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The role of microglia in central nervous system immunity and glioma immunology
Open accessAbstract
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, 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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“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).”
BackgroundInfluentialNeonatal 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
“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…”
BackgroundIron 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 74
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 73
Nitric oxide-mediated tumoricidal activity of murine microglial cells
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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
The role of STAT3 in tumor-mediated immune suppression
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Glial Cell AMPA Receptors in Nervous System Health, Injury and Disease
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“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].”
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Inhibition of glioma progression by a newly discovered CD38 inhibitor
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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
“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
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 70
“, 2020), brain tumors (Yang et al., 2010; Saijo and Glass, 2011), tuberous sclerosis complex (Wong, 2019), encephalopathy (Hamid et al.”
BackgroundInsights 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 78
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 69
“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.”
BackgroundInfluentialResistance 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 68
“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…”
BackgroundRole 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
“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”
BackgroundMerighi, 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
“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].”
BackgroundXie, 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
“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).”
BackgroundInfluentialJacobs, 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
“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.”
BackgroundExtracellular 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
“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).”
BackgroundCurrent 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
Hamilton, L., Astell, K. R., Velikova, G., & Sieger, D. (2016) · Zebrafish · doi:10.1089/zeb.2016.1339 · Cited by 60
“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 64
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
“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.”
BackgroundAdvances 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
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
“chemoattractants and growth factors by glioma cells (Yang et al., 2010).”
BackgroundPhenotypic dynamics of microglial and monocyte-derived cells in glioblastoma-bearing mice
Ricard, C., Tchoghandjian, A., Luche, H., Grenot, P., Figarella‐Branger, D., Rougon, G., Malissen, M., & Debarbieux, F. C. (2016) · Scientific Reports · doi:10.1038/srep26381 · Cited by 57
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Nurieva, R., Wang, J., & Sahoo, A. (2013) · Immunotherapy · doi:10.2217/imt.13.33 · Cited by 62
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
Levy, A., Blacher, E., Vaknine, H., Lund, F. E., Stein, R., & Mayo, L. (2012) · Neuro-Oncology · doi:10.1093/neuonc/nos121 · Cited by 56
“Schartner,(1) Watters, Schartner, and Badie,(3) and Yang et al.(4)).”
Background
Metadata
- Authors
- Yang, I., Han, S. J., Kaur, G., Crane, C., & Parsa, A. T.
- Affiliations
- University of California, San Francisco (US)
- Venue
- Journal of Clinical Neuroscience
- Publisher
- Elsevier BV
- Published
- 2010-01
- Volume
- 17
- Issue
- 1
- Pages
- 6-10
- ISSN
- 0967-5868 (ISSN-L)
- 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
- 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 › Oncology › 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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