P. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0636-8 · Cited by 138 · see citing works
“Rice et al. (2017) used this approach to promote microglial turnover following inducible hippocampal neuron death and found microglial depletion and repopulation following hippocampal lesion ameliorated chronic microgliosis, leukocyte infiltration, and inflammatory gene expression [55].”
MethodA Tilted Axis: Maladaptive Inflammation and HPA Axis Dysfunction Contribute to Consequences of TBI
Tapp, Z. M., Godbout, J. P., & Kokiko‐Cochran, O. N. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.00345 · Cited by 130 · see citing works
Zhang, Y., Zhao, L., Wang, X., Ma, W., Lazere, A., Qian, H., Zhang, J., Abu-Asab, M. S., Fariss, R. N., Roger, J. E., et al. (2018) · Science Advances · doi:10.1126/sciadv.aap8492 · Cited by 145 · see citing works
Microglial deletion and inhibition alleviate behavior of post-traumatic stress disorder in mice
Li, S., Liao, Y., Dong, Y., Li, X., Li, J., Cheng, Y., Cheng, J., & Yuan, Z. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-020-02069-9 · Cited by 112 · see citing works
Han, J., Zhu, K., Zhang, X., & Harris, R. A. (2018) · Glia · doi:10.1002/glia.23529 · Cited by 114 · see citing works
“…role in many neuro- logical disorders (Salter & Stevens, 2017; Wendeln et al., 2018), then microglia-directed therapy, including specific microglia depletion strat- egies, can be regarded as a promising immunotherapy for neurological diseases (Du et al., 2017; Feng et al., 2017; Rice et al., 2015).”
BackgroundLiu, Y., Given, K. S., Dickson, E. L., Owens, G. P., Macklin, W. B., & Bennett, J. L. (2019) · Experimental Neurology · doi:10.1016/j.expneurol.2019.04.011 · Cited by 105 · see citing works
Weber, M. D., McKim, D. B., Niraula, A., Witcher, K. G., Yin, W., Sobol, C. G., Wang, Y., Sawicki, C. M., Sheridan, J. F., & Godbout, J. P. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.10.009 · Cited by 110 · see citing works
“Several other studies show similar kinetics of microglial repopulation (40, 41, 54, 55).”
ResultProtective Microglial Subset in Development, Aging, and Disease: Lessons From Transcriptomic Studies
Benmamar‐Badel, A., Owens, T., & Włodarczyk, A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00430 · Cited by 135 · 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
“…et al., 2012), as well as regulation of neurogenesis (Antony, Paquin, Nutt, Kaplan, & Miller, 2011); this function is maintained in the adult brain, where they continue to regulate neuronal structures and connections (Rice et al., 2015; Rice et al., 2017; Tremblay, Lowery, & Majewska, 2010).”
BackgroundSelf-citationMicroglia in the developing retina
Li, F., Jiang, D., & Samuel, M. A. (2019) · Neural Development · doi:10.1186/s13064-019-0137-x · Cited by 109 · see citing works
Ma, D., Zhao, Y., Huang, L., Xiao, Z., Chen, B., Shi, Y., Shen, H., & Dai, J. (2020) · Biomaterials · doi:10.1016/j.biomaterials.2020.119830 · Cited by 104 · see citing works
Depletion of microglia augments the dopaminergic neurotoxicity of MPTP
Yang, X., Ren, H., Wood, K., Li, M., Qiu, S., Shi, F., Ma, C., & Liu, Q. (2018) · The FASEB Journal · doi:10.1096/fj.201700833rr · Cited by 115 · see citing works
Krukowski, K., Feng, X., Paladini, M. S., Chou, A., Sacramento, K., Grue, K., Riparip, L.-K., Jones, T., Campbell-Beachler, M., Nelson, G., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-26039-7 · Cited by 92 · see citing works
Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders
Hu, B., Duan, S., Wang, Z., Li, X., Zhou, Y., Zhang, X., Zhang, Y., Xu, H., & Zheng, H. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.789834 · Cited by 105 · see citing works
Rosin, J. M., Vora, S. R., & Kurrasch, D. M. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.07.023 · Cited by 110 · see citing works
Walker, D. G., Tang, T. M., & Lue, L. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00244 · Cited by 93 · see citing works
“Studies by one group used two related CSF-1R inhibitors, PLX3397, or PLX5622 administered in the animal feed, produced almost complete ablation of microglia from the animal brain at the highest dose (Elmore et al., 2014, 2015; Rice et al., 2015, 2017; Spangenberg et al., 2016).”
BackgroundMethodMicroglia modulate stable wakefulness via the thalamic reticular nucleus in mice
Liu, H., Wang, X., Chen, L., Chen, L., Tsirka, S. E., Ge, S., & Xiong, Q. (2021) · Nature Communications · doi:10.1038/s41467-021-24915-x · Cited by 95 · see citing works
Epigenetic regulation of innate immune memory in microglia
Zhang, X., Kracht, L., Lerário, A. M., Dubbelaar, M. L., Brouwer, N., Wesseling, E. M., Boddeke, E., Eggen, B. J. L., & Kooistra, S. M. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02463-5 · Cited by 113 · see citing works
“However, it is currently unclear whether microglia malfunction contributes to the development of the disease pathology, is a consequence of the ongoing neurodegeneration or both (Krasemann et al., 2017; Rice et al., 2017; Safaiyan et al., 2016; Venegas et al., 2017).”
BackgroundYang, G., Xu, X., Gao, W., Wang, X., Zhao, Y., & Xu, Y. (2025) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2025.1700692 · Cited by 85 · see citing works
“Interestingly, withdrawal of CSF1R inhibitors facilitated microglial repopulation, which promoted brain recovery and reduced inflammation following injury (Rice et al., 2017).”
Kokkosis, A. G., Madeira, M. M., Hage, Z., Valais, K., Koliatsis, D., Resutov, E., & Tsirka, S. E. (2023) · Glia · doi:10.1002/glia.24464 · Cited by 87 · see citing works
“The repopulation depends solely on clonal expansion of the surviving microglial cells (Huang et al., 2018; Tay et al., 2017), which can rapidly replenish their numbers within 5 – 7 days after removal of the CSF1R inhibitor (Huang et al., 2018; Rice et al., 2017).”
BackgroundColeman, L. G., Zou, J., & Crews, F. T. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1678-y · Cited by 87 · see citing works
CNS border-associated macrophages in the homeostatic and ischaemic brain
Gerganova, G., Riddell, A., & Miller, A. A. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108220 · Cited by 72 · see citing works
Wang, W., Li, Y., Ma, F., Sheng, X., Chen, K., Zhuo, R., Wang, C., Zheng, H., Zhang, Y.-W., Bu, G., et al. (2023) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2023.07.011 · Cited by 71 · see citing works
Zhan, L., Fan, L., Kodama, L., Sohn, P., Wong, M. Y., Mousa, G. A., Zhou, Y., Li, Y., & Gan, L. (2020) · eLife · doi:10.7554/elife.51796 · Cited by 79 · see citing works
“While depletion efficiency varies, complete microglial ablation has never been reported (Acharya et al., 2016; Rice et al., 2017; Huang et al., 2018; Zhan et al., 2019).”
BackgroundThe Impact of Obesity on Microglial Function: Immune, Metabolic and Endocrine Perspectives
Alexaki, V. I. (2021) · Cells · doi:10.3390/cells10071584 · Cited by 83 · see citing works
Kerkhofs, D., van Hagen, B. T. J., Milanova, I. V., Schell, K. J., van Essen, H., Wijnands, E., Goossens, P., Blankesteijn, W. M., Unger, T., Prickaerts, J., et al. (2020) · Theranostics · doi:10.7150/thno.44394 · Cited by 70 · see citing works
Wong, K. A., & Benowitz, L. I. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231710179 · Cited by 66 · see citing works
Risbrough, V. B., Vaughn, M. N., & Friend, S. F. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.11.012 · Cited by 75 · see citing works
Neuroimmune cleanup crews in brain injury
Bolte, A. C., & Lukens, J. R. (2021) · Trends in Immunology · doi:10.1016/j.it.2021.04.003 · Cited by 68 · see citing works
Barca, C., Foray, C., Hermann, S., Herrlinger, U., Remory, I., Laoui, D., Schäfers, M., Grauer, O. M., Zinnhardt, B., & Jacobs, A. H. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.787307 · Cited by 64 · see citing works
“Repopulation reduced almost half of the 46 genes overexpressed following neuronal lesion (40).”
BackgroundInfluentialHohsfield, L. A., Najafi, A. R., Ghorbanian, Y., Soni, N., Hingco, E. E., Kim, S. J., Jue, A. D., Swarup, V., Inlay, M. A., & Green, K. N. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01931-0 · Cited by 64 · see citing works
Self-citationHan, J., Sarlus, H., Wszolek, Z. K., Karrenbauer, V. D., & Harris, R. A. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-01093-3 · Cited by 65 · see citing works
Macrophage Depletion Ameliorates Peripheral Neuropathy in Aging Mice
Yuan, X., Klein, D., Kerscher, S. R., West, B. L., Weis, J., Katona, I., & Martini, R. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.3030-17.2018 · Cited by 69 · see citing works
“…that the Wallerian degeneration-like phenotype of the peripheral nerve macrophages is related to a potential descent from “fresh” blood monocytes while replacement of burned-out parenchymal microglial cells in the CNS may be limited under aging conditions (Prinz et al., 2017; Rice et al., 2017).”
BackgroundSelf-citationZhao, J., Bi, W., Zhang, J., Xiao, S., Zhou, R., Tsang, C. K., Lu, D., & Zhu, L. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.04.052 · Cited by 64 · see citing works
Circulating Pro-Inflammatory Exosomes Worsen Stroke Outcomes in Aging
Zhang, H., Lin, S., McElroy, C. L., Wang, B. Z., Jin, D., Uteshev, V. V., & Jin, K. (2021) · Circulation Research · doi:10.1161/circresaha.121.318897 · Cited by 60 · see citing works
Neuroinflammation: targeting microglia for neuroprotection and repair after spinal cord injury
Cavalcanti, R. R., de Almeida, F. M., Martinez, A. M. B., & Freria, C. M. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1670650 · Cited by 54 · see citing works
“…the treated mice also showed improved functional recovery, supporting the concept that transient CSF1R inhibition removes detrimental microglia and allows for the emergence of a more homeostatic, neuroprotective microglial population that facilitates recovery following brain injury (86).”
Microglial Function and Regulation during Development, Homeostasis and Alzheimer’s Disease
Casali, B. T., & Reed-Geaghan, E. G. (2021) · Cells · doi:10.3390/cells10040957 · Cited by 64 · see citing works
Incretin Mimetics as Rational Candidates for the Treatment of Traumatic Brain Injury
Glotfelty, E. J., Delgado, T., Tovar‐y‐Romo, L. B., Luo, Y., Hoffer, B. J., Olson, L., Karlsson, T. E., Mattson, M. P., Harvey, B. K., Tweedie, D., et al. (2019) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.9b00003 · Cited by 48 · see citing works
Gargouri, B., Yousif, N. M., Bouchard, M., Fetoui, H., & Fiebich, B. L. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1198-1 · Cited by 48 · see citing works
Novel Microglia-based Therapeutic Approaches to Neurodegenerative Disorders
Zhang, L., Wang, Y., Liu, T., Mao, Y. Q., & Peng, B. (2023) · Neuroscience Bulletin · doi:10.1007/s12264-022-01013-6 · Cited by 56 · see citing works
Function of Glia in Aging and the Brain Diseases
Vallés, S. L., Iradi, A., Aldasoro, M., Vila, J. M., Aldasoro, C., de la Torre, J., Campos-Campos, J., & Jorda, A. (2019) · International Journal of Medical Sciences · doi:10.7150/ijms.37769 · Cited by 43 · see citing works
Role of Macrophages and Microglia in Zebrafish Regeneration
Var, S. R., & Byrd-Jacobs, C. A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21134768 · Cited by 48 · see citing works
“For example, after traumatic brain injury, there is chronic activation of microglia that hinder functional recovery [161–165]; therefore, removal of reactive microglia followed by repopulation with fresh microglial cells offers a potential strategy to resolve neuroinflammation and encourage recovery [166].”
BackgroundBasilico, B., Ferrucci, L., Khan, A., Angelantonio, S. D., Ragozzino, D., & Reverte, I. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.1022431 · Cited by 48 · see citing works
“Similarly, after brain injury microglia repopulation promotes brain recovery (Rice et al., 2017) and improves cognition (Henry et al., 2020; Willis et al., 2020).”
BackgroundLi, Q., Shen, C., Liu, Z., Ma, Y., Wang, J., Dong, H., Zhang, X., Wang, Z., Yu, M., Ci, L., et al. (2021) · Cell Proliferation · doi:10.1111/cpr.13094 · Cited by 50 · see citing works
Cai, Z., Ye, T., Xu, X., Gao, M., Zhang, Y.-R., Wang, D., Gu, Y., Zhu, H., Tong, L., Lu, J., et al. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.109931 · Cited by 43 · see citing works
Hohsfield, L. A., Najafi, A. R., Ghorbanian, Y., Soni, N., Crapser, J. D., Velez, D. X. F., Jiang, S., Royer, S. E., Kim, S. J., Henningfield, C. M., et al. (2021) · eLife · doi:10.7554/elife.66738 · Cited by 46 · see citing works
“Following CSF1Ri-dependent microglial depletion, we and others have shown that subsequent withdrawal of CSF1R inhibitors from the microglial-depleted brain results in rapid microglial repopulation derived from surviving microglia (Elmore et al., 2014; Zhan et al., 2019; Najafi et al., 2018; Elmore et al., 2018; Rice e…”
Self-citationMichels, M., Ávila, P. R. M., Pescador, B., Vieira, A. A. D. S., Abatti, M. R., Cucker, L., Borges, H. D. M., Goulart, A. I., Carvalho, C. C., Barichello, T., et al. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-1606-2 · Cited by 47 · see citing works
Park, S.-Y., Karthivashan, G., Ko, H., Cho, D.-Y., Kim, J., Cho, D., Ganesan, P., Su-Kim, I., & Choi, D. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/3175214 · Cited by 40 · see citing works
Mehdipour, M., Etienne, J., Chen, C., Gathwala, R., Rehman, M., Kato, C., Liu, C., Liu, Y., Zuo, Y., Conboy, M. J., et al. (2019) · Aging · doi:10.18632/aging.102148 · Cited by 42 · see citing works
Harley, S. B. R., Willis, E. F., Shaikh, S., Blackmore, D. G., Sah, P., Ruitenberg, M. J., Bartlett, P. F., & Vukovic, J. (2021) · Journal of Neuroscience · doi:10.1523/jneurosci.2539-20.2021 · Cited by 52 · see citing works
The role of microglia in ischemic preconditioning
McDonough, A., & Weinstein, J. R. (2019) · Glia · doi:10.1002/glia.23695 · Cited by 38 · see citing works
“…progenitors (Elmore et al., 2014; Huang et al., 2018), functional consequences of microglial depletion and replenishment (Elmore, Lee, West, & Green, 2015; Rice et al., 2017), and biological roles of microglia in injury and disease models (Hilla, Diekmann, & Fischer, 2017; Rice et al., 2015).”
BackgroundFerle, V., Repouskou, A., Aspiotis, G., Raftogianni, A., Chrousos, G. P., Stylianopoulou, F., & Stamatakis, A. (2019) · Physiology & Behavior · doi:10.1016/j.physbeh.2019.112791 · Cited by 34 · see citing works
An overview of microglia ontogeny and maturation in the homeostatic and pathological brain
Mendes, M. S., & Majewska, A. K. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.15225 · Cited by 35 · see citing works
“Treatment with a CSF1R inhibitor (PLX) to deplete all microglia, irrespective of phenotype, protects against synapse loss in AD mouse models (Rice et al., 2017; Spangenberg et al., 2016), suggesting that at least one prominent AD- related microglial population contributes to synapse elimination.”
BackgroundChen, Y., Hong, T., Chen, F., Sun, Y., Wang, Y., & Cui, L. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.631827 · Cited by 39 · see citing works
“Therefore, short-term elimination of microglia and cell proliferation may be a clinically feasible and novel method to solve neuroinflammatory events and promote brain recovery in brains affected by microglial dysfunction (Rice et al., 2017; Son et al., 2020).”
BackgroundGroh, J., Klein, D., Berve, K., West, B. L., & Martini, R. (2018) · Glia · doi:10.1002/glia.23539 · Cited by 33 · see citing works
Self-citationHu, L., Zhang, S., Ooi, K., Wu, X., Wu, J., Cai, J., Sun, Y., Wang, J., Zhu, D., Chen, F., et al. (2020) · Neuroscience Bulletin · doi:10.1007/s12264-020-00484-9 · Cited by 38 · see citing works
Shi, W., Zhang, J., Shang, Z., Zhang, Y., Xia, Y., Fu, H., & Yu, T. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.969127 · Cited by 25 · see citing works
“These results suggest that chronic inflammation is inherent with the microglia and not completely dependent on the environment (92).”
BackgroundInfluentialAndrew, P. M., & Lein, P. J. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.674325 · Cited by 33 · see citing works
The origin and repopulation of microglia
Zhang, L., Cao, Y., Zhang, X., Gu, X., Mao, Y. Q., & Peng, B. (2021) · Developmental Neurobiology · doi:10.1002/dneu.22862 · Cited by 36 · see citing works
“Microglia were thought to originate from a single developmental source of primitive hematopoietic progenitor cells arising in the YS, and then infiltrating into the brain during early embryogenesis and renewing themselves throughout adulthood (Saijo & Glass, 2011).”
BackgroundGuo, S., Geng, X., Lee, H., & Ding, Y.-C. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02542-3 · Cited by 30 · see citing works
Liu, Y., Given, K. S., Owens, G. P., Macklin, W. B., & Bennett, J. L. (2018) · Glia · doi:10.1002/glia.23512 · Cited by 33 · see citing works
Neuroprotection and Beyond: The Central Role of CB1 and CB2 Receptors in Stroke Recovery
Bietar, B., Tanner, S., & Lehmann, C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242316728 · Cited by 31 · see citing works
“…by the microglia, which are resident immune cells of the CNS that can detect pathologic changes and respond by exhibiting characteristic macrophage functions such as cytokine release (mainly, tumor necrosis factor (TNF), interleukin-1 β (IL-1 β ), and interleukin-6 (IL-6)), phagocytosis,…”
Karaahmet, B., Le, L., Mendes, M. S., Majewska, A. K., & O’Banion, M. K. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02532-9 · Cited by 29 · see citing works
“These new-born microglia are thought to be “rejuvenated” and beneficial in the context of disease settings such as toxin-induced acute neuronal lesion as well as normal aging [30, 31].”
BackgroundMicroglia as therapeutic targets for central nervous system remyelination
Mahmood, A., & Miron, V. E. (2022) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2022.102188 · Cited by 28 · see citing works
Yegla, B., Boles, J. S., Kumar, A., & Foster, T. C. (2021) · Glia · doi:10.1002/glia.23975 · Cited by 32 · see citing works
“…known as Pexidartinib; MedChemExpress, NJ) inhibits the tyrosine protein kinase c-Kit, CSF1R, and FMS-related tyrosine kinase 3, resulting in substantial reductions in microglial population within the brain (Elmore et al., 2014; Rice et al., 2015; Spangenberg et al., 2016; Thompson et al., 2015).”
BackgroundMicroglia and Their Promising Role in Ischemic Brain Injuries: An Update
Yu, L., Su, X., Li, S., Zhao, F., Mu, D., & Qu, Y. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00211 · Cited by 34 · see citing works
“Although several studies have shown that their population of microglia can fully restore microglial functions and attenuate brain damage (Rice et al., 2017; Zhang et al., 2018), the capacity for microglial repopulation is limited.”
BackgroundLessons Learned about Neurodegeneration from Microglia and Monocyte Depletion Studies
Lund, H., Pieber, M., & Harris, R. A. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00234 · Cited by 27 · see citing works
“…mouse post-lesion Microglial elimination and repopulation, largely resolves chronic neuroinflammatory responses and improved behavioral abilities Rice et al. (2017) LPS-induced striatal neurodegeneration Clodronate depletion i.v in gerbils Attenuated striatal macrophage infiltration reduced the…”
BackgroundPacker, J., Giammo, S. G., Wangler, L., Davis, A. C., Bray, C., & Godbout, J. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03451-1 · Cited by 26 · see citing works
“Moreover, microglia depletion with the CSF1R antagonist PLX5622, improved neuronal physiology [10, 11], neuronal dendritic restructuring [10, 11], and cognitive deficits following TBI [11–13, 21, 22].”
InfluentialImplications of microglial heterogeneity in spinal cord injury progression and therapy
Fang, Y., Qin, Z.-H., Zhang, Y., & Ning, B. (2022) · Experimental Neurology · doi:10.1016/j.expneurol.2022.114239 · Cited by 33 · see citing works
Tarale, P., & Alam, M. M. (2022) · Inflammopharmacology · doi:10.1007/s10787-022-00958-4 · Cited by 26 · see citing works
Microglia depletion leads to increased susceptibility to ocular hypertension-dependent glaucoma
Diemler, C. A., MacLean, M., Heuer, S. E., Hewes, A. A., Marola, O. J., Libby, R. T., & Howell, G. R. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1396443 · Cited by 26 · see citing works
“Studies in AD suggest repopulation of microglia with a short (one to 3 week) treatment of PLX5622, is beneficial, presumed to be because repopulated microglia are primarily in a homeostatic state (Rice et al., 2017).”
BackgroundCellular Localization of Kynurenine 3-Monooxygenase in the Brain: Challenging the Dogma
Sathyasaikumar, K. V., de la Cruz, V. P., Pineda, B., Cervantes, G. I. V., Ortega, D. R., Donley, D. W., Severson, P. L., West, B. L., Giorgini, F., Fox, J. H., et al. (2022) · Antioxidants · doi:10.3390/antiox11020315 · Cited by 29 · see citing works
Self-citationWahane, S., & Sofroniew, M. V. (2021) · Cell and Tissue Research · doi:10.1007/s00441-021-03487-8 · Cited by 25 · see citing works
Microglia react to partner loss in a sex- and brain site-specific manner in prairie voles
Pohl, T. T., Jung, O., Benedetto, B. D., Young, L. J., & Bosch, O. J. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.05.026 · Cited by 48 · see citing works
Ren, J., Wang, Q., Hong, H., & Tang, C. (2025) · Microorganisms · doi:10.3390/microorganisms13081956 · Cited by 27 · see citing works
“Remarkably, two months following the procedure, the patient exhibited enhanced mental acuity and emotional well-being, as evidenced by a rise in his MMSE score from 20 to 26.”
- Authors
- Rice, R. A., Pham, J., Lee, R. J., Najafi, A. R., West, B. L., & Green, K. N.
- Affiliations
- University of California, Irvine (US)
- Plexxikon (United States) (US)
- Corresponding author
- Green, Kim N.
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2017-03-02
- Volume
- 65
- Issue
- 6
- Pages
- 931-944
- ISSN
- 0894-1491 (ISSN-L)
- PMC
- PMC5395311
- OpenAlex
- W2594403755
- Cited by
- 228
- References
- 43
- Citations by year
- 2026: 15 · 2025: 20 · 2024: 28 · 2023: 16 · 2022: 37 · 2021: 38 · 2020: 29 · 2019: 19 · 2018: 20 · 2017: 6
- FWCI
- 10.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Glia (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute on Aging (P50AG016573)
- National Institute of Neurological Disorders and Stroke (F31NS086409, R01NS083801)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- microglial repopulation, CSF1R inhibitor, brain injury recovery, neuronal loss, hippocampal neurons, synaptic plasticity, PSD-95, synaptophysin, functional recovery, neuroinflammation
- MeSH terms
- Animals, Astrocytes, Brain, Calcium-Binding Proteins, Disease Models, Animal, Encephalitis, Female, Male, Mice, Transgenic, Microfilament Proteins, Neurons, Synapses, Neuroimmunomodulation, Cell Death, Microglia, Maze Learning, Recovery of Function, Cell Proliferation
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