The role of microglia in central nervous system immunity and glioma immunology

Yang, Isaac; Han, Seunggu J.; Kaur, Gurvinder; Crane, Courtney; Parsa, Andrew T.

doi:10.1016/j.jocn.2009.05.006

Cited by 410Neuroinflammation and Neurodegeneration MechanismsGlioma Diagnosis and TreatmentImmune cells in cancer

The role of microglia in central nervous system immunity and glioma immunology

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Yang, Isaac, Han, Seunggu J., Kaur, Gurvinder, Crane, Courtney, Parsa, Andrew T.·2010·Journal of Clinical Neuroscience

DOI 10.1016/j.jocn.2009.05.006PMC PMC3786731

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Abstract

The central nervous system (CNS) historically has been considered an immune-privileged organ, lacking a lymphatic system and shielded from the circulatory system by the blood-brain barrier. Microglia are an abundant portion of the CNS cell population, comprising 5% to 20% of the total glial cell population, and are as numerous as neurons. A crucial function of microglia is the ability to generate significant innate and adaptive immune responses. Microglia are involved in first line innate immunity of the CNS. Proper antigen presentation is critical in the generation of specific, durable responses by the adaptive immune system, and requires interaction between the T cell receptor and processed antigen peptide presented on major histocompatibility complex (MHC) molecules by the antigen presenting cells (APC). Microglia also have a large regulatory role in CNS immunity. Histopathologic studies of glioma tissue have consistently shown high levels of infiltrating microglia. Microglia are also localized diffusely throughout the tumor, rather than to the areas of necrosis, and phagocytosis of glioma cells or debris by microglia is not observed. Recent evidence indicates that glioma-infiltrating microglia/macrophages might be promoting tumor growth by facilitating immunosuppression of the tumor microenvironment. When activated, microglia can be potent immune effector cells, able to perform a broad range of functions, and they mediate both innate and adaptive responses during CNS injury and disease while remaining quiescent in the steady state. Their versatility in bridging the gap between the immune-privileged CNS and the peripheral immune system, in addition to their significant numbers in gliomas, makes them an attractive candidate in immunotherapy for gliomas. An enhanced understanding of microglia-glioma interaction may provide better methods to manipulate the glioma microenvironment to allow the generation of a specific and durable anti-glioma immunity. The role of microglia in CNS immunity is reviewed, with a focus on key advances made in glioma immunology.

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Microglia are the resident mononuclear phagocytes of the CNS and play key roles in immune surveillance and defense, synaptic remodeling, and homeostasis.
“Microglia, the resident mononuclear phagocytes of the CNS, play key roles in immune surveillance and defense [39], synaptic remodeling [40], and homeostasis [41].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [39]

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Background
In Vitro Modulation of Microglia Motility by Glioma Cells Is Mediated by Hepatocyte Growth Factor/Scatter Factor
Badie, B., Schartner, J. M., Klaver, J., & Vorpahl, J. (1999) · Neurosurgery · doi:10.1097/00006123-199905000-00075 · Cited by 109 · see citing works
Differential expression of MHC class II molecules by microglia and neoplastic astroglia: relevance for the escape of astrocytoma cells from immune surveillance
Trần, Wolz, Egensperger, Kösel, Imai, Bise, Kohsaka, Mehraein, & Graeber (1998) · Neuropathology and Applied Neurobiology · doi:10.1046/j.1365-2990.1998.00120.x · Cited by 94 · cited 1× · see citing works
“Although MHC molecule expression is seen on microglia within glioma tissues [85, 86], they appear deficient in proper antigen presentation [87] for cytotoxic and helper T cell activation.”
Background
Modulation of major histocompatibility complex Class I molecules and major histocompatibility complex—bound immunogenic peptides induced by interferon-α and interferon-γ treatment of human glioblastoma multiforme
Yang, I., Kremen, T. J., Giovannone, A. J., Paik, E., Odesa, S. K., Prins, R. M., & Liau, L. M. (2004) · Journal of neurosurgery · doi:10.3171/jns.2004.100.2.0310 · Cited by 84 · cited 1× · see citing works
“Within the CNS under resting states, MHC class I and II expression is generally absent or minimally present [3, 57].”
BackgroundSelf-citation
The mononuclear cell infiltrate compared with survival in high-grade astrocytomas
Rossi, M. I., Jones, N., Candy, E., Nicoll, J. A. R., Compton, J. S., Hughes, J. T., Esiri, M. M., Moss, T., Cruz-Sánchez, F. F., & Coakham, H. B. (1989) · Acta Neuropathologica · doi:10.1007/bf00688208 · Cited by 78 · see citing works
Microglia only weakly present glioma antigen to cytotoxic T cells
Flügel, A., Labeur, M. S., Grasbon‐Frodl, E., Kreutzberg, G. W., & Graeber, M. B. (1999) · International Journal of Developmental Neuroscience · doi:10.1016/s0736-5748(99)00020-9 · Cited by 73 · cited 1× · see citing works
“Although MHC molecule expression is seen on microglia within glioma tissues [85, 86], they appear deficient in proper antigen presentation [87] for cytotoxic and helper T cell activation.”
Background
CpG-oligonucleotides for cancer immunotherapy review of the literature and potential applications in malignant glioma
Carpentier, A. F. (2003) · Frontiers in bioscience · doi:10.2741/934 · Cited by 72 · cited 4× · see citing works
“For example, Carpentier and colleagues demonstrated long-term survival in animals with glioma using single intratumoral injection of CpG oligodeoxynucleotide, an immuno-stimulatory sequence that signals through TLR9 to induce the production of IFN-α, IFN-β, IL-12, and TNF-α [97, 98].”
BackgroundInfluential
Expression of Vascular Endothelial Growth Factor (VEGF) and Platelet-Derived Growth Factor Receptor-β (PDGFR-β) in Human Gliomas
Lafuente, J. V., Adan, B., Alkiza, K., Garibi, J., Rossi, M., & Ff, C.-S. (1999) · Journal of Molecular Neuroscience · doi:10.1385/jmn:13:1-2:177 · Cited by 71 · see citing works
Colony stimulating factor-1 expression in human glioma
Alterman, R. L., & Stanley, E. R. (1994) · Molecular and Chemical Neuropathology · doi:10.1007/bf02815350 · Cited by 70 · see citing works
Dexamethasone-induced abolition of the inflammatory response in an experimental glioma model: a flow cytometry study
Badie, B., Schartner, J. M., Paul, J. S., Bartley, B., Vorpahl, J., & Preston, J. K. (2000) · Journal of neurosurgery · doi:10.3171/jns.2000.93.4.0634 · Cited by 69 · cited 2× · see citing works
“Flow cytometry studies by Badie and colleagues demonstrated that as many as one-third of cells of glioma tissues express resident microglia markers, consisting of the largest population of immune cells [2].”
Background
Persistent immune activation associated with a mouse model of Staphylococcus aureus-induced experimental brain abscess
Baldwin, A. C., & Kielian, T. (2004) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2004.02.002 · Cited by 69 · cited 1× · see citing works
“These changes in turn decrease the stringency of the blood-brain barrier, allowing entry of soluble factors and peripheral immune cells [46], including macrophages, natural killer cells and lymphocytes [47, 48].”
Background
Differential expression of MHC class II and B7 costimulatory molecules by microglia in rodent gliomas
Badie, B., Bartley, B., & Schartner, J. M. (2002) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(02)00350-8 · Cited by 68 · cited 1× · see citing works
“In contrast, the expressions of MHC class II and costimulatory B7 molecules were significantly increased when freshly isolated microglia were cultured in the absence of glioma cells [88].”
Background
Induction of macrophage inflammatory protein MIP-1α mRNA on glial cells after focal cerebral ischemia in the rat
Takami, S., Nishikawa, H., Minami, M., Nishiyori, A., Sato, M., Akaike, A., & Satoh, M. (1997) · Neuroscience Letters · doi:10.1016/s0304-3940(97)00338-8 · Cited by 67 · cited 1× · see citing works
“Specifically, cytokines released by activated microglia include interleukin (IL)-1 [39], IL-6 [40] and tumor necrosis factor-alpha (TNF-α) [41], as well as monocyte chemoattractant protein-1 (MCP-1) [42], macrophage inflammatory protein-1 [43, 44] and RANTES [45], and chemokines for lymphocyte recruitment.”
Background
The shared tumor-specific antigen encoded by mouse geneP1A is a target not only for cytolytic T lymphocytes but also for tumor rejection
Brändle, D., Bilsborough, J., Rülicke, T., Uyttenhove, C., Boon, T., & den Eynde, B. J. V. (1998) · European Journal of Immunology · doi:10.1002/(sici)1521-4141(199812)28:12 · Cited by 62 · see citing works
Selective induction of interleukin-6 in mouse microglia by granulocyte-macrophage colony-stimulating factor
Suzumura, A., Sawada, M., & Marunouchi, T. (1996) · Brain Research · doi:10.1016/0006-8993(95)01535-3 · Cited by 56 · cited 2× · see citing works
“Microglia and local immune suppression by glioma Glioma cells produce anti-inflammatory cytokines such as IL-6 and TGF-β2 and PGE2 along with producing tumor growth promoting cytokines such as IL-1 and bFGF [1, 91].”
Background
Reactive microglia in dysmyelination and demyelination
Zhang, S., Goetz, B. D., Carré, J., & Duncan, I. D. (2001) · Glia · doi:10.1002/glia.1045 · Cited by 51 · cited 2× · see citing works
“until stimuli from injury, infection or neurodegenerative process activate their transformation into amoeboid phagocytic cells [10, 11].”
Background
Implication of macrophages in tumor rejection induced by CpG-oligodeoxynucleotides without antigen.
Auf, G., Carpentier, A. F., Chen, L., Clanche, C. L., & Delattre, J. (2001) · PubMed · Cited by 50 · see citing works
Coexpression of Fas/FasL and Bax on brain and infiltrating T cells in the central nervous system is closely associated with apoptotic cell death during autoimmune encephalomyelitis
Kohji, T., & Matsumoto, Y. (2000) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(00)00238-1 · Cited by 48 · cited 2× · see citing works
“Microglia in turn also express FAS molecules which, upon binding FASL, leads to their own apoptosis [66].”
Background
T-cell apoptosis in human glioblastoma multiforme: Implications for immunotherapy
Walker, D., Chuah, T., Rist, M., & Pender, M. P. (2006) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2006.03.006 · Cited by 48 · cited 1× · see citing works
“Microglia in intracranial tumors express FASL and inhibition of FASL leads to a dramatic increase in the number of peripheral immune effector cells seen within tumors [69, 96].”
Background
Infiltrative microgliosis: activation and long-distance migration of subependymal microglia following periventricular insults.
Carbonell, W. S., Murase, S., Horwitz, A. F., & Mandell, J. W. (2005) · Journal of Neuroinflammation · doi:10.1186/1742-2094-2-5 · Cited by 47 · see citing works
Cellular Inflammatory Response Associated with Breakdown of the Blood-Brain Barrier After Closed Head Injury in Rats
Lu, J., Moochhala, S., Kaur, C., & Ling, E. (2001) · Journal of Neurotrauma · doi:10.1089/089771501750170976 · Cited by 45 · cited 1× · see citing works
“These changes in turn decrease the stringency of the blood-brain barrier, allowing entry of soluble factors and peripheral immune cells [46], including macrophages, natural killer cells and lymphocytes [47, 48].”
Background
Inhibition of Complement as a Therapeutic Approach in Inflammatory Central Nervous System (CNS) Disease
Barnum, S. R. (1999) · Molecular Medicine · doi:10.1007/bf03402070 · Cited by 45 · cited 1× · see citing works
“Upon activation, microglia upregulate opsonic receptors including complement receptors (CR1, CR3, CR4) and Fc gamma receptors (I, II, III), which enhance phagocytic activity by binding to complement components and immunoglobulin fragments respectively [50, 51].”
Background
The human astrocytoma cell line U373MG produces monocyte chemotactic protein (MCP)-1 upon stimulation with β-amyloid protein
Prat, E., Baron, P., Meda, L., Scarpini, E. A., Galimberti, D., Ardolino, G., Catania, A., & Scarlato, G. (2000) · Neuroscience Letters · doi:10.1016/s0304-3940(00)00966-6 · Cited by 44 · cited 1× · see citing works
“MCP-1 is produced by glioma cells, and microglia express a specific MCP-1 receptor, CCR2 [75, 76].”
Background
Phagocytosis of apoptotic lymphocytes by oligodendrocytes in experimental autoimmune encephalomyelitis
Nguyen, K. B., & Pender, M. P. (1998) · Acta Neuropathologica · doi:10.1007/s004010050763 · Cited by 40 · cited 1× · see citing works
“A similar phenomenon is seen in animal models of multiple sclerosis – T cell debris undergoes phagocytosis by microglia [53].”
Background
Experimental Gliosarcoma Induces Chemokine Receptor Expression in Rat Brain
Galasso, J. M., Stegman, L. D., Blaivas, M., Harrison, J. K., Ross, B. D., & Silverstein, F. S. (2000) · Experimental Neurology · doi:10.1006/exnr.1999.7249 · Cited by 37 · cited 1× · see citing works
“MCP-1 is produced by glioma cells, and microglia express a specific MCP-1 receptor, CCR2 [75, 76].”
Background
Reaction of microglial cells in human astrocytomas (preliminary report).
Wierzba‐Bobrowicz, T., Kuchna, I., & Matyja, E. (1994) · PubMed · Cited by 37 · see citing works
GM‐CSF and M‐CSF modulate β‐chemokine and HIV‐1 expression in microglia
Si, Q., Cosenza, M., Zhao, M., Goldstein, H., & Lee, S. C. (2002) · Glia · doi:10.1002/glia.10095 · Cited by 35 · see citing works
Local Neurochemicals and Site-Specific Immune Regulation in the CNS
McCluskey, L. P., & Lampson, L. A. (2000) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/59.3.177 · Cited by 34 · cited 1× · see citing works
“A complex set of interactions exist between local stimulatory and inhibitory signals in shaping microglial responses: while some neurotransmitters like substance P enhance the active phenotype of microglia [30], electrically active neurons inhibit the increase in expression of MHC class II molecules on microglia in re…”
Background
Site-specific immune response to implanted gliomas
Proescholdt, M. A., Merrill, M. J., Ikejiri, B. L., Walbridge, S., Akbaşak, A., Jacobson, S., & Oldfield, E. H. (2001) · Journal of neurosurgery · doi:10.3171/jns.2001.95.6.1012 · Cited by 31 · cited 1× · see citing works
“Although MHC molecule expression is seen on microglia within glioma tissues [85, 86], they appear deficient in proper antigen presentation [87] for cytotoxic and helper T cell activation.”
Background
Cellular immune response in brain tumors.
Streit, W. J. (1994) · PubMed · Cited by 30 · see citing works
Modulation of Fas-Ligand (Fas-L) on human microglial cells: an in vitro study
Frigerio, S., Silei, V., Ciusani, E., Massa, G. A., Lauro, G. M., & Salmaggi, A. (2000) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(99)00227-1 · Cited by 29 · cited 1× · see citing works
“The FASL expression on microglia has been described in vitro [64, 65] and in mouse models of multiple sclerosis [66].”
Background
Resident microglia from adult mice are refractory to nitric oxide‐inducing stimuli due to impaired NOS2 gene expression
Brannan, C. A., & Roberts, M. R. (2004) · Glia · doi:10.1002/glia.20066 · Cited by 25 · see citing works
Regulation of cell migration and cytokine production by HGF-like protein (HLP) / macrophage stimulating protein (MSP) in primary microglia
Suzuki, Y., Funakoshi, H., Machide, M., Matsumoto, K., & Nakamura, T. (2008) · Biomedical Research · doi:10.2220/biomedres.29.77 · Cited by 25 · see citing works
Glioma Immunology and Immunotherapy
Parney, I. F., Hao, C., & Petruk, K. C. (2000) · Neurosurgery · doi:10.1227/00006123-200004000-00002 · Cited by 22 · see citing works
Local proliferation of microglia cells in response to neocortical injury in vitro
Eliason, D. A., Cohen, S. A., Baratta, J. L., Yu, J. Z., & Robertson, R. T. (2002) · Developmental Brain Research · doi:10.1016/s0165-3806(02)00413-3 · Cited by 20 · cited 1× · see citing works
“In the context of CNS insult or injury, microglia convert to an active phenotype, with increased proliferation [8], motility [9], and phagocytic activity [10, 11], and release cytokines and reactive oxygen species [12].”
Background
Double‐stranded RNA stimulates chemokine expression in microglia through vacuolar pH‐dependent activation of intracellular signaling pathways
Nakamichi, K., Saiki, M., Sawada, M., Yamamuro, Y., Morimoto, K., & Kurane, I. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03354.x · Cited by 17 · cited 1× · see citing works
“For example, microglia express TLR [22] and initiate innate responses with the production of cytokines, chemokines and nitric oxide (NO) [37, 38].”
Background
Differential microglial regulation in the human spinal cord under normal and pathological conditions
Stoll, M., Capper, D., Dietz, K., Warth, A., Schleich, A., Schlaszus, H., Meyermann, R., & Mittelbronn, M. G. A. (2006) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2006.00774.x · Cited by 15 · cited 2× · see citing works
“MHC molecules are generally restricted to microglia in low levels [6, 57, 58].”
Background
Comparison of the timing of acute blood‐brain barrier breakdown to rabbit immunoglobulin G in the cerebellum and spinal cord of mice with experimental autoimmune encephalomyelitis
Tonra, J. R., Reiseter, B. S., Kolbeck, R., Nagashima, K., Robertson, R., Keyt, B. A., & Lindsay, R. M. (2001) · The Journal of Comparative Neurology · doi:10.1002/1096-9861(20010129)430:1 · Cited by 1 · see citing works
Untitled work
(1996) · doi:10.1002/(sici)1098-1136(199609)18:1
Untitled work
(1999) · doi:10.1002/(sici)1521-4141(199909)29:09

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Treatment of Brain Inflammatory Diseases by Delivering Exosome Encapsulated Anti-inflammatory Drugs From the Nasal Region to the Brain
Zhuang, X., Xiang, X., Grizzle, W., Sun, D., Zhang, S., Axtell, R. C., Ju, S., Mu, J., Zhang, L., Steinman, L., et al. (2011) · Molecular Therapy · doi:10.1038/mt.2011.164 · Cited by 1,356 · see citing works
Microglial cell origin and phenotypes in health and disease
Saijo, K., & Glass, C. K. (2011) · Nature Reviews Immunology · doi:10.1038/nri3086 · Cited by 1,100 · see citing works
“Regardless of their classification as M2-like or MDSC-like, glioma-associated microglia express low levels of MHC class II molecules, which are required to present tumour-specific antigens to T cell”
Background
Emerging therapies for glioblastoma: current state and future directions
Rong, L., Li, N., & Zhang, Z. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-022-02349-7 · Cited by 515 · see citing works
“In adults, microglia account for approximately 10% of CNS cells and maintain a quiescent phenotype in the normal CNS, expressing low levels of MHC molecules and costimulatory molecules [43].”
Background
Bidirectional Microglia–Neuron Communication in Health and Disease
Szepesi, Z., Manouchehrian, O., Bachiller, S., & Deierborg, T. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00323 · Cited by 459 · see citing works
Complement in the brain
Veerhuis, R., Nielsen, H. M., & Tenner, A. J. (2011) · Molecular Immunology · doi:10.1016/j.molimm.2011.04.003 · Cited by 420 · see citing works
“…immune effector cells and are able to produce cytokines and chemokines as well as to phagocytose up targets upon stimulation (Dong and Benveniste, 2001;Nielsen et al., 2010;Familian et al., 2007;Nielsen et al., 2009;Fraser et al., 2010;Bohlson et al., 2007;Yang et al., 2010;Watabe et al., 1989).”
Background
Differentiation of human and murine induced pluripotent stem cells to microglia-like cells
Pandya, H., Shen, M. J., Ichikawa, D. M., Sedlock, A. B., Choi, Y., Johnson, K. R., Kim, G., Brown, M. A., Elkahloun, A. G., Maric, D., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4534 · Cited by 405 · see citing works
Elevated cd3+ and cd8+ tumor-infiltrating immune cells correlate with prolonged survival in glioblastoma patients despite integrated immunosuppressive mechanisms in the tumor microenvironment and at the systemic level
Kmiecik, J., Poli, A., Brons, N. H. C., Waha, A., Eide, G. E., Enger, P. Ø., Zimmer, J., & Chekenya, M. (2013) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2013.08.013 · Cited by 389 · see citing works
“Several recent studies observed positive correlation of increased numbers of glioma infiltrating lymphocytes with better patients' survival (Yang et al., 2010b; Lohr et al., 2011; Kim et al., 2012), while some older reports describe negative (Safdari et al., 1985) or no correlation (Rossi et al.,…”
The molecular profile of microglia under the influence of glioma
Li, W., & Graeber, M. B. (2012) · Neuro-Oncology · doi:10.1093/neuonc/nos116 · Cited by 341 · see citing works
“It is therefore speculated that microglial cells play a role in tumor progression by supporting angiogenesis as well.(19,255) Molecules contributing to glioma growth and invasion.”
Background
Tumor infiltrating immune cells in gliomas and meningiomas.
Domingues, P., González-Tablas, M., Otero, Á., Pascual, D., Miranda, D., Ruíz, L., Sousa, P., Ciudad, J., Gonçalves, J., Lopes, M. C., et al. (2016) · Brain, behavior, and immunity · doi:10.1016/j.bbi.2015.07.019 · Cited by 258 · see citing works
Neuroinflammation as a target for treatment of stroke using mesenchymal stem cells and extracellular vesicles
Dabrowska, S., Andrzejewska, A., Łukomska, B., & Janowski, M. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1571-8 · Cited by 302 · see citing works
“Nevertheless, the transformation of M1-type macrophages (CD16+CD32+CD86+) towards M2-type macrophages (CD206+Arginase-1+) is essential for the induction of tissue regenerative processes.”
Background
Challenges and potential of PD-1/PD-L1 checkpoint blockade immunotherapy for glioblastoma
Wang, X., Guo, G., Guan, H., Yu, Y., Lu, J., & Yu, J. (2019) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-019-1085-3 · Cited by 287 · see citing works
Differential Regulation of Interleukin-1 Receptor-associated Kinase-1 (IRAK-1) and IRAK-2 by MicroRNA-146a and NF-κB in Stressed Human Astroglial Cells and in Alzheimer Disease
Cui, J. G., Li, Y. Y., Zhao, Y., Bhattacharjee, S., & Lukiw, W. J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.178848 · Cited by 240 · see citing works
Focus on Extracellular Vesicles: Physiological Role and Signalling Properties of Extracellular Membrane Vesicles
Iraci, N., Leonardi, T., Gessler, F., Vega, B., & Pluchino, S. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17020171 · Cited by 301 · see citing works
“During brain inflammation, T lymphocytes cross the blood–brain barrier (BBB) and directly interact with microglia to recognise antigens and ultimately to mediate a pro-inflammatory response [134].”
Background
Harnessing innate immune pathways for therapeutic advancement in cancer
Hu, A.-K., Sun, L., Lin, H., Liao, Y., Yang, H., & Mao, Y. Q. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01765-9 · Cited by 265 · see citing works
Glioblastoma-associated microglia and macrophages: targets for therapies to improve prognosis
Poon, C. C., Sarkar, S., Yong, V. W., & Kelly, J. J. (2017) · Brain · doi:10.1093/brain/aww355 · Cited by 246 · see citing works
The inflammation hypothesis in geriatric depression
Alexopoulos, G. S., & Morimoto, S. S. (2011) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.2672 · Cited by 225 · see citing works
Minocycline alleviates depression-like symptoms by rescuing decrease in neurogenesis in dorsal hippocampus via blocking microglia activation/phagocytosis
Bassett, B., Subramaniyam, S., Yang, F., Varney, S., Pan, H., Carneiro, A. M. D., & Chung, C. Y. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.11.009 · Cited by 217 · see citing works
Therapeutic activation of macrophages and microglia to suppress brain tumor-initiating cells
Sarkar, S., Döring, A., Zemp, F. J., Silva, C., Lun, X. Q., Wang, X., Kelly, J. J., Hader, W. J., Hamilton, M. G., Mercier, P., et al. (2013) · Nature Neuroscience · doi:10.1038/nn.3597 · Cited by 202 · see citing works
A dialog between glioma and microglia that promotes tumor invasiveness through the CCL2/CCR2/interleukin-6 axis
Zhang, J., Sarkar, S., Cua, R., Zhou, Y., Hader, W. J., & Yong, V. W. (2011) · Carcinogenesis · doi:10.1093/carcin/bgr289 · Cited by 196 · see citing works
Proteoglycans and their roles in brain cancer
Wade, A., Robinson, A. E., Engler, J. R., Petritsch, C. K., James, C. D., & Phillips, J. J. (2013) · FEBS Journal · doi:10.1111/febs.12109 · Cited by 193 · see citing works
GM-CSF Promotes the Immunosuppressive Activity of Glioma-Infiltrating Myeloid Cells through Interleukin-4 Receptor-α
Kohanbash, G., McKaveney, K., Sakaki, M., Ueda, R., Mintz, A. H., Amankulor, N. A., Fujita, M., Ohlfest, J. R., & Okada, H. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-4124 · Cited by 189 · see citing works
“Although glioblastoma is densely infiltrated by microglia/macrophages (19, 46), to our knowledge, our current study is one of the first to characterize the phenotype and function of MDSCs in human gliomas.”
BackgroundResult
Glioma-derived IL-33 orchestrates an inflammatory brain tumor microenvironment that accelerates glioma progression
Boeck, A. D., Ahn, B. Y., D’Mello, C., Lun, X. Q., Menon, S. V., Alshehri, M. M., Szulzewsky, F., Shen, Y., Khan, L., Dang, N. H., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18569-4 · Cited by 181 · see citing works
Recent Advances of the NLRP3 Inflammasome in Central Nervous System Disorders
Zhou, K., Shi, L., Wang, Y., Chen, S., & Zhang, J. (2016) · Journal of Immunology Research · doi:10.1155/2016/9238290 · Cited by 175 · see citing works
“[100] I.”
Brain dendritic cells: biology and pathology
D’Agostino, P. M., Gottfried‐Blackmore, A., Anandasabapathy, N., & Bulloch, K. (2012) · Acta Neuropathologica · doi:10.1007/s00401-012-1018-0 · Cited by 176 · see citing works
Microglia and Macrophages in Malignant Gliomas: Recent Discoveries and Implications for Promising Therapies
da Fonseca, A. C. C., & Badie, B. (2013) · Clinical and Developmental Immunology · doi:10.1155/2013/264124 · Cited by 175 · see citing works
“presentation [7], their effector immune function in gliomas”
Background
MicroRNA in Glioblastoma: An Overview
Banelli, B., Forlani, A., Allemanni, G., Morabito, A., Pistillo, M. P., & Romani, M. (2017) · International Journal of Genomics · doi:10.1155/2017/7639084 · Cited by 167 · see citing works
“Microglia and astrocytes, along with macrophages, are part of the glioma microenvironment, astrocytes are part of the brain immune system as they express cytokines and chemokines, and glioma cells produce and are targets of inflammatory molecules [78, 79].”
Background
The Role of Macrophages in Neuroinflammatory and Neurodegenerative Pathways of Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis: Pathogenetic Cellular Effectors and Potential Therapeutic Targets
Mammana, S., Fagone, P., Cavalli, E., Basile, M. S., Petralia, M. C., Nicoletti, F., Bramanti, P., & Mazzon, E. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19030831 · Cited by 166 · see citing works
“However, once activated, microglia and CNS-infiltrating monocyte-derived macrophages upregulate many surface molecules, including major histocompatibility class II (MCHII) complexes and co-stimulatory molecules, which make them capable of presenting antigens to T cells more efficiently than astrocytes but less efficie…”
Background
Role of microbiota and tryptophan metabolites in the remote effect of intestinal inﬂammation on brain and depression
Waclawiková, B., & El Aidy, S. (2018) · Pharmaceuticals · doi:10.3390/ph11030063 · Cited by 172 · see citing works
Regulation of microglia activation and deactivation by nuclear receptors
Saijo, K., Crotti, A., & Glass, C. K. (2012) · Glia · doi:10.1002/glia.22423 · Cited by 148 · see citing works
“Alternative activation of microglia in the context of brain tumors has been the subject of recent reviews (Charles et al., 2011; Ghosh and Chaudhuri, 2010; Yang et al., 2010).”
Background
Evaluating the role of Toll-like receptors in diseases of the central nervous system.
Carty, M., & Bowie, A. (2011) · Biochemical Pharmacology · doi:10.1016/j.bcp.2011.01.003 · Cited by 154 · see citing works
Challenges in Immunotherapy Presented by the Glioblastoma Multiforme Microenvironment
Jackson, C. M., Ruzevick, J., Phallen, J. A., Belcaid, Z., & Lim, M. K. (2011) · Clinical and Developmental Immunology · doi:10.1155/2011/732413 · Cited by 142 · see citing works
“Microglia [14], macrophages, and dendritic cells [15, 16] act as powerful APCs in the CNS.”
Background
A review of antibiotics, depression, and the gut microbiome
Hao, W., Li, X., Zhang, P.-W., & Chen, J. (2019) · Psychiatry Research · doi:10.1016/j.psychres.2019.112691 · Cited by 144 · see citing works
Toll-like receptors in cerebral ischemic inflammatory injury
Wang, Y., Lin, S., & Yang, Q. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-134 · Cited by 133 · see citing works
Friend or Foe: S100 Proteins in Cancer
Allgöwer, C., Kretz, A.-L., von Karstedt, S., Wittau, M., Henne‐Bruns, D., & Lemke, J. (2020) · Cancers · doi:10.3390/cancers12082037 · Cited by 131 · see citing works
Immune cell infiltrate differences in pilocytic astrocytoma and glioblastoma: evidence of distinct immunological microenvironments that reflect tumor biology
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STAT3 Activation in Glioblastoma: Biochemical and Therapeutic Implications
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“Several in vitro and in vivo studies of STAT3 inhibitors suggest that STAT3 downregulation can induce cell cycle arrest and apoptosis, often in a dose-dependent manner [77–79].”
Background
Glioblastoma cells: A heterogeneous and fatal tumor interacting with the parenchyma
Alves, T. R., Lima, F. R. S., Kahn, S. A., Lobo, D. S., Dubois, L. G., Soletti, R. C., Borges, H. L., & Moura‐Neto, V. (2011) · Life Sciences · doi:10.1016/j.lfs.2011.04.022 · Cited by 125 · see citing works
“A better understanding regarding the activities of these CNS defense cells is essential in order to establish effective strategies to combat malignant gliomas (Ghosh and Chaudhuri, 2010; Kostianovsky et al., 2008; Yang et al., 2010).”
Background
CNS: Not an immunoprivilaged site anymore but a virtual secondary lymphoid organ
Negi, N., & Das, B. K. (2018) · International Reviews of Immunology · doi:10.1080/08830185.2017.1357719 · Cited by 123 · see citing works
“1, CD40, CD80, and CD86 on their surface [36].”
Background
Role of AHR and HIF-1α in Glioblastoma Metabolism
Gabriely, G., Wheeler, M. A., Takenaka, M. C., & Quintana, F. J. (2017) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2017.02.009 · Cited by 122 · see citing works
Peripheral immune contributions to the maintenance of central glial activation underlying neuropathic pain
Grace, P. M., Rolan, P. E., & Hutchinson, M. R. (2011) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2011.04.003 · Cited by 114 · see citing works
“…of immunoregulatory molecules such as cellular adhesion molecules, MHC class II and costimulatory molecules that regulate leukocyte infiltration and engagement with APCs (Vass and Lassmann, 1990; Gehrmann et al., 1995; Kreutzberg, 1996; Aloisi, 2001; McCluskey and Lampson, 2001; Yang et al., 2010).”
Background
Targeting glioblastoma with NK cells and mAb against NG2/CSPG4 prolongs animal survival
Poli, A., Wang, J., Domingues, O., Planagumà, J., Yan, T., Rygh, C. B., Skaftnesmo, K. O., Thorsen, F. A., McCormack, E., Hentges, F., et al. (2013) · Oncotarget · doi:10.18632/oncotarget.1291 · Cited by 115 · see citing works
Chronic Intermittent Hypoxia Induces Chronic Low-Grade Neuroinflammation in the Dorsal Hippocampus of Mice
Sapin, E., Peyron, C., Roche, F., Gay, N., Carcenac, C., Savasta, M., Levy, P. A., & Demattéis, M. (2015) · SLEEP · doi:10.5665/sleep.5042 · Cited by 112 · see citing works
Neuropsychiatric systemic lupus erythematosus and cognitive dysfunction: The MRL-lpr mouse strain as a model
Jeltsch‐David, H., & Muller, S. (2014) · Autoimmunity Reviews · doi:10.1016/j.autrev.2014.08.015 · Cited by 110 · see citing works
“On the other hand, cytokines are produced within the CNS by neurons and microglia, the surveillance cells of the CNS (for a review, see [132]), and take part in the regulation of neurogenesis, cell survival, proliferation and differentiation of new neurons that is crucial for hippocampal functions such as learning and…”
Background
Tumor Microenvironment in the Brain
Lorger, M. (2012) · Cancers · doi:10.3390/cancers4010218 · Cited by 110 · see citing works
“It has been suggested that upon stimulation, these resident microglia can be rapidly activated via at least two different and functionally distinct morphological states, termed activated and reactive/amoeboid microglia [89,101].”
Background
Ultrasound in tumor immunotherapy: Current status and future developments
Ho, Y.-J., Li, J.-P., Fan, C., Liu, H.-L., & Yeh, C. (2020) · Journal of Controlled Release · doi:10.1016/j.jconrel.2020.04.023 · Cited by 110 · see citing works
Potential therapeutic and pharmacological effects of Wogonin: an updated review
Huynh, D. L., Ngau, T. H., Nguyen, N. H., Tran, G., & Nguyen, C. T. (2020) · Molecular Biology Reports · doi:10.1007/s11033-020-05972-9 · Cited by 109 · see citing works
Resident macrophages in the cochlear blood-labyrinth barrier and their renewal via migration of bone-marrow-derived cells
Shi, X. (2010) · Cell and Tissue Research · doi:10.1007/s00441-010-1040-2 · Cited by 109 · see citing works
“Perivascular resident macrophages (PVMs) are found in the brain and retina and in other tissues (Cuadros and Navascues 1998; Kezic and McMenamin 2008; Yang et al. 2009, Brigitte et al. 2009; Guth et al. 2009).”
Background
Integrative multi-omics module network inference with lemon-tree
Bonnet, E., Calzone, L., & Michoel, T. (2015) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003983 · Cited by 98 · see citing works
“They constitute the dominant form of glioma tumor infiltrating immune cells, and they might promote tumor growth by facilitating immunosuppression of the tumor microenvironment [39].”
Isolation of highly enriched primary human microglia for functional studies
Rustenhoven, J., Park, T. I.-H., Schweder, P., Scotter, J., Correia, J., Smith, A. M., Gibbons, H. M., Oldfield, R. L., Bergin, P. S., Mee, E. W., et al. (2016) · Scientific Reports · doi:10.1038/srep19371 · Cited by 99 · see citing works
Aberrant Expression of Interleukin-1β and Inflammasome Activation in Human Malignant Gliomas
Tarassishin, L., Casper, D., & Lee, S. C. (2014) · PLoS ONE · doi:10.1371/journal.pone.0103432 · Cited by 97 · see citing works
Vagotomy Attenuates Brain Cytokines and Sleep Induced by Peripherally Administered Tumor Necrosis Factor-α and Lipopolysaccharide in Mice
Zielinski, M. R., Dunbrasky, D. L., Taishi, P., Souza, G., & Krueger, J. M. (2013) · Sleep · doi:10.5665/sleep.2892 · Cited by 94 · see citing works
The Translational Potential of Microglia and Monocyte-Derived Macrophages in Ischemic Stroke
Wicks, E. E., Ran, K. R., Kim, J. E., Xu, R., Lee, R. P., & Jackson, C. M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.897022 · Cited by 92 · see citing works
“In the adult brain, estimates of microglial abundance range from 5-20% (16).”
Background
Glioblastoma-derived Macrophage Colony-stimulating Factor (MCSF) Induces Microglial Release of Insulin-like Growth Factor-binding Protein 1 (IGFBP1) to Promote Angiogenesis
Nijaguna, M. B., Patil, V., Urbach, S., Shwetha, S. D., Sravani, K., Hegde, A. S., Chandramouli, B. A., Arivazhagan, A., Marin, P., Santosh, V., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.664037 · Cited by 88 · see citing works
“Moreover, macrophages/microglia has been implicated in glioma pathophysiology (7-9).”
Background
Nervous and immune systems signals and connections: Cytokines in hippocampus physiology and pathology
Arisi, G. M. (2014) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2014.01.017 · Cited by 87 · see citing works
“Microglia are the surveillance cells on the CNS; they are derived not from the neuroectodermal lineage but from the bone marrow (for a review, read [18]).”
The Glioblastoma Microenvironment: Morphology, Metabolism, and Molecular Signature of Glial Dynamics to Discover Metabolic Rewiring Sequence
Virtuoso, A., Giovannoni, R., Luca, C. D., Gargano, F., Cerasuolo, M., Maggio, N., Lavitrano, M., & Papa, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073301 · Cited by 80 · see citing works
“In the healthy brain, professional macrophages are located around the vessels and in the proximity of the ventricular areas [64], while microglia represents 5–20% of the glial population [65].”
Background
Microglia: Activation in acute and chronic inflammatory states and in response to cardiovascular dysfunction
Badoer, E. (2010) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2010.07.005 · Cited by 80 · see citing works
Immunotherapy of Primary Brain Tumors: Facts and Hopes
Buerki, R. A., Chheda, Z. S., & Okada, H. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-2769 · Cited by 80 · see citing works
Next Generation CAR T Cells for the Immunotherapy of High-Grade Glioma
Petersen, C. T., & Krenciute, G. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00069 · Cited by 79 · see citing works
CD38 and Regulation of the Immune Response Cells in Cancer
Dwivedi, S., Rendon‐Huerta, E. P., Ortiz-Navarrete, V. F., & Montaño, L. F. (2021) · Journal of Oncology · doi:10.1155/2021/6630295 · Cited by 77 · see citing works
MiR‐30a‐5p ameliorates spinal cord injury‐induced inflammatory responses and oxidative stress by targeting Neurod 1 through MAPK / ERK signalling
Fu, X., Shen, Y., Wang, W., & Li, X. (2017) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.12856 · Cited by 79 · see citing works
Isolation of a new cell population in the glioblastoma microenvironment
The Grand Ouest Glioma Project Network, Clavreul, A., Etcheverry, A., Chassevent, A., Quillien, V., Avril, T., Jourdan, M.-L., Michalak, S., François, P., Carré, J., et al. (2011) · Journal of Neuro-Oncology · doi:10.1007/s11060-011-0701-7 · Cited by 78 · see citing works
“We now have some knowledge of the cancer stem cell biology of GB [10, 11], but, other than for angiogenesis and immune cells, very little is known about the stromal cells of GB [12–14].”
Background
Potential substrates for nicotine and alcohol interactions: A focus on the mesocorticolimbic dopamine system
Doyon, W. M., Thomas, A. M., Ostroumov, A., Dong, Y., & Dani, J. A. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.07.007 · Cited by 77 · see citing works
“During an immune response, foreign stimuli activate macrophages (peripheral) and microglia (central) of the innate immune system to elicit the release of inflammatory cytokines [286].”
Tumor initiating cells induce Cxcr4-mediated infiltration of pro-tumoral macrophages into the brain
Chia, K., Mazzolini, J., Mione, M., & Sieger, D. (2018) · eLife · doi:10.7554/elife.31918 · Cited by 78 · see citing works
“Microglia and infiltrating macrophages have been shown to infiltrate high-grade gliomas and can account for up to 30% of the tumoral mass (Graeber et al., 2002; Badie and Schartner, 2001; Li and Graeber, 2012; Yang et al., 2010; Coniglio and Segall, 2013).”
Background
Brain Innate Immunity in the Regulation of Neuroinflammation: Therapeutic Strategies by Modulating CD200-CD200R Interaction Involve the Cannabinoid System
Hernangómez, M., Carrillo-Salinas, F. J., Mecha, M., Correa, F., Mestre, L., Loría, F., Feliú, A., Docagne, F., & Guaza, C. (2014) · Current Pharmaceutical Design · doi:10.2174/1381612820666140130202911 · Cited by 77 · see citing works
“, [10], in 1919, Ramón y Cajal’s disciple, Pío del Río-Hortega recognised microglial cells as a different cell type from the other glial cells.”
Unique biology of gliomas: challenges and opportunities
Watkins, S., & Sontheimer, H. W. (2012) · Trends in Neurosciences · doi:10.1016/j.tins.2012.05.001 · Cited by 76 · see citing works
Natural killer cells in intracranial neoplasms: presence and therapeutic efficacy against brain tumours
Kmiecik, J., Zimmer, J., & Chekenya, M. (2013) · Journal of Neuro-Oncology · doi:10.1007/s11060-013-1265-5 · Cited by 76 · see citing works
“However, this concept has been revised, as immune cells have been shown to infiltrate brain tumours [4] and play important roles in both anti-tumour immunity [4] and tumour progression [5, 6].”
Background
Glioma cell-derived placental growth factor induces regulatory B cells
Han, S. I., Feng, S., Ren, M., Ma, E., Wang, X., Xu, L., & Xu, M. (2014) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2014.10.005 · Cited by 75 · see citing works
Self-citation
Dendritic cell activation enhances anti-PD-1 mediated immunotherapy against glioblastoma
Garzón-Muvdi, T., Theodros, D., Luksik, A. S., Maxwell, R., Kim, E. S., Jackson, C. M., Belcaid, Z., Ganguly, S., Tyler, B., Brem, H., et al. (2018) · Oncotarget · doi:10.18632/oncotarget.25061 · Cited by 74 · see citing works
Microglial Inflammatory-Metabolic Pathways and Their Potential Therapeutic Implication in Major Depressive Disorder
Rahimian, R., Belliveau, C., Chen, R., & Mechawar, N. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.871997 · Cited by 73 · see citing works
“CB2 receptors are much less expressed in the CNS compared to CB1 receptors, however, they have been found in the brainstem, cerebellum and hippocampus among other areas (212) and are primarily found on immune cells, astrocytes and less commonly in neurons (215).”
BackgroundInfluential
Neonatal Rat Primary Microglia: Isolation, Culturing, and Selected Applications
Ni, M., & Aschner, M. (2010) · Current Protocols in Toxicology · doi:10.1002/0471140856.tx1217s43 · Cited by 73 · see citing works
“A brief list includes studies on the role of microglia in immunity (Yang et al., 2009), protective effects of microglia on co-cultured neurons (Park et al., 2001), modulators of microglial secretion of growth factors (Wang et al., 2009) and cytokines (Ye and Johnson, 1999; Chang, 2007), and the…”
Background
Iron Oxide as an Mri Contrast Agent for Cell Tracking: Supplementary Issue
Korchinski, D. J., Taha, M., Yang, R., Nathoo, N., & Dunn, J. F. (2015) · Magnetic Resonance Insights · doi:10.4137/mri.s23557 · Cited by 73 · see citing works
Neuroimmunomodulatory Properties of Flavonoids and Derivates: A Potential Action as Adjuvants for the Treatment of Glioblastoma
do Nascimento, R. P., dos Santos, B. L., Amparo, J. A. O., Soares, J. R. P., da Silva, K. C., de Santana, M. R., Almeida, Á. M. A. N., da Silva, V. D. A., Costa, M. D. F. D., Ulrich, H., et al. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14010116 · Cited by 71 · see citing works
Nitric oxide-mediated tumoricidal activity of murine microglial cells
Brantley, E. C., Guo, L., Zhang, C., Lin, Q., Yokoi, K., Langley, R. R., Kruzel, E., Maya, M., Kim, S. W., Kim, S.-J., et al. (2010) · Translational Oncology · doi:10.1593/tlo.10208 · Cited by 71 · see citing works
Human Leukocyte Antigen-G Is Frequently Expressed in Glioblastoma and May Be Induced in Vitro by Combined 5-Aza-2′-Deoxycytidine and Interferon-γ Treatments
Wastowski, I. J., Simões, R. T., Yaghi, L., Donadi, E. A., Pancoto, J. A. T., Poras, I., Lechapt, E., Bernaudin, M., Valable, S., Carlotti, C. G., et al. (2012) · American Journal Of Pathology · doi:10.1016/j.ajpath.2012.10.021 · Cited by 71 · see citing works
The role of STAT3 in tumor-mediated immune suppression
Ferguson, S. D., Srinivasan, V. M., & Heimberger, A. B. (2015) · Journal of Neuro-Oncology · doi:10.1007/s11060-015-1731-3 · Cited by 70 · see citing works
Glial Cell AMPA Receptors in Nervous System Health, Injury and Disease
Ceprián, M., & Fulton, D. J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20102450 · Cited by 70 · see citing works
“In addition, microglia express major histocompatibility complex (MHC) I and II molecules, particularly under pathological conditions including perinatal hypoxia, thus a role in the detection of pathological conditions and the stimulation of adaptive immune responses are ascribed to these cells [229].”
Background
The interrelationship between cerebral ischemic stroke and glioma: a comprehensive study of recent reports
Ghosh, M. K., Chakraborty, D., Sarkar, S., Bhowmik, A., & Basu, M. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0075-4 · Cited by 69 · see citing works
Inhibition of glioma progression by a newly discovered CD38 inhibitor
Blacher, E., Baruch, B. B., Levy, A., Geva, N., Green, K. D., Garneau‐Tsodikova, S., Fridman, M., & Stein, R. (2014) · International Journal of Cancer · doi:10.1002/ijc.29095 · Cited by 69 · see citing works
Down-regulation of IKKβ expression in glioma-infiltrating microglia/macrophages is associated with defective inflammatory/immune gene responses in glioblastoma
Mieczkowski, J., Kocyk, M., Nauman, P., Gabrusiewicz, K. R., Sielska, M., Przanowski, P., Maleszewska, M., Rajan, W. D., Pszczolkowska, D., Tykocki, T., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.5310 · Cited by 69 · see citing works
“Type and quality of immune responses in tumor microenvironment are predictive of patient outcome [1].”
Untangling senescent and damage‐associated microglia in the aging and diseased brain
Ng, P. Y., McNeely, T. L., & Baker, D. J. (2023) · The FEBS Journal · doi:10.1111/febs.16315 · Cited by 68 · see citing works
Astrocytes as a target for therapeutic strategies in epilepsy: current insights
Çarçak, N., Onat, F., & Sitnikova, E. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2023.1183775 · Cited by 69 · see citing works
“, 2020), brain tumors (Yang et al., 2010; Saijo and Glass, 2011), tuberous sclerosis complex (Wong, 2019), encephalopathy (Hamid et al.”
Background
Insights into the glioblastoma tumor microenvironment: current and emerging therapeutic approaches
Tripathy, D. K., Panda, L. P., Biswal, S., & Barhwal, K. K. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1355242 · Cited by 71 · see citing works
Recent advances in the role of toll-like receptors and TLR agonists in immunotherapy for human glioma
Deng, S., Zhu, S., Qiao, Y., Liu, Y., Chen, W., Zhao, G., & Chen, J. (2014) · Protein & Cell · doi:10.1007/s13238-014-0112-6 · Cited by 67 · see citing works
“Furthermore, regarding DCs in vaccines, the most important APCs are artificially derived in an in vitro environment to enhance contact between the cells and the antigens.”
BackgroundInfluential
Resistance Mechanisms and Barriers to Successful Immunotherapy for Treating Glioblastoma
Adhikaree, J., Moreno-Vicente, J., Kaur, A. P., Jackson, A. M., & Patel, P. M. (2020) · Cells · doi:10.3390/cells9020263 · Cited by 66 · see citing works
“Microglia release chemoattractants (monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1) when associated with glioma cells promoting further microglial/monocyte recruitment from the peripheral blood and, in combination with the cytokine milieu (IL-10, TGF-β and IL-6), promote further immun…”
Background
Role of microglia in fungal infections of the central nervous system
Koutsouras, G. W., Ramos, R. L., & Martinez, L. R. (2016) · Virulence · doi:10.1080/21505594.2016.1261789 · Cited by 64 · see citing works
“cells is continuously being maintained from the periphery, while self-replication characteristics of parenchymal microglia safeguard their maintenance.(11,12,24) In pathological conditions, microglia and perivascular macrophages release chemokines that regulate the”
Background
A 2B adenosine receptors stimulate IL-6 production in primary murine microglia through p38 MAPK kinase pathway
Merighi, S., Bencivenni, S., Vincenzi, F., Varani, K., Borea, P. A., & Gessi, S. (2016) · Pharmacological Research · doi:10.1016/j.phrs.2016.11.024 · Cited by 65 · see citing works
“4 Discussion Microglia represent a significant fraction of the CNS cells, including 5% to 20% of the total glial population, and are as numerous as neurons [29].”
Background
Monocytes, microglia, and CD 200‐ CD 200R1 signaling are essential in the transmission of inflammation from the periphery to the central nervous system
Xie, X., Luo, X., Liu, N., Li, X., Lou, F., Zheng, Y., & Ren, Y. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.13972 · Cited by 64 · see citing works
“These data strongly suggest the involvement of peripheral immunity dysfunction in the development of PD. Microglia, as the surveillance cell of the CNS, plays a crucial role in regulating brain microenvironment (Yang et al. 2010).”
BackgroundInfluential
Propentofylline decreases tumor growth in a rodent model of glioblastoma multiforme by a direct mechanism on microglia
Jacobs, V. L., Landry, R. P., Liu, Y., Romero-Sandoval, E. A., & Leo, J. A. D. (2011) · Neuro-Oncology · doi:10.1093/neuonc/nor194 · Cited by 63 · see citing works
“Once thought to play an antitumor role against established tumors, microglia (central nervous system [CNS] cells of monocytic lineage) are now known to contribute to GBM’s progression and growth.(8) Microglia and macrophages are highly abundant in GBM, compared with normal brain, and provide 10%–34% of the tumor mass.”
Background
Extracellular Membrane Vesicles and Immune Regulation in the Brain
Cossetti, C., Smith, J. A., Iraci, N., Leonardi, T., Alfaro‐Cervelló, C., & Pluchino, S. (2012) · Frontiers in Physiology · doi:10.3389/fphys.2012.00117 · Cited by 61 · see citing works
“Once they have been presented with antigens, T cells fulfill a variety of effector functions including pro-inflammatory recruitment, formation of immunological memories, and secretion of cytotoxic molecules (Yang et al., 2010).”
Background
Current status of gene therapy for brain tumors
Murphy, A. M., & Rabkin, S. D. (2012) · Translational research · doi:10.1016/j.trsl.2012.11.003 · Cited by 62 · see citing works
A Zebrafish Live Imaging Model Reveals Differential Responses of Microglia Toward Glioblastoma Cells In Vivo
Hamilton, L., Astell, K. R., Velikova, G., & Sieger, D. (2016) · Zebrafish · doi:10.1089/zeb.2016.1339 · Cited by 61 · see citing works
“Strikingly, a comparable course of events is observed during glioma progression in the brain, where microglia and infiltrating macrophages are attracted to and colonize the tumor.(6,7,9,16,17) However, instead of antitumoral activity they display protumoral functions and promote tumor growth.”
Hypoxia and macrophages promote glioblastoma invasion by the CCL4-CCR5 axis
Wang, Y., Liu, T., Yang, N., Xu, S., Li, X., & Wang, D. (2016) · Oncology Reports · doi:10.3892/or.2016.5171 · Cited by 59 · see citing works
A New Hypothesis for Alzheimer’s Disease: The Lipid Invasion Model
Rudge, J. D. (2022) · Journal of Alzheimer's Disease Reports · doi:10.3233/adr-210299 · Cited by 58 · see citing works
“This central role is perhaps unsurprising, given that the “immune-privileged” status conferred on the brain compartment by the BBB leaves microglia as the primary immune cell [242, 243], a role not seen as a rule in macrophages in the rest of the body.”
Background
Advances in NK cell therapy for brain tumors
Fares, J., Davis, Z., Rechberger, J. S., Toll, S. A., Schwartz, J., Daniels, D. J., Miller, J. S., & Khatua, S. (2023) · npj Precision Oncology · doi:10.1038/s41698-023-00356-1 · Cited by 67 · see citing works
Opposite changes in cannabinoid CB1 and CB2 receptor expression in human gliomas
de Jesús, M. L., Hostalot, C., Garibi, J., Sallés, J., Meana, J. J., & Callado, L. F. (2010) · Neurochemistry International · doi:10.1016/j.neuint.2010.03.007 · Cited by 59 · see citing works
“chemoattractants and growth factors by glioma cells (Yang et al., 2010).”
Background
Phenotypic dynamics of microglial and monocyte-derived cells in glioblastoma-bearing mice
Ricard, C., Tchoghandjian, A., Luche, H., Grenot, P., Figarella-Branger, D. F., Rougon, G. N., Malissen, M., & Debarbieux, F. C. (2016) · Scientific Reports · doi:10.1038/srep26381 · Cited by 57 · see citing works
Ginsenoside Re exhibits neuroprotective effects by inhibiting neuroinflammation via CAMK/MAPK/NF‑κB signaling in microglia
Madhi, I., Kim, J.-H., Shin, J., & Kim, Y. (2021) · Molecular Medicine Reports · doi:10.3892/mmr.2021.12337 · Cited by 56 · see citing works
T-Cell Tolerance in Cancer
Nurieva, R., Wang, J., & Sahoo, A. (2013) · Immunotherapy · doi:10.2217/imt.13.33 · Cited by 56 · see citing works
Basic Concepts in Glioma Immunology
Parney, I. F. (2012) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-3146-6_4 · Cited by 56 · see citing works
CD38 deficiency in the tumor microenvironment attenuates glioma progression and modulates features of tumor-associated microglia/macrophages
Levy, A., Blacher, E., Vaknine, H., Lund, F. E., Stein, R., & Mayo, L. (2012) · Neuro-Oncology · doi:10.1093/neuonc/nos121 · Cited by 56 · see citing works
“Schartner,(1) Watters, Schartner, and Badie,(3) and Yang et al.(4)).”
Background

Research advances in the study of microglia and their immunological effects in the central nervous system and glioma
张倜, & 钱程 (2010) · Int J Immunol · doi:10.3760/cma.j.issn.1673-4394.2010.06.010
Microglia and Central Nervous System Immunity
Kaur, G., Han, S. J., Yang, I., & Crane, C. A. (2009) · Neurosurgery Clinics of North America · doi:10.1016/j.nec.2009.08.009 · Cited by 74 · see citing works
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Role of microglia in glioma biology
Badie, B., & Schartner, J. M. (2001) · Microscopy Research and Technique · doi:10.1002/jemt.1125 · Cited by 184 · see citing works
Immunomodulatory Effect of Microglia-Released Cytokines in Gliomas
Lanza, M., Casili, G., Campolo, M., Paterniti, I., Colarossi, C., Mare, M., Giuffrida, R., Caffo, M., Esposito, E., & Cuzzocrea, S. (2021) · Brain Sciences · doi:10.3390/brainsci11040466 · Cited by 47 · see citing works
Microglia in Gliomas: Friend or Foe?
Kaminska, B. (2014) · Springer eBooks · doi:10.1007/978-3-7091-1431-5_9 · Cited by 6 · see citing works

Authors: Yang, I., Han, S. J., Kaur, G., Crane, C., & Parsa, A. T.
Affiliations: University of California, San Francisco (US)
ORCID: Yang, Isaac
Han, Seunggu J.
Venue: Journal of Clinical Neuroscience
Publisher: Elsevier BV
Published: 2010-01
Volume: 17
Issue: 1
Pages: 6-10
ISSN: 0967-5868 (ISSN-L)
DOI: 10.1016/j.jocn.2009.05.006
PMC: PMC3786731
OpenAlex: W2161737261
Cited by: 410
References: 101
Citations by year: 2026: 13 · 2025: 21 · 2024: 26 · 2023: 33 · 2022: 41 · 2021: 26 · 2020: 23 · 2019: 24 · 2018: 15 · 2017: 19 · 2016: 22 · 2015: 23 · 2014: 23 · 2013: 27 · 2012: 27
FWCI: 1.92
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Journal of Clinical Neuroscience (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Cancer Institute (P50CA097257)
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords: microglia, central nervous system immunity, tumor microenvironment, immunosuppression, antigen presentation, T cell receptor, major histocompatibility complex, antigen-presenting cells, microglial activation, glioma immunotherapy, blood-brain barrier, immune privilege
MeSH terms: Animals, Brain Neoplasms, Cell Communication, Central Nervous System, Glioma, Humans, Immune Tolerance, Immunity, Innate, Immunologic Surveillance, Neuroimmunomodulation, Microglia, Adaptive Immunity

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The role of microglia in central nervous system immunity and glioma immunology

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