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Cross talk between activation of microglia and astrocytes in pathological conditions in the central nervous system
Abstract
Microglia and astrocytes in the central nervous system are now recognized as active participants in various pathological conditions such as trauma, stroke, or chronic neurodegenerative disorders. Their activation is closely related with the development and severity of diseases. Interestingly, activation of microglia and astrocytes occurs with a spatially and temporarily distinct pattern. The present review explores the cross talk in the process of their activation. Microglia, activated earlier than astrocytes, promote astrocytic activation. On the other hand, activated astrocytes not only facilitate activation of distant microglia, but also inhibit microglial activities. Molecules contributing to their intercommunication include interleukin-1 (IL-1), adenosine triphosphate (ATP), and transforming growth factor beta (TGF-β). A better understanding about the cross talk between activation of microglia and astrocytes would be helpful to elucidate the role of glial cells in pathological conditions, which could accelerate the development of treatment for various diseases.
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“Previous research has shown that activated astrocytes release adenosine triphosphate (ATP) that can activate the purinergic receptors on neighboring microglia, resulting in microglial activation (Figure 3A) (Davalos et al., 2005;Liu et al., 2011;Schipke et al., 2002;Verderio and Matteoli, 2001).”
From Single-cell resolution analysis of the crosstalk between chemogenically activated astrocytes and microglia (2020) · cites this paper as Liu et al., 2011
In the citing paper
“As mentioned earlier, activated astrocytes release ATP which activates the purinergic receptors on microglia, resulting in microglial activation (Figure 3A) (Davalos et al., 2005;Liu et al., 2011;Schipke et al., 2002;Verderio and Matteoli, 2001).”
From Single-cell resolution analysis of the crosstalk between chemogenically activated astrocytes and microglia (2020) · cites this paper as Liu et al., 2011
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“Previous research has shown that activated astrocytes release adenosine triphosphate (ATP) that can activate the purinergic receptors on neighboring microglia, resulting in microglial activation (Figure 3A) (Davalos et al., 2005; Liu et al., 2011; Schipke et al., 2002; Verderio and Matteoli, 2001).”
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“Indeed, the chronic activation of microglia in the brain, aside from other immune cells, exacerbates A β and tau pathologies and could be a link in the pathogenesis of AD [321–323].”
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“Although microglia are the primary producers of inflammatory cytokines, astrocytes also contribute significantly to cytokine release in response to brain damage (Liu et al., 2011).”
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“Further, microglia have been shown to be the first IL-1β producing cells in response to insults such as nerve injury, CNS lesions, and neurodegenerative diseases, followed by astrocytic IL1β production a few days later (Herx and Yong, 2001; Liu et al., 2011).”
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AAV8 vector induced gliosis following neuronal transgene expression
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“It is widely assumed that astrocytic activation is dependent upon microglial activation (Liu et al., 2011; Jha et al., 2019) although evidence also points to the opposite occurring (Kwon et al., 2017).”
BackgroundRETRACTED: Exploring the role of astrocytic dysfunction and AQP4 in depression
Rana, T., Behl, T., Shamsuzzaman, M., Singh, S., Sharma, N., Sehgal, A., Alshahrani, A. M., Aldahish, A. A., Chidambaram, K., Dailah, H. G., et al. (2022) · Cellular Signalling · doi:10.1016/j.cellsig.2022.110359 · Cited by 8
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Therapeutic targeting of neuroinflammation in methamphetamine use disorder
Jeffery, N., Mock, P. Y., Yang, K., Tham, C. L., Israf, D. A., Li, H., Wang, X., & Lam, K. W. (2024) · Future Medicinal Chemistry · doi:10.1080/17568919.2024.2447226 · Cited by 7
Primate-specific response of astrocytes to stroke limits peripheral macrophage infiltrationPreprint
Boghdadi, A. G., Spurrier, J. M., Teo, L., Li, M., Škarica, M., Cao, B., Kwan, W. C., Merson, T. D., Nilsson, S. K., Šestan, N., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.05.08.083501 · Cited by 6
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“Microglia and astrocytes are differentially activated in temporal and spatial patterns and can regulate each other via cellular crosstalk [27].”
BackgroundLack of estrogen receptor α in astrocytes of progranulin-deficient mice
Mio, D., Matsuwaki, T., Yamanouchi, K., & Nishihara, M. (2016) · Journal of Reproduction and Development · doi:10.1262/jrd.2016-067 · Cited by 4
“Since activated astrocytes are reported to activate microglia [35], the deficiency of ERα in astrocytes could be a major factor causing hyperactivation of microglia and neuroinflammation in KO mice.”
Microglia: roles and rules in brain traumatic injury
Alvis-Miranda, H. R., Alcalá‐Cerra, G., & Moscote‐Salazar, L. R. (2013) · Romanian Neurosurgery · doi:10.2478/v10282-012-0019-9 · Cited by 3
“The exact mechanism leading to microglial overactivation is still not fully understood, but glial-neuronal crosstalk seems to be central (106), but because of activated microglia can release cytotoxic factors such as NO and ROS and secrete pro-inflammatory cytokines that can potentially damage neurons, oligodendrocyte…”
BackgroundÇetin, S., Uysal, S., Girgin, D., Alp, A., Kiliç, E., & Çıray, R. O. (2025) · Neuroglia · doi:10.3390/neuroglia6030034 · Cited by 4
“These reciprocal interactions further accelerate neuronal maturation [207,208].”
Microglial landscape and signaling in spinal cord injury
Zhou, Q., Liu, J., Fang, Q., Zhang, C., Liu, W., & Sun, Y. (2025) · Spinal Cord · doi:10.1038/s41393-025-01103-y · Cited by 3
“Microglia are now recognized as active participants in various pathological conditions of the central nervous system (CNS), such as trauma, stroke, and neurodegenerative disorders [4].”
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Assessment of the effect of post-natal lead exposure on the hippocampus of developing Wistar rats
Olatomide, O. D., Adebisi, S., & Musa, S. (2019) · African Journal of Cellular Pathology · doi:10.5897/ajcpath2019.0021 · Cited by 3
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“Next, the debris from myelin lamellae activates microglia to secrete interleukin-1, which promotes astrocytic activation (Liu et al., 2011).”
BackgroundGupta, K. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-821567-8.00035-x · Cited by 3
Fontes‐Dutra, M., Rabelo, B. F., Santos‐Terra, J., Deckmann, I., Schwingel, G. B., & Gottfried, C. (2020) · Progress in inflammation research · doi:10.1007/978-3-030-39335-9_11 · Cited by 3
Gap Junction-Mediated Neuroprotection
Kozoriz, M. G., & Naus, C. C. G. (2012) · Elsevier eBooks · doi:10.1016/b978-0-12-415901-3.00014-1 · Cited by 3
Gong, M., Lan, J. X., & Miao, J. (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1908574 · Cited by 3
“…cell types, including disease-associated microglia (DAM), amyloid-responsive microglia, dystrophic and terminally inflammatory microglia, as well as disease-associated astrocytes (DAAs) and multiple regionally constrained reactive states (Mucke et al., 2000; Liu W. et al., 2011; Zhang et al., 2025).”
Sonic Hedgehog-Gli1 signaling promotes microglial activation via the IKKβ/NF-κB pathway
Xu, Z., Wu, K., Guo, R., Wang, P., Ouyang, J., Cao, Z.-Q., Yang, H., Kim, J.-H., Zhang, X.-H., Suk, K., et al. (2026) · Acta Pharmacologica Sinica · doi:10.1038/s41401-026-01777-x · Cited by 2
“Astrocytes are also key participants in this neuroimmune network: activated microglia release IL-1 β , TNF-α , and ATP, which trigger reactive astrogliosis [10, 11].”
Dong, L., He, H., Chen, Z., Wang, X., Li, Y., Lü, G., Wang, B., & Kuang, L. (2024) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.70269 · Cited by 3
Clay, A., Carr, R. L., Dubien, J., & To, F. (2024) · Brain Injury · doi:10.1080/02699052.2024.2349144 · Cited by 2
“As such, we hypothesize that perhaps the significant influx of reactive astrocytes, often recruited by microglial cells (61,62), occurs at an alternative or later recovery time point as similarly seen in Chen et al. (63).”
Brenna, S., Altmeppen, H., Mohammadi, B., Rissiek, B., Schlink, F., Ludewig, P., Failla, A., Schneider, C., Glatzel, M., Puig, B., et al. (2019) · bioRxiv · doi:10.1101/850099 · Cited by 2
Blood-Brain Barrier Changes in Traumatic Brain Injury
Chodobski, A., Zink, B., & Szmydynger-Chodobska, J. (2015) · doi:10.1201/b19299-8 · Cited by 2
The Neuroinflammation in the Physiopathology of Amyotrophic Lateral Sclerosis
Bowerman, M., Vincent, T., Scamps, F., Camu, W., & Raoul, C. (2013) · InTech eBooks · doi:10.5772/56489 · Cited by 5
“cytokines and growth factors as well as produce nitric oxide (NO)(reviewed in [3]).”
BackgroundAbbasi, A. A., Khan, H., Xu, S., Zhao, Y., Zhang, K., Shen, Y., Lv, J., Zhu, X., Fu, X., & Li, P. (2026) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2026.153248 · Cited by 1
Differential opioid receptor expression and biochemical coupling profiles on glia
Kadhim, S., McDonald, J. F., Bird, M. F., Guerrini, R., Calò, G., & Lambert, D. G. (2025) · Biochemical Pharmacology · doi:10.1016/j.bcp.2025.117559 · Cited by 1
Cardozo, P. L., Lee, C., Lacerda, J. P. S., Fahel, J. S., Trindade, P., Vitória, G., Chicaybam, L., Cordeiro, R. C., de Faria, I. J. S., Silva, N. C., et al. (2025) · Glia · doi:10.1002/glia.70085 · Cited by 2
“In addition, reactive astrocytes display increased expression of a wide range of cytokines with pleiotropic activities (Bernaus et al. 2020; Linnerbauer et al. 2020; Liu et al. 2011; Moraga et al. 2014; Trindade et al. 2020), making them important targets for further investigation.”
Phosphodiesterase 4 inhibition as a novel treatment for stroke
Zhong, J., Yu, X.-H., & Lin, Z. (2025) · PeerJ · doi:10.7717/peerj.18905 · Cited by 1
“In the early stage of cerebral ischemia, astrocytes and microglia are activated, and their cell morphology and function are also altered, further involved in the regulation of various pathways of nerve damage ( Liu, Tang & Feng, 2011 ; Gabryel et al., 2015 ; Choudhury & Ding, 2016 ).”
Gong, Q., Lin, Y., Lu, Z.-N., & Xiao, Z.-M. (2020) · doi:10.21203/rs.3.rs-21978/v1 · Cited by 1
“IL-18 might activate microglia and astrocytes in an autocrine or paracrine manner, then synthesized and released pro-inflammatory cytokines, neurotransmitters and neuromodulators, amplifying neuronal excitability[4, 5, 11, 14] and inducing migraine attacks.”
BackgroundConvergence of Parkinson’s disease and diabetes: focus on glia
Miller, O., Kern, T., & Mieyal, J. J. (2018) · Macrophage · doi:10.14800/macrophage.1504
Astrocytes and microglia in Parkinson's disease and animal models
Kuter, K. Z. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-815950-7.00006-0 · Cited by 1
4.30 Nanomaterials for Drug Delivery to the Brain
Gaudin, A., Seo, Y.-E., Song, E., Quijano, E., King, A. R., & Saltzman, W. M. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-803581-8.09288-2 · Cited by 1
Fonte, D. D. (2017) · doi:10.20381/ruor-638 · Cited by 1
“, 2004) which involve reactive microglia and astrocytes (Liu et al., 2011).”
BackgroundGoins, J., Henkel, N., Coulibaly, A. P., & Isaacson, L. G. (2020) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-020-00853-y · Cited by 6
Chen, Y., Shan, Y., Zhao, S.-N., Cao, W.-P., & Pu, J.-F. (2026) · Neurocritical Care · doi:10.1007/s12028-026-02680-3
Hasan, S. A., Fathy, N., & Shaheen, A. A. (2026) · Neurochemical Research · doi:10.1007/s11064-026-04906-4
Zhang, M., Li, H., & Zhang, W. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1831494
Yan, S.-L., Li, H., Liu, Y., Chen, H.-N., Zhang, Y., Shen, Y., Feng, H.-H., Yang, Y.-Q., Wei, X.-Y., Yuan, L., et al. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1819195
“Microglia can adopt pro-inflammatory or reparative activation states, releasing cytokines and modulating synaptic pruning (Yu et al., 2023; Liu et al., 2011; Devinsky et al., 2013; Orihuela et al., 2016; Boche et al., 2013; Tang and Le, 2016).”
Cai, H., Xu, X.-R., Zhuo, X., Liu, Z., Liu, H., & Sun, Y. (2026) · Journal of Integrative Neuroscience · doi:10.31083/jin49777
Sun, L., Liu, R., Han, X., Wang, N., Zhao, T., Chen, Y.-N., Wu, J.-P., Chen, J.-F., & Wang, Q. (2026) · Epilepsy Research · doi:10.1016/j.eplepsyres.2026.107751
Garcia, M. L., Denton, A. R., Jackson, N. L., Scofield, M. D., & McMahon, L. L. (2025) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2025.1690410
“…et al., 2016; Davies et al., 2017), and their crosstalk with astrocytes amplifies neuroinflammation (Chen et al., 2025; Lopez-Ortiz and Eyo, 2024; Deng et al., 2024; Matejuk and Ransohoff, 2020; Drago et al., 2017; Jo et al., 2017; Liu et al., 2024; Liu et al., 2011; Xie et al., 2020).”
Editorial: Regulation of neuroinflammation by multiorgan network
Koyama, Y., Itokazu, T., Hattori, T., & Takamura, H. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.1047113
“It is well documented that sustained inflammatory responses cause the release of harmful mediators such as cytokines and chemokines from activated glial cells, and further affect neuronal cells by triggering neurodegeneration (Liu et al., 2011; Lian et al., 2016; Norden et al., 2016; Jo et al., 2017).”
BackgroundSala‐Jarque, J., García-Lara, E., Carreras-Dominguez, P., Zhou, C., Rabaneda‐Lombarte, N., Solà, C., Vidal-Taboada, J. M., Feiler, A. A., Abrahamsson, N., Kozlova, E. N., et al. (2022) · Nanomedicine · doi:10.2217/nnm-2022-0026 · Cited by 1
Natural populations of Galphimia spp. attenuates peripheral and central inflammationPreprint
Gesto-Borroto, R., Meneses, G., Espinosa-Cerón, A., Granados, G., Cervantes-Torres, J., Cardoso-Taketa, A., Sciutto, E., & Villarreal, M. (2021) · Research Square · doi:10.21203/rs.3.rs-315697/v1
“The uncontrolled activation of microglia induces the production of pro-in ammatory cytokines and cytotoxic mediators, which are factors implicated in neuropathological conditions (Liu et al. 2011; Meneses et al. 2017; Kabba et al. 2018; Vainchtein and Molofsky 2020).”
Backgroundde Jesus, A. A. (2019) · doi:10.11606/d.17.2019.tde-07022019-132708
“O cérebro contém células gliais também conhecidas como neuroglia que incluem os astrócitos, micróglia e oligodentrócitos, (LIU et al,2011).”
Targeting glial dysfunction to treat post-surgical neuropathic pain
Richnern, M., Vægter, C. B., & Pallesen, L. T. (2015) · Scandinavian Journal of Pain · doi:10.1016/j.sjpain.2015.10.001
Laurent, C. (2013) · theses.fr (ABES) · doi:10.70675/03ed9498z69bfz4543zb662z2c85c03cea04
“Une fois activés, les astrocytes peuvent donner naissance à une vague calcique qui se propagera le long du réseau astrocytaire et permettra d’activer les cellules microgliales plus éloignées (Liu et al., 2011).”
Effect of oxidative stress on microglial activation and iron accumulation
Suntawalimp, R., & Cheepsunthorn, P. (2019) · Chula Digiverse · doi:10.58837/chula.the.2019.363
“(1, 2) Upon brain infection or injury, microglia would change morphology reflect a highly activated state, cell bodies enlargement while cell processes are shortening.”
BackgroundKim, S., & Son, Y. (2021) · Preprints.org · doi:10.20944/preprints202107.0331.v1
“Furthermore, cross-talk between astrocytes and neurons and microglia and neurons were vigorously studied [18,19], whereas crosstalk between astrocytes and microglia is relatively less studied.”
BackgroundPerinatal Inflammation and Adult Psychopathology: From Preclinical Models to Humans
Parnham, M. J., Schmidtko, A., Teixeira, A., Macêdo, D., & Baune, B. (2020) · Progress in Inflammation Research · doi:10.1007/978-3-030-39335-9
“Infection during pregnancy can also lead to restricted uterine blood flow infection in association with increased placental CRH [126], inferring an underlying relationship between inflammation and altered fetal HPA-axis activity.”
BackgroundInfluentialGeneration and Phenotyping of Progranulin-Deficient Mice
Matsuwaki, T. (2019) · Springer eBooks · doi:10.1007/978-981-13-6186-9_9
Progranulin and Central Nervous System Disorders
Hara, H., Hosokawa, M., Nakamura, S., Shimohata, T., & Nishihara, M. (2019) · Springer Singapore · doi:10.1007/978-981-13-6186-9
Metadata
- Authors
- Liu, W., Tang, Y., & Feng, J.
- Affiliations
- Guangzhou University of Chinese Medicine (CN)
- Sun Yat-sen University (CN)
- Corresponding author
- Liu, W.
- Tang, Y.
- ORCID
- Tang, Y.
- Venue
- Life Sciences
- Publisher
- Elsevier BV
- Published
- 2011-08
- Volume
- 89
- Issue
- 5-6
- Pages
- 141-146
- ISSN
- 0024-3205 (ISSN-L)
- OpenAlex
- W2036224773
- Cited by
- 303
- References
- 84
- Citations by year
- 2026: 11 · 2025: 21 · 2024: 15 · 2023: 11 · 2022: 18 · 2021: 20 · 2020: 35 · 2019: 20 · 2018: 20 · 2017: 24 · 2016: 29 · 2015: 20 · 2014: 15 · 2013: 22 · 2012: 18
- FWCI
- 1.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Life Sciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Guangzhou University of Chinese Medicine
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- microglia, astrocytes, microglial activation, astrocyte activation, central nervous system pathology, neuroinflammation, stroke, traumatic brain injury, neurodegenerative diseases, interleukin-1, adenosine triphosphate, TGF-beta, glial communication
- MeSH terms
- Animals, Astrocytes, Cell Communication, Central Nervous System Diseases, Humans, Macrophage Activation, Microglia, Calcium Signaling, Receptor Cross-Talk
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