Role of microglia in CNS inflammation

Graeber, Manuel B.; Li, Wei; Rodriguez, Michael L.

doi:10.1016/j.febslet.2011.08.033

Cited by 392Neuroinflammation and Neurodegeneration MechanismsInflammasome and immune disordersTryptophan and brain disorders

Role of microglia in CNS inflammation

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Graeber, Manuel B., Li, Wei, Rodriguez, Michael L.·2011·FEBS Letters

DOI 10.1016/j.febslet.2011.08.033

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Abstract

There is increasing confusion about the meaning of the terms inflammation, neuroinflammation, and microglial inflammation. We aim in this review to achieve greater clarity regarding these terms, which are essential for our understanding of the role of microglia in CNS inflammatory conditions. The important concept of sterile inflammation is explained against the backdrop of classical inflammation, and its key differences from what researchers refer to when they use the terms neuroinflammation and microglial inflammation are illustrated. We propose to replace the term "neuroinflammation" with "microglial activation" or "CNS pseudo-inflammation", if microglial activation does not suffice. In addition, we recommend abandoning the terms "microglial inflammation" and "inflamed microglia" because of the lack of a clear concept behind them.

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Microglial activation impairs BBB function by the release of various molecules leading to a hyperpermeability condition associated with inflammation similar to what occurs in certain neurodegenerative disorders, including AD and MS.
“Considering all the studies mentioned above, microglial activation impairs BBB function by the release of various molecules leading to a hyperpermeability condition associated with inflammation that is similar to what occurs in certain neurodegenerative disorders, including AD and Multiple Sclerosis (MS).”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Graeber et al., 2011
Microglia certainly play an important role in inflammatory pathologies of the CNS.
“but undoubtedly microglia certainly play an important role in these pathologies (Perry et al., 2010; Graeber et al., 2011).”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Graeber et al., 2011

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Rübsam, A., Parikh, S., & Fort, P. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19040942 · Cited by 750 · see citing works
The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders
Réus, G. Z., Fries, G. R., Stertz, L., Badawy, M., Passos, I. C., Barichello, T., Kapczinski, F., & Quevedo, J. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.05.018 · Cited by 594 · see citing works
“Thus, only by determining the phenotype of microglia can one identify its role in cytotoxicity and/or neuroprotection (Colton and Wilcock, 2010; Graeber et al., 2011; Marshall et al., 2013).”
The impact of microglial activation on blood-brain barrier in brain diseases
da Fonseca, A. C. C., Matias, D., Garcia, C., Amaral, R., Geraldo, L. H., Freitas, C., & Lima, F. R. S. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00362 · Cited by 572 · see citing works
“We do not discard the entering and the action of bone marrow derived myeloid cells into the CNS in inflammatory conditions, but undoubtedly microglia certainly play an important role in these pathologies (Perry et al., 2010; Graeber et al., 2011).”
Background
Obesity-Induced Neuroinflammation: Beyond the Hypothalamus
Guillemot‐Legris, O., & Muccioli, G. G. (2017) · Trends in Neurosciences · doi:10.1016/j.tins.2017.02.005 · Cited by 565 · see citing works
Targeting the TLR4 signaling pathway by polyphenols: A novel therapeutic strategy for neuroinflammation
Rahimifard, M., Maqbool, F., Moeini-Nodeh, S., Niaz, K., Abdollahi, M., Braidy, N., Nabavi, S. M., & Nabavi, S. F. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.02.004 · Cited by 481 · see citing works
Advanced oxidation protein products induce microglia-mediated neuroinflammation via MAPKs-NF-κB signaling pathway and pyroptosis after secondary spinal cord injury
Liu, Z., Yao, X., Jiang, W., Li, W., Zhu, S., Liao, C., Zou, L., Ding, R., & Chen, J. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01751-2 · Cited by 430 · see citing works
“Microglia are major innate immune cells of the central nervous system (CNS) and play a prominent role in neuroinflammation [4].”
The Role of Microglia in Diabetic Retinopathy: Inflammation, Microvasculature Defects and Neurodegeneration
Altmann, C., & Schmidt, M. H. H. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19010110 · Cited by 410 · see citing works
“However, in vivo, microglia had an intermediates phenotype [104,107], suggesting that the distinction between M1 and M2 microglia is hazy and that microglia can adapt their phenotype to meet demands [3,108].”
Background
Diabetic Macular Edema Pathophysiology: Vasogenic versus Inflammatory
Romero‐Aroca, P., Baget‐Bernaldiz, M., Ríos, A., López-Gálvez, M., Navarro-Gil, R., & Verges, R. (2016) · Journal of Diabetes Research · doi:10.1155/2016/2156273 · Cited by 405 · see citing works
“[38] observed, in a murine diabetic model, that, in the case of diabetes, the number of holes in epithelium pigment retina layer (EPR) increased in order to permit the transport of more inflammatory cellules to the choroid space; they also observed an increase of ICAM-1 and caviling-1 (CAV-1), both which are implicate…”
Background
Cell-to-cell Communication by Extracellular Vesicles: Focus on Microglia
Paolicelli, R. C., Bergamini, G., & Rajendran, L. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2018.04.003 · Cited by 599 · see citing works
Microglia express distinct M1 and M2 phenotypic markers in the postnatal and adult central nervous system in male and female mice
Crain, J. M., Nikodémová, M., & Watters, J. J. (2013) · Journal of Neuroscience Research · doi:10.1002/jnr.23242 · Cited by 335 · see citing works
“At the same time, they increase their production of a wide array of chemokines, cytokines, nitric oxide, and reactive oxygen species that mediate neuroinflammation (Hoek et al., 2000; Streit et al., 2005; Graeber et al., 2011).”
Chronic Stress Induced Remodeling of the Prefrontal Cortex: Structural Re-Organization of Microglia and the Inhibitory Effect of Minocycline
Hinwood, M., Tynan, R. J., Charnley, J. L., Beynon, S. B., Day, T. A., & Walker, F. R. (2012) · Cerebral Cortex · doi:10.1093/cercor/bhs151 · Cited by 325 · see citing works
“With respect to signals driving the stress-induced secondary hyper-ramification, we have again confirmed that chronic stress, using the repeated restraint paradigm, does not induce any measurable alterations in proteins associated with inflammation or neurodegeneration (Mattsson et al. 2006; Graeber et al. 2011).”
Background
Myeloid microvesicles are a marker and therapeutic target for neuroinflammation
Verderio, C., Muzio, L., Turola, E., Bergami, A., Novellino, L., Ruffini, F., Riganti, L., Corradini, I., Francolini, M., Garzetti, L., et al. (2012) · Annals of Neurology · doi:10.1002/ana.23627
Cholinergic modulation of the immune system presents new approaches for treating inflammation
Hoover, D. B. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.05.002 · Cited by 301 · see citing works
“While some of these disorders do not involve inflammation in the classical sense (Graeber et al., 2011), there is the common thread that microglial activation to theM1 phenotype contributes to pathology (Graeber et al.”
BackgroundInfluential
Diabetic Macular Edema: Current Understanding, Molecular Mechanisms and Therapeutic Implications
Zhang, J., Zhang, J., Zhang, J., Zhang, J., Gu, L., Luo, D., & Qiu, Q. (2022) · Cells · doi:10.3390/cells11213362 · Cited by 320 · see citing works
“model [73], which facilitated the migration of the inflammatory cells.”
Background
Cytokines in CAR T Cell–Associated Neurotoxicity
Gust, J., Ponce, R. A., Liles, W. C., Garden, G. A., & Turtle, C. J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.577027 · Cited by 268 · see citing works
“Here, there is evidence a protective role in a brain that has been injured by primary degenerative processes, but also the possibility of additional injury via an accelerated inflammatory response (186).”
Background
Aquaporin 4: a player in cerebral edema and neuroinflammation
Fukuda, A. M., & Badaut, J. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-279 · Cited by 265 · see citing works
Ibrutinib suppresses LPS-induced neuroinflammatory responses in BV2 microglial cells and wild-type mice
Nam, H. Y., Nam, J. H., Yoon, G., Lee, J., Nam, Y., Kang, H., Cho, H.-J., Kim, J., & Hoe, H. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1308-0 · Cited by 268 · see citing works
Review: Neuroinflammatory pathways as treatment targets and biomarker candidates in epilepsy: emerging evidence from preclinical and clinical studies
van Vliet, E. A., Aronica, E., Vezzani, A., & Ravizza, T. (2017) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12444 · Cited by 260 · see citing works
Neuroprotection by dihydrotestosterone in LPS-induced neuroinflammation
Yang, L., Zhou, R., Tong, Y., Chen, P., Shen, Y., Miao, S., & Liu, X. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104814 · Cited by 249 · see citing works
“Activated microglia lead to neuroinflammatory responses, neuronal damage and cognitive dysfunction (Graeber et al., 2011; Liu and Hong, 2003).”
Noninvasive Molecular Imaging of Neuroinflammation
Jacobs, A. H., Tavitian, B., & the INMiND consortium (2012) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2012.53 · Cited by 245 · see citing works
“…by (1) changes in local vasculature (increased blood flow and vascular permeability), (2) activation of resident immune competent cells, (3) infiltration of mobile cells of the immune system (neutrophils, macrophages, and lymphocytes), and (4) cytokine production (Graeber et al, 2011).”
BackgroundInfluential
Microglial activation is not equivalent to neuroinflammation in alcohol-induced neurodegeneration: The importance of microglia phenotype
Marshall, S. A., McClain, J. A., Kelso, M. L., Hopkins, D. M., Pauly, J. R., & Nixon, K. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.12.016 · Cited by 243 · see citing works
“Furthermore, although fully activated microglia are one component of classical inflammation, observation of “activated” microglia alone is not equivalent to nor very informative about the inflammation state (Graeber et al., 2011).”
Microglia: A new frontier for synaptic plasticity, learning and memory, and neurodegenerative disease research
Morris, G. P., Clark, I. A., Zinn, R., & Vissel, B. (2013) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2013.07.002 · Cited by 236 · see citing works
Immune System Dysfunction in the Elderly
Eduardo Fuentes, Q., FUENTES, M., Alarcón, M. A., & Palomo, I. F. (2017) · Anais da Academia Brasileira de Ciências · doi:10.1590/0001-3765201720160487 · Cited by 234 · see citing works
The Role of GPNMB in Inflammation
Saade, M., Araujo de Souza, G., Scavone, C., & Kinoshita, P. F. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.674739 · Cited by 216 · see citing works
“Besides the brain region, GPNMB is mostly expressed by microglial cells, which are resident brain cells most responsible for mediating inflammatory stimuli and maintaining cerebral homeostasis by phagocytosis, tissue repair, and cytokine release (68).”
Background
An Overview of in vitro Methods to Study Microglia
Timmerman, R., Burm, S. M., & Bajramovic, J. J. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00242 · Cited by 222 · see citing works
“Activation of microglia is characterized by an amoeboid morphology, by the production of cytotoxic molecules and pro-inflammatory cytokines, and by the increased expression of complement receptors and histocompatibility complex molecules (Graeber et al., 2011).”
Background
Alzheimer’s disease as an inflammatory disease
Bolós, M., Perea, J. R., & Avila, J. (2017) · BioMolecular Concepts · doi:10.1515/bmc-2016-0029 · Cited by 216 · see citing works
Microglial Activation – Tuning and Pruning Adult Neurogenesis
Ekdahl, C. T. (2012) · Frontiers in Pharmacology · doi:10.3389/fphar.2012.00041 · Cited by 211 · see citing works
“The diversity is reflected by numerous reports describing both beneficial and detrimental effects on neurogenesis, primarily on the proliferation, survival, and cell fate.”
Background
The gut microbiome regulates the increases in depressive-type behaviors and in inflammatory processes in the ventral hippocampus of stress vulnerable rats
Pearson-Leary, J., Zhao, C., Bittinger, K., Eacret, D., Luz, S., Vigderman, A. S., Dayanim, G., & Bhatnagar, S. (2020) · Molecular Psychiatry · doi:10.1038/s41380-019-0380-x · Cited by 206 · see citing works
Vagus nerve stimulation in brain diseases: Therapeutic applications and biological mechanisms
Wang, Y., Zhan, G., Cai, Z., Jiao, B., Zhao, Y., Li, S., & Luo, A. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.04.018 · Cited by 207 · see citing works
Inflammation in Parkinson's Disease
Tüfekçi, K. U., Meuwissen, R. L. J., Genç, Ş., & Genç, K. (2012) · Advances in protein chemistry and structural biology · doi:10.1016/b978-0-12-398314-5.00004-0 · Cited by 199 · see citing works
Targeting microglial autophagic degradation in NLRP3 inflammasome-mediated neurodegenerative diseases
Wu, A., Zhou, X., Qiao, G., Yu, L., Tang, Y., Yan, L., Qiu, W., Pan, R., Yu, C., Law, B. Y. K., et al. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101202 · Cited by 193 · see citing works
Excitotoxicity, neuroinflammation and oxidant stress as molecular bases of epileptogenesis and epilepsy-derived neurodegeneration: The role of vitamin E
Ambrogini, P., Torquato, P., Bartolini, D., Albertini, M. C., Lattanzi, D., Palma, M. D., Marinelli, R., Betti, M., Minelli, A., Cuppini, R., et al. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2019.01.026 · Cited by 186 · see citing works
“The interaction between the innate immune system and injured brain tissue is known as neuroinflammation, a complex process that involves the release of inflammatory molecules mainly by microglia and astrocytes [77].”
Background
Microglia regulate synaptic development and plasticity
Andoh, M., & Koyama, R. (2021) · Developmental Neurobiology · doi:10.1002/dneu.22814 · Cited by 188 · see citing works
“…by microglia [Color figure can be viewed at wileyonlinelibrary.com] 580 | ANDOH AND KOYAMA inflammation, but increased expression of inflammatory molecules alone should not be considered inflammation in itself if the inflammatory response is not verified (Graeber et al., 2011; Ransohoff, 2016).”
Background
Proteases and glycosidases on the surface of exosomes: Newly discovered mechanisms for extracellular remodeling
Sanderson, R. D., Bandari, S., & Vlodavsky, I. (2017) · Matrix Biology · doi:10.1016/j.matbio.2017.10.007 · Cited by 179 · see citing works
“facilitated mechanism of neurotrophin regulation is potentially of great importance as microglia are known to be involved in maintenance of brain cells and in development of neurological diseases including Alzheimer’s and multiple sclerosis [36].”
Circadian and sleep dysfunction in Alzheimer’s disease
Uddin, M. S., Tewari, D., Mamun, A. A., Kabir, M. T., Niaz, K., Wahed, M. I. I., Barreto, G. E., & Ashraf, G. M. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101046 · Cited by 180 · see citing works
Alzheimer's Disease Puzzle: Delving into Pathogenesis Hypotheses
(2024) · aging and disease · doi:10.14336/ad.2023.0608 · Cited by 183 · see citing works
“Microglia possesses a chief role in inflammatory responses, in addition to promoting synaptic plasticity, energy metabolism, and ion homeostasis [57].”
Background
Glial influences on BBB functions and molecular players in immune cell trafficking
Lécuyer, M., Kébir, H., & Prat, A. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.10.004 · Cited by 163 · see citing works
Journal of Clinical & Cellular Immunology
Abcouwer, S. F. (2019) · Journal of Clinical & Cellular Immunology · doi:10.4172/2155-9899 · Cited by 162 · see citing works
“It has been proposed that neuroinflammation should simply be described as “microglial activation,” or perhaps as neural “pseudo-inflammation” because astrocytes, as well as microglia, become activated and produce inflammatory mediators [167].”
Background
Amyotrophic lateral sclerosis: a long preclinical period?
Eisen, A., Kiernan, M. C., Mitsumoto, H., & Swash, M. (2014) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2013-307135 · Cited by 163 · see citing works
Mast Cells and Neuroinflammation
Dong, H., Zhang, X., & Qian, Y. (2014) · Medical science monitor basic research/Medical science monitor. Basic research · doi:10.12659/msmbr.893093 · Cited by 161 · see citing works
“In acute neuroinflammation, microglia become reactive and limit the area of injury through phagocytosing dying cells and releasing pro-inflammatory cytokines [1].”
Background
Viral infection, inflammation and schizophrenia
Kneeland, R. E., & Fatemi, S. H. (2013) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2012.02.001 · Cited by 152 · see citing works
Schizophrenia and inflammation research: a bibliometric analysis
Sun, H.-L., Bai, W., Li, X.-H., Huang, H., Cui, X.-L., Cheung, T., Su, Z.-H., Yuan, Z., Ng, C. H., & Xiang, Y.-T. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.907851 · Cited by 148 · see citing works
“Neuroinflammation, an innate activation response to an inflammatory stimulus, was often used in connection with microglia (65).”
Method
Stress-induced neuroinflammatory priming: A liability factor in the etiology of psychiatric disorders
Frank, M. G., Weber, M. D., Watkins, L. R., & Maier, S. F. (2015) · Neurobiology of Stress · doi:10.1016/j.ynstr.2015.12.004 · Cited by 148 · see citing works
“When elaborated under a variety of neuropathological conditions, including neurodegeneration, brain trauma, ischemia and seizure, thesemediators induce the hallmarks of neuroinflammation, which may include recruitment of peripheral leukocytes into the CNS (Graeber et al., 2011).”
Decreased glial reactivity could be involved in the antipsychotic-like effect of cannabidiol
Gomes, F. V., Llorente, R., Del Bel, E. A., Viveros, M.-P., López-Gallardo, M., & Guimarães, F. S. (2015) · Schizophrenia Research · doi:10.1016/j.schres.2015.01.015 · Cited by 147 · see citing works
“Microglia and astrocytes are the major immune cells in the central nervous system (CNS), regulating the induction as well as the limitation of inflammatory processes (Sofroniew and Vinters, 2010; Graeber et al., 2011).”
Background
Microglial priming of antigen presentation and adaptive stimulation in Alzheimer’s disease
Das, R., & Chinnathambi, S. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03132-2 · Cited by 147 · see citing works
Nutritional n-3 PUFAs deficiency during perinatal periods alters brain innate immune system and neuronal plasticity-associated genes
Madore, C., Nadjar, A., Delpech, J.-C., Séré, A., Aubert, A., Portal, C., Joffre, C., & Layé, S. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2014.03.021 · Cited by 144 · see citing works
The central role of aquaporins in the pathophysiology of ischemic stroke
Vella, J. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00108 · Cited by 143 · see citing works
Regulation of inflammatory responses by neuregulin-1 in brain ischemia and microglial cells in vitro involves the NF-kappa B pathway
Simmons, L. J., Surles-Zeigler, M. C., Li, Y., Ford, G. D., Newman, G. W., & Ford, B. D. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0703-7 · Cited by 144 · see citing works
“Activated microglia release inflammatory mediators such as reactive oxygen species (ROS), nitric oxide (NO), tumor necrosis factor α (TNF-α), and interleukin-1β (IL1β) [17–19].”
Background
Cannabidiol reduces neuroinflammation and promotes neuroplasticity and functional recovery after brain ischemia
Mori, M., Meyer, E., Soares, L. M., Milani, H., Guimarães, F. S., & de Oliveira, R. M. W. (2016) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2016.11.005 · Cited by 144 · see citing works
“Moreover, a large proportion of microglial cells undergo phenotypic transformation and present a reactive phenotype, indicating that these cells actively produce inflammatory cytokines, which may lead to neuronal apoptosis (Graeber et al., 2011).”
Oxidative and Nitrosative Stress and Immune-inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS)
Morris, G., & Maes, M. H. J. (2014) · Current Neuropharmacology · doi:10.2174/1570159x11666131120224653 · Cited by 139 · see citing works
“For a more detailed description of the processes and players involved in the generation of neuroinflammation the reader is referred to [161].”
Background
The importance of glial cells in the homeostasis of the retinal microenvironment and their pivotal role in the course of diabetic retinopathy
Sorrentino, F. S., Allkabes, M., Salsini, G., Bonifazzi, C., & Perri, P. (2016) · Life Sciences · doi:10.1016/j.lfs.2016.08.001 · Cited by 143 · see citing works
“As Graeber and coauthors claimed, microglial activation is the main mechanism by which neuroinflammation is induced in response to nervous tissue perturbations [14].”
Alzheimer's Disease: The Role of Microglia in Brain Homeostasis and Proteopathy
Clayton, K. A., Enoo, A. A. V., & Ikezu, T. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00680 · Cited by 132 · see citing works
“Microglia modulate the stress response to a variety of pathological triggers in CNS diseases reviewed extensively by Streit and Graeber et al. (Streit et al., 2004; Graeber et al., 2011).”
Background
Neuroinflammation mediates noise-induced synaptic imbalance and tinnitus in rodent models
Wang, W., Zhang, L. S., Zinsmaier, A. K., Patterson, G., Leptich, E. J., Shoemaker, S. L., Yatskievych, T. A., Gibboni, R., Pace, E., Luo, H., et al. (2019) · PLoS Biology · doi:10.1371/journal.pbio.3000307 · Cited by 134 · see citing works
“Neuroinflammation is the central nervous system’s response to external and internal insults, such as infection, injury, diseases, and abnormal neural activity [22].”
BackgroundResult
MicroRNA let-7 and viral infections: focus on mechanisms of action
Letafati, A., Najafi, S., Mottahedi, M., Karimzadeh, M., Shahini, A., Garousi, S., Abbasi‐Kolli, M., Nahand, J. S., Zadeh, S. S. T., Hamblin, M. R., et al. (2022) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-022-00317-9 · Cited by 134 · see citing works
“Microglia are specific types of macrophages with a mesodermal/mesenchymal origin generally located in the CNS, and are critical mediators of inflammation within the CNS (neuroinflammation) [265].”
Background
Minocycline prevents retinal inflammation and vascular permeability following ischemia-reperfusion injury
Abcouwer, S. F., Lin, C., Shanmugam, S., Muthusamy, A., Barber, A. J., & Antonetti, D. A. (2013) · Journal of Neuroinflammation · doi:10.1186/1742-2094-10-149 · Cited by 130 · see citing works
Modulation of neuronal excitability by immune mediators in epilepsy
Iori, V., Frigerio, F., & Vezzani, A. (2015) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2015.11.002 · Cited by 130 · see citing works
“This phenomenon, often defined as neuroinflammation [14], raised the key question of the pathophysiological role that these molecules may play in epilepsy.”
The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes
Betlazar, C., Middleton, R. J., Banati, R. B., & Liu, G. J. (2020) · Cells · doi:10.3390/cells9020512 · Cited by 131 · see citing works
Phagocytosis of full-length Tau oligomers by Actin-remodeling of activated microglia
Das, R. R., Balmik, A. A., & Chinnathambi, S. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1694-y · Cited by 129 · see citing works
Microglia in Aging and Alzheimer’s Disease: A Comparative Species Review
Edler, M. K., Mhatre-Winters, I., & Richardson, J. R. (2021) · Cells · doi:10.3390/cells10051138 · Cited by 126 · see citing works
“Levels of iNOS and 3-nitrotyrosine produced by microglia increased with age in the subcortical white matter of rhesus monkeys [76].”
BackgroundInfluential
Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods
VanElzakker, M. B., Brumfield, S. A., & Mejia, P. S. L. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2018.01033 · Cited by 125 · see citing works
Neuroinflammatory Signals in Alzheimer Disease and APP/PS1 Transgenic Mice
López‐González, I., Schlüter, A., Aso, E., Garcia‐Esparcia, P., Ansoleaga, B., Llorens, F., Carmona, M., Moreno, J. R., Fuso, A., Portero‐Otín, M., et al. (2015) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0000000000000176 · Cited by 125 · see citing works
“In contrast to sAD, human AA40 and AA42 levels are increased in APP/ PS1 mice aged 3 months when compared with WT animals, in which no human AA can be evidenced, and the expression of human AA40 and AA42 is markedly increased in APP/PS1 mice aged 6 and 12 months (48).”
Background
Review on pharmacological effects of gastrodin
Xiao, G., Tang, R., Yang, N., & Chen, Y. (2023) · Archives of Pharmacal Research · doi:10.1007/s12272-023-01463-0 · Cited by 125 · see citing works
Multifaces of neuropeptide Y in the brain – Neuroprotection, neurogenesis and neuroinflammation
Malva, J. O., Xapelli, S., Baptista, S., Valero, J., Agasse, F., Ferreira, R., & Silva, A. P. (2012) · Neuropeptides · doi:10.1016/j.npep.2012.09.001 · Cited by 123 · see citing works
A critical review of Astragalus polysaccharides: From therapeutic mechanisms to pharmaceutics
Du, Y., Wan, H., Huang, P. C., Yang, J., & He, Y. T. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.112654 · Cited by 117 · see citing works
MAPK and NF-κB pathways are involved in bisphenol A-induced TNF-α and IL-6 production in BV2 microglial cells
Zhu, J., Jiang, L., Liu, Y., Qian, W., Liu, J., Zhou, J., Gao, R., Xiao, H., & Wang, J. (2015) · Inflammation · doi:10.1007/s10753-014-9971-5 · Cited by 122 · see citing works
“Microglial cells (MG), the local macrophage-like residential cells in the brain, have been proposed to perform critical roles in the innate immune response of the central nervous system [19, 20].”
Background
Schisandrin B exerts anti-neuroinflammatory activity by inhibiting the Toll-like receptor 4-dependent MyD88/IKK/NF-κB signaling pathway in lipopolysaccharide-induced microglia
Zeng, K.-W., Zhang, T., Fu, H., Liu, G.-X., & Wang, X.-M. (2012) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2012.05.030 · Cited by 116 · see citing works
Circadian Rhythm and Alzheimer’s Disease
Homolak, J., Mudrovčić, M., Vukić, B., & Toljan, K. (2018) · Medical Sciences · doi:10.3390/medsci6030052 · Cited by 115 · see citing works
“Microglial cells are considered to be the key players in brain inflammatory processes in many diseases [69,70].”
Background
Tricyclodecan-9-yl-Xanthogenate (D609) Mechanism of Actions: A Mini-Review of Literature
Rao, A. M., Hatcher, J. F., & Gusain, A. (2011) · Neurochemical Research · doi:10.1007/s11064-011-0659-z · Cited by 110 · see citing works
PET radiotracers for molecular imaging in the brain: Past, present and future
Zimmer, L., & Luxen, A. (2011) · NeuroImage · doi:10.1016/j.neuroimage.2011.12.037 · Cited by 107 · see citing works
“tivation of microglial cells (Graeber et al., 2011) accompanied by expression of the peripheral benzodiazepine receptor (PBR), also known as the 18 kDa-translocator protein (TSPO) (Venneti et al.”
HSP60 critically regulates endogenous IL-1β production in activated microglia by stimulating NLRP3 inflammasome pathway
Swaroop, S., Mahadevan, A., Shankar, S. K., Adlakha, Y. K., & Basu, A. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1214-5 · Cited by 107 · see citing works
“the defense cells of the CNS, play a major role in neuroinflammation [5].”
Genetic and Transcriptomic Profiles of Inflammation in Neurodegenerative Diseases: Alzheimer, Parkinson, Creutzfeldt-Jakob and Tauopathies
López González, I., Garcia-Esparcia, P., Llorens, F., & Ferrer, I. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17020206 · Cited by 101 · see citing works
“Inflammation, as defined by microglial activation, and accompanied by astrocyte responses, together with increased expression of cytokines and mediators of the immune system in the brain and cerebrospinal fluid (CSF), is constant in all these neurodegenerative diseases and has been described in many studies and review…”
Result
Recombinant Adiponectin Peptide Ameliorates Brain Injury Following Intracerebral Hemorrhage by Suppressing Astrocyte-Derived Inflammation via the Inhibition of Drp1-Mediated Mitochondrial Fission
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“A hallmark of neuroinflammation is the activation of glial cells [8, 9].”
Background
Alcohol and adult hippocampal neurogenesis: Promiscuous drug, wanton effects
Geil, C., Hayes, D. M., McClain, J. A., Liput, D. J., Marshall, S. A., Chen, K. Y., & Nixon, K. (2014) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2014.05.003 · Cited by 104 · see citing works
Rapid Trimming of Cell Surface Polysialic Acid (PolySia) by Exovesicular Sialidase Triggers Release of Preexisting Surface Neurotrophin
Sumida, M., Hane, M., Yabe, U., Shimoda, Y., Pearce, O. M. T., Kiso, M., Miyagi, T., Sawada, M., Varki, A. P., Kitajima, K., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.638759 · Cited by 102 · see citing works
“In addition, microglia are involved in the development of neurological diseases, such as Alzheimer disease and multiple sclerosis (54).”
Background
Microglia-targeting nanotherapeutics for neurodegenerative diseases
Zhao, N., Francis, N. L., Calvelli, H. R., & Moghe, P. V. (2020) · APL Bioengineering · doi:10.1063/5.0013178 · Cited by 104 · see citing works
C/EBPβ: The structure, regulation, and its roles in inflammation-related diseases
Ren, Q., Liu, Z., Wu, L., Yin, G., Xie, X., Kong, W., Zhou, J., & Liu, S. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115938 · Cited by 104 · see citing works
Targeting connexin 43 provides anti-inflammatory effects after intracerebral hemorrhage injury by regulating YAP signaling
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The roles of blood-derived macrophages and resident microglia in the neuroinflammatory response to implanted Intracortical microelectrodes
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VISTA expression by microglia decreases during inflammation and is differentially regulated in CNS diseases
Borggrewe, M., Grit, C., Den Dunnen, W. F. A., Burm, S. M., Bajramovic, J. J., Noelle, R. J., Eggen, B. J. L., & Laman, J. D. (2018) · Glia · doi:10.1002/glia.23517 · Cited by 91 · see citing works
Microglia mediate diesel exhaust particle-induced cerebellar neuronal toxicity through neuroinflammatory mechanisms
Roqué, P. J., Dao, K., & Costa, L. G. (2016) · NeuroToxicology · doi:10.1016/j.neuro.2016.08.006 · Cited by 93 · see citing works
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript neurodevelopmental and neurodegenerative disorders (Koutsilieri et al., 2002; Kraft and Harry, 2011; Graeber et al., 2011).”
Background
Propofol Attenuates Inflammatory Response in LPS-Activated Microglia by Regulating the miR-155/SOCS1 Pathway
Zheng, X., Huang, H., Liu, J., Li, M., Liu, M., & Luo, T. (2017) · Inflammation · doi:10.1007/s10753-017-0658-6 · Cited by 92 · see citing works
Sesquiterpene dimer (DSF-52) from Artemisia argyi inhibits microglia-mediated neuroinflammation via suppression of NF-κB, JNK/p38 MAPKs and Jak2/Stat3 signaling pathways
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Sesquiterpenes from Essential Oils and Anti-Inflammatory Activity
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“Neuroinflammation is a condition believed to cause brain damage in various neurodegenerative disorders as a result of over-activation of microglia, an innate immune cell found in the central nervous system [69].”
Background
Rho kinase inhibitor fasudil regulates microglia polarization and function
Zhang, H., Li, Y., Yu, J., Guo, M., Meng, J., Liu, C., Xie, Y., Feng, L., Xiao, B., & Ma, C. (2013) · Neuroimmunomodulation · doi:10.1159/000351221 · Cited by 90 · see citing works
The activation of μ‐opioid receptor potentiates LPS‐induced NF‐kB promoting an inflammatory phenotype in microglia
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Human and mouse neuroinflammation markers in Niemann‐Pick disease, type C1
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“Within the CNS, the innate immune system of microglia, astrocytes and perivascular macrophages serve as a first line of defense (Graeber et al 2011; Veerhuis et al 2011).”
Background
Human CNS immune senescence and neurodegeneration
Streit, W. J., & Xue, Q.-S. (2014) · Current Opinion in Immunology · doi:10.1016/j.coi.2014.05.005 · Cited by 86 · see citing works
Anti-neuroinflammatory effects of grossamide from hemp seed via suppression of TLR-4-mediated NF-κB signaling pathways in lipopolysaccharide-stimulated BV2 microglia cells
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Hypothalamic lipid‐laden astrocytes induce microglia migration and activation
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Japanese Encephalitis Virus‐induced let‐7a/b interacted with the NOTCH ‐ TLR 7 pathway in microglia and facilitated neuronal death via caspase activation
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“Neuroinflammation is defined as an “innate immunological response of the nervous system, involving its own immune cells (microglia, astrocytes), releasing cytokines and chemokines, thus activating down-stream inflammatory effector molecules, and related molecular processes” (Graeber et al., 2011).”
Naringenin Produces Neuroprotection Against LPS-Induced Dopamine Neurotoxicity via the Inhibition of Microglial NLRP3 Inflammasome Activation
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“Upon the introduction of stimuli, such as brain injury, inflammation and pathogens, microglia became activated and released a large number of neurotoxic factors, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL18, and then these factors would work in concert to trigger neurodegeneration (3).”
Background
Opposing effects of apoE2 and apoE4 on microglial activation and lipid metabolism in response to demyelination
Wang, N., Wang, M., Jeevaratnam, S., Rosenberg, C., Ikezu, T. C., Shue, F., Doss, S. V., Alnobani, A., Martens, Y. A., Wren, M., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00577-1 · Cited by 82 · see citing works
Arsenic trioxide mediates HAPI microglia inflammatory response and subsequent neuron apoptosis through p38/JNK MAPK/STAT3 pathway
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Corrigendum: Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods
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Anti‐neuroinflammatory effects of tannic acid against lipopolysaccharide‐induced BV2 microglial cells via inhibition of NF‐κB activation
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Glia-Driven Neuroinflammation and Systemic Inflammation in Alzheimer’s Disease
Hashioka, S., Wu, Z., & Klegeris, A. (2021) · Current Neuropharmacology · doi:10.2174/1570159x18666201111104509 · Cited by 78 · see citing works
“An alternative view of microglia in AD was that these cells merely alter their phenotype in response to neuronal loss without actively contributing to the disease pathology [8].”
Background
Regulation of neuropeptide Y in body microenvironments and its potential application in therapies: a review
Zhang, Y., Liu, C.-Y., Chen, W.-C., Shi, Y., Wang, C., Lin, S., & He, H. (2021) · Cell & Bioscience · doi:10.1186/s13578-021-00657-7 · Cited by 80 · see citing works
Redox Signaling, Neuroinflammation, and Neurodegeneration
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Volume of the hippocampal subfields in healthy adults: differential associations with age and a pro-inflammatory genetic variant
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“Because of their involvement in plasticity, synaptic pruning, and neurogenesis (Arisi 2014; Graeber et al. 2011; Huang and Sheng 2010; Yirmiya and Goshen 2011), it is premature to infer what aspect of IL-1b is central to the influence on hippocampal volume observed in this cross-sectional study.”

Authors: Graeber, M. B., Li, W., & Rodriguez, M. L.
Affiliations: The University of Sydney (AU)
Sydney Local Health District (AU)
Corresponding author: Graeber, Manuel B.
ORCID: Rodriguez, Michael L.
Venue: FEBS Letters
Publisher: Wiley
Published: 2011-08-30
Volume: 585
Issue: 23
Pages: 3798-3805
ISSN: 0014-5793 (ISSN-L)
1873-3468
DOI: 10.1016/j.febslet.2011.08.033
OpenAlex: W2040423913
Cited by: 392
References: 67
Citations by year: 2026: 13 · 2025: 10 · 2024: 20 · 2023: 16 · 2022: 38 · 2021: 33 · 2020: 38 · 2019: 28 · 2018: 35 · 2017: 30 · 2016: 25 · 2015: 28 · 2014: 25 · 2013: 29 · 2012: 21
FWCI: 2.19
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
creativecommons.org/licenses/by-nc-nd/3.0/ (vor)
Locations: FEBS Letters (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords: microglia, neuroinflammation, sterile inflammation, microglial activation, terminology
MeSH terms: Animals, Mental Disorders, Brain, Central Nervous System, Humans, Inflammation, Nerve Degeneration, Microglia

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