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Cited by 94Neuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology ResearchNeurological Disease Mechanisms and Treatments

The DOI matches its Crossref record; 234 of the 235 references it cites were found in a registry or an index, and 1 are not checked yet.

Microglia-orchestrated neuroinflammation and synaptic remodeling: roles of pro-inflammatory cytokines and receptors in neurodegeneration

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Yang, Guang, Xu, Xiao, Gao, Waimao, Wang, Xingyu, Zhao, Yan, Xu, Ying·2025·Frontiers in Cellular Neuroscience
DOI 10.3389/fncel.2025.1700692PMC PMC12641016
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Abstract

Microglia, the innate immune cells of the central nervous system (CNS), play essential roles in maintaining neural homeostasis through dynamic interactions with neurons and other brain structures. While their protective functions are well-established, recent studies have illuminated the detrimental consequences of sustained microglial activation in the context of neurodegeneration. In particular, overactivated microglia contribute to neuroinflammation and induce synaptic alterations through the release of pro-inflammatory cytokines and engagement of specific receptors. These interactions disrupt synaptic structure and function, compromising connectivity, plasticity, and cognitive processes. Notably, neuronal synapses are primary targets of such inflammation-driven dysfunction, where prolonged exposure to cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor- α (TNF-α), and signaling via receptor systems including cluster of differentiation-200 (CD200)/CD200 receptor (CD200R), C-X3-C motif chemokine ligand 1 (CX3CL1)/CX3C receptor 1 (CX3CR1), colony-stimulating factor 1 (CSF1)/CSF1 receptor (CSF1R), and interferon- γ (IFN-γ)/IFN-γ receptor (IFN-γR), lead to impaired learning, excitotoxicity, and neurodegenerative progression. This review synthesizes emerging evidence on the mechanisms by which microglia-mediated immune responses regulate synaptic remodeling, emphasizing the roles of pro-inflammatory cytokines and their receptors in neurodegenerative disorders.

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Crossref · 10.3389/fncel.2025.1700692

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Figures

Figure 1 Neuron–microglia interactions under physiological conditions. (Left) Neurons secrete signaling molecules such as CX3CL1, CSF1, and IFN-γ, which bind to their respective microglial receptors, CX3CL1R, CSF1R, and IFN-γR, to regulate microglial surveillance and activation. Additionally, neuronal CD200 interacts with microglial CD200R to maintain microglial quiescence. (Right) Activated microglia release pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α, which bind to neuronal receptors IL-1βR, IL-6R, and TNF-αR, respectively. These bidirectional interactions coordinate immune homeostasis and contribute to the maintenance of neuronal and synaptic integrity.
Figure 1 Neuron–microglia interactions under physiological conditions. (Left) Neurons secrete signaling molecules such as CX3CL1, CSF1, and IFN-γ, which bind to their respective microglial receptors, CX3CL1R, CSF1R, and IFN-γR, to regulate microglial surveillance and activation. Additionally, neuronal CD200 interacts with microglial CD200R to maintain microglial quiescence. (Right) Activated microglia release pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α, which bind to neuronal receptors IL-1βR, IL-6R, and TNF-αR, respectively. These bidirectional interactions coordinate immune homeostasis and contribute to the maintenance of neuronal and synaptic integrity.CC BY · PubMed Central
Figure 2 Mechanisms of pro-inflammatory factors-induced synaptic plasticity impairment under pathological conditions. Overactivated microglia release IL-1β, IL-6, and TNF-α, each disrupting synaptic function via distinct signaling pathways. IL-1β activates NLRP3 inflammasomes and the 2-DG metabolic pathway, promoting inflammation and metabolic reprogramming that further enhance microglial activation. Binding of IL-1β to IL-1βR engages signaling cascades such as NF-κB, NF-κB/REST, MECP2, mTOR, and CREB, leading to impaired synaptic downscaling, altered dendritic spine morphology, hippocampal LTP suppression, and reduced gene expression. Additionally, IL-1β disrupts synaptic protein synthesis through the Akt/mTOR pathway. IL-6 signaling via IL-6R facilitates basal synaptic transmission and L-LTP through mTOR activation. TNF-α, via TNF-αR, impairs hippocampal LTP and LTD through NLRP3/NF-κB and JAK/STAT3 pathways, while also affecting LTP and neuronal regeneration via the EphB2/NF-κB axis. Collectively, these cytokine-mediated mechanisms contribute to synaptic dysfunction and neurodegeneration by disrupting neuronal and microglial signaling homeostasis.
Figure 2 Mechanisms of pro-inflammatory factors-induced synaptic plasticity impairment under pathological conditions. Overactivated microglia release IL-1β, IL-6, and TNF-α, each disrupting synaptic function via distinct signaling pathways. IL-1β activates NLRP3 inflammasomes and the 2-DG metabolic pathway, promoting inflammation and metabolic reprogramming that further enhance microglial activation. Binding of IL-1β to IL-1βR engages signaling cascades such as NF-κB, NF-κB/REST, MECP2, mTOR, and CREB, leading to impaired synaptic downscaling, altered dendritic spine morphology, hippocampal LTP suppression, and reduced gene expression. Additionally, IL-1β disrupts synaptic protein synthesis through the Akt/mTOR pathway. IL-6 signaling via IL-6R facilitates basal synaptic transmission and L-LTP through mTOR activation. TNF-α, via TNF-αR, impairs hippocampal LTP and LTD through NLRP3/NF-κB and JAK/STAT3 pathways, while also affecting LTP and neuronal regeneration via the EphB2/NF-κB axis. Collectively, these cytokine-mediated mechanisms contribute to synaptic dysfunction and neurodegeneration by disrupting neuronal and microglial signaling homeostasis.CC BY · PubMed Central
Figure 3 A summary of the impact of overactivated microglia on neuronal synapses under neuroinflammatory conditions. Following infection or injury, microglia transition into hyperactivated pro-inflammatory states and secrete cytokines such as IL-1β, IL-6, TNF-α and IFN-γ, which exacerbate neuroinflammation and contribute to synaptic impairment. Disruption of key neuron–microglia ligand-receptor interactions, such as CD200/CD200R, CX3CL1/CX3CL1R, CSF1/CSF1R, Lipoproteins/Misfolded proteins/TREM2 and BDNF/TrkB, leads to dysregulated synaptic homeostasis. The resulting microglial activation promotes excessive synaptic pruning, impaired synaptic scaling, abnormal receptor expression, and altered synaptic transmission. These changes ultimately disturb the excitatory-inhibitory balance and compromise overall neuronal function.
Figure 3 A summary of the impact of overactivated microglia on neuronal synapses under neuroinflammatory conditions. Following infection or injury, microglia transition into hyperactivated pro-inflammatory states and secrete cytokines such as IL-1β, IL-6, TNF-α and IFN-γ, which exacerbate neuroinflammation and contribute to synaptic impairment. Disruption of key neuron–microglia ligand-receptor interactions, such as CD200/CD200R, CX3CL1/CX3CL1R, CSF1/CSF1R, Lipoproteins/Misfolded proteins/TREM2 and BDNF/TrkB, leads to dysregulated synaptic homeostasis. The resulting microglial activation promotes excessive synaptic pruning, impaired synaptic scaling, abnormal receptor expression, and altered synaptic transmission. These changes ultimately disturb the excitatory-inhibitory balance and compromise overall neuronal function.CC BY · PubMed Central

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Research works printed but not linked: 2

  1. Han, 2016, Seizure induced synaptic plasticity alteration in hippocampus is mediated by IL-1β receptor through PI3K/Akt pathway, Am. J. Transl. Res., 15, 4499
  2. Ngwa, 2019, CD200-CD200R signaling and diseases: a potential therapeutic target, Int J Physiol Pathophysiol Pharmacol, 11, 297

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Metadata

Authors
Yang, G., Xu, X., Gao, W., Wang, X., Zhao, Y., & Xu, Y.
Affiliations
Shanghai University of Traditional Chinese Medicine (CN)
Corresponding author
  • Zhao, Yan
  • Xu, Ying
ORCID
Venue
Frontiers in Cellular Neuroscience
Publisher
Frontiers Media SA
Published
2025-11-10
Volume
19
Pages
1700692-1700692
ISSN
1662-5102 (ISSN-L)
DOI
10.3389/fncel.2025.1700692
PMC
PMC12641016
OpenAlex
W4416096320
Cited by
85
References
234
Citations by year
2026: 83 · 2025: 2
FWCI
8.24
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China
  • China Postdoctoral Science Foundation
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
microglia, neuroinflammation, synaptic remodeling, inflammatory cytokines, neurodegeneration, IL-1β, interleukin-6, TNF-α, CX3CL1/CX3CR1, excitotoxicity, learning disabilities, neurodegenerative diseases

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