Astrocyte-derived CCL2 participates in surgery-induced cognitive dysfunction and neuroinflammation via evoking microglia activation

Xu, Jiawen; Dong, Huijuan; Qian, Qingqing; Zhang, Xiang; Wang, Yiwei; Jin, Wenjie; Qian, Yanning

doi:10.1016/j.bbr.2017.05.066

Cited by 116 publications

(96 citation statements)

References 44 publications

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“…In our study, we found that TMT induces an increased number of reactive astrocytes and the elevated expression of proinflammatory cytokines, including IL-6, IL-1β, and TNF-α. The expression of CCL2 and CXCL10, which are proinflammatory chemokines produced by astrocytes that have been proven to promote neuroinflammation, [52][53][54] was also elevated by TMT treatment. Melatonin treatment induced a significant reduction in all inflammatory cytokines and chemokines in the hippocampus of TMT-treated mice.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of SERPINA3N‐dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity

Liu

Hong

et al. 2019

Journal of Pineal Research

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Trimethyltin chloride (TMT) is a potent neurotoxin that causes neuroinflammation and neuronal cell death. Melatonin is a well‐known anti‐inflammatory agent with significant neuroprotective activity. Male C57BL/6J mice were intraperitoneally injected with a single dose of melatonin (10 mg/kg) before exposure to TMT (2.8 mg/kg, ip). Thereafter, the mice received melatonin (10 mg/kg, ip) once a day for another three consecutive days. Melatonin dramatically alleviated TMT‐induced neurotoxicity in mice by attenuating hippocampal neuron loss, inhibiting epilepsy‐like seizures, and ameliorating memory deficits. Moreover, melatonin markedly suppressed TMT‐induced neuroinflammatory responses and astrocyte activation, as shown by a decrease in inflammatory cytokine production as well as the downregulation of neurotoxic reactive astrocyte phenotype markers. Mechanistically, serine peptidase inhibitor clade A member 3N (SERPINA3N) was identified as playing a central role in the protective effects of melatonin based on quantitative proteome and bioinformatics analysis. Most importantly, melatonin significantly suppressed TMT‐induced SERPINA3N upregulation at both the mRNA and protein levels. The overexpression of Serpina3n in the mouse hippocampus abolished the protective effects of melatonin on TMT‐induced neuroinflammation and neurotoxicity. Melatonin protected cells against TMT‐induced neurotoxicity by inhibiting SERPINA3N‐mediated neuroinflammation. Melatonin may be a promising and practical agent for reducing TMT‐induced neurotoxicity in clinical practice.

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Section: Discussionmentioning

confidence: 99%

Inhibition of SERPINA3N‐dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity

Liu

Hong

et al. 2019

Journal of Pineal Research

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“…In addition to its well-characterised immune response function, CCL2 has recently demonstrated a pathophysiological role in several CNS diseases such as stroke, epilepsy, ischaemic brain injury [1], and neurodegenerative diseases [21,22]. Previously, studies have reported increased CCL2 expression in the cerebrospinal fluid of patients with AD and HAND [6][7][8][9] in association with cognitive decline [6,10]. Our previous study has demonstrated that CCL2 dose-dependently impairs spatial memory and object recognition in rats [23].…”

Section: Discussionmentioning

confidence: 99%

“…Our previous study has demonstrated that CCL2 dose-dependently impairs spatial memory and object recognition in rats [23]. Furthermore, in-depth investigations have elucidated that the potential mechanisms are related to inflammation, oxidative stress, excitotoxicity, and neuronal apoptosis [6,10]. Thus, CCL2, a multi-potent pathological factor, could be established as a therapeutic target to prevent or treat neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

“…In the brain, CCL2 is mainly produced by macrophages and microglia, the key mediators of neuroinflammation [24]. During inflammatory progression, CCL2 not only attracts immune cells to specific sites but also promotes the release of other inflammatory factors, including IL-6 and IL-1β, exacerbating the extent of neuroinflammation [10,11]. Researchers have revealed that naringin demonstrates anti-inflammatory activity.…”

Section: Discussionmentioning

confidence: 99%

“…Elevated CCL2 has been detected in the cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) and HIV-associated neurocognitive disorder (HAND) [6][7][8][9]. In the brain, CCL2 is produced mainly by macrophages and microglia, which, in turn, activate microglia and release numerous inflammatory cytokines [10,11], such as interleukin 6 (IL-6) and interleukin 1β (IL-1β), exacerbating the extent of inflammation and resulting in neuronal injury. Thus, as a potential proinflammatory mediator, we postulated that CCL2 is closely associated with neuroinflammation and cognitive impairment.…”

Section: Introductionmentioning

confidence: 99%

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Naringin provides neuroprotection in CCL2-induced cognition impairment by attenuating neuronal apoptosis in the hippocampus

et al. 2020

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Background: Chemokine CC motif ligand 2 (CCL2) is one of the most widely recognised proinflammatory chemokines in cognitive disorders. Currently, CCL2-targeting drugs are extremely limited. Thus, this study aimed to explore the neuroprotection afforded by naringin in CCL2-induced cognitive impairment in rats. Methods: Before the CCL2 intra-hippocampal injection, rats were treated with naringin for 3 consecutive days via intraperitoneal injection. Two days post-surgery, the Morris water maze (MWM) and novel object recognition (NORT) tests were performed to detect spatial learning and memory and object cognition, respectively. Nissl staining and dUTP nick-end labelling (TUNEL) staining were performed to assess histopathological changes in the hippocampus. Commercial kits were used to measure the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and the content of malondialdehyde (MDA). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to examine the relative mRNA expression of interleukin 1β, (IL-1β), interleukin 6 (IL-6), glutamate/aspartate transporter (GLAST), glutamate transporter-1 (GLT-1), phosphate-activated glutaminase (PAG), cysteine aspartic acidspecific protease 8 (caspase-8), cysteine aspartic acid-specific protease 3 (caspase-3), cell lymphoma/leukaemia-2 (Bcl-2), and Bcl-2 associated X protein (Bax). Results: In the MWM, the average escape latency and average swimming distance were significantly reduced and the crossing times were increased in the naringin-treated groups, compared with the CCL2 group. The NORT results revealed that, compared with the CCL2 rats, the discrimination index in the naringin-treated rats increased significantly. Nissl and TUNEL staining revealed that naringin protected the structure and survival of the neurons in the CA1 zone of the hippocampus. In the naringin-treated groups, the SOD and GSH-Px activities were increased, whereas the MDA levels were decreased. Furthermore, in the naringin-treated groups, the relative mRNA expression of IL-1β and IL-6 was significantly decreased; GLAST and GLT-1 mRNA expression levels were increased, whereas PAG was decreased. In the naringin-treated groups, the relative mRNA expression levels of caspase-8, caspase-3, and Bax were decreased, whereas that of Bcl-2 was increased.

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IL‐10 and Cdc42 modulate astrocyte‐mediated microglia activation in methamphetamine‐induced neuroinflammation

Silva,

Socodato,

Pinto

et al. 2024

Glia

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Methamphetamine (Meth) use is known to induce complex neuroinflammatory responses, particularly involving astrocytes and microglia. Building upon our previous research, which demonstrated that Meth stimulates astrocytes to release tumor necrosis factor (TNF) and glutamate, leading to microglial activation, this study investigates the role of the anti‐inflammatory cytokine interleukin‐10 (IL‐10) in this process. Our findings reveal that the presence of recombinant IL‐10 (rIL‐10) counteracts Meth‐induced excessive glutamate release in astrocyte cultures, which significantly reduces microglial activation. This reduction is associated with the modulation of astrocytic intracellular calcium (Ca2+) dynamics, particularly by restricting the release of Ca2+ from the endoplasmic reticulum to the cytoplasm. Furthermore, we identify the small Rho GTPase Cdc42 as a crucial intermediary in the astrocyte‐to‐microglia communication pathway under Meth exposure. By employing a transgenic mouse model that overexpresses IL‐10 (pMT‐10), we also demonstrate in vivo that IL‐10 prevents Meth‐induced neuroinflammation. These findings not only enhance our understanding of Meth‐related neuroinflammatory mechanisms, but also suggest IL‐10 and Cdc42 as putative therapeutic targets for treating Meth‐induced neuroinflammation.

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Astrocyte-derived CCL2 participates in surgery-induced cognitive dysfunction and neuroinflammation via evoking microglia activation

Cited by 116 publications

References 44 publications

Inhibition of SERPINA3N‐dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity

Inhibition of SERPINA3N‐dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity

Naringin provides neuroprotection in CCL2-induced cognition impairment by attenuating neuronal apoptosis in the hippocampus

IL‐10 and Cdc42 modulate astrocyte‐mediated microglia activation in methamphetamine‐induced neuroinflammation

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