IMMUNITY
·
2024
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IF 25.5
Yangning Lan,Xiaoxuan Zhang,Shaorui Liu,Chen Guo,Yuxiao Jin,Hui Li,Linyixiao Wang,Jinghong Zhao,Yilin Hao,Zhicheng Li,Zhaoyuan Liu,Florent Ginhoux,Qi Xie,Heping Xu,Jie-Min Jia,Danyang He
Microglial reactivity to injury and disease is emerging as a heterogeneous, dynamic, and crucial determinant in neurological disorders. However, the plasticity and fate of disease-associated microglia (DAM) remain largely unknown. We established a lineage tracing system, leveraging the expression dynamics of secreted phosphoprotein 1（Spp1） to label and track DAM-like microglia during brain injury and recovery. Fate mapping of Spp1 + microglia during stroke in juvenile mice revealed an irreversible state of DAM-like microglia that were ultimately eliminated from the injured brain. By contrast, DAM-like microglia in the neonatal stroke models exhibited high plasticity, regaining a homeostatic signature and integrating into the microglial network after recovery. Furthermore, neonatal injury had a lasting impact on microglia, rendering them intrinsically sensitized to subsequent immune challenges. Therefore, our findings highlight the plasticity and innate immune memory of neonatal microglia, shedding light on the fate of DAM-like microglia in various neuropathological conditions.
研究领域:
神经科学
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免疫学
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细胞生物学
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PubMed
高影响因子
JOURNAL OF NEUROIMMUNOLOGY
·
2026
·
IF 3.1
Jingkun Wu,Liang Hou,Qinghua Zhu,Hongbin Wang,Naizhu Wang
Interferon regulatory factor 8 (Irf8) is a transcription factor expressed only in the microglia in the brain and directs the expression of many genes that serve microglial functions. This report investigates the role of Irf8 in microglia during the progression of hypertensive intracerebral hemorrhage (ICH). L-NAME and angiotensin II initiated the ICH mouse model after stereotactic injection of knockdown and overexpression vectors. Inflammatory responses were induced in the mouse microglia cell line BV-2 using lipopolysaccharide (LPS), and lentiviral infection was conducted to manipulate gene expression. Irf8 was significantly overexpressed in the brain tissues of ICH mice and LPS-induced BV-2 cells. Downregulation of Irf8 hampered microglial M1 polarization and the inflammatory response and partially alleviated limb dysfunction caused by neurological impairment resulting from ICH. Irf8 interacted with the signal transducer and activator of transcription 1 (Stat1), thus mediating the transcriptional activation of Stat1 on tripartite motif-containing protein 5 (Trim5) in microglia. Overexpression of Trim5 reversed the inhibitory effect of sh-Irf8 on the inflammatory response in microglia and exacerbated cerebral hemorrhage in ICH mice. Thus, it was suggested that Irf8 overexpression activated the Stat1/Trim5 axis and mediated a microglial proinflammatory phenotype, thereby exacerbating hypertensive ICH.
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高影响因子
BRAIN BEHAVIOR AND IMMUNITY
·
2026
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IF 7.5
Tao Ye,Xinhuang Lv,Qiyao Li,Xiaolan Liao,Lu Zhan,Conghui Dai,Kun Xiang,Xiaoou Lin,Jing Sun,Jiaming Liu
Gut microbial metabolites abnormity links to Alzheimer’s disease (AD) progression, yet the mechanism remains unknown. Here, we observed a markedly decreased level of indole-3-acetic acid (IAA) in AD patients, and the IAA level was negatively correlated with cognitive impairment. IAA supplementation improved cognitive dysfunction and synaptic damage, and suppressed microglial activation and synaptic phagocytosis in AD mouse and cell models. RNA sequencing revealed an increase in phagocytosis-associated pathway activity and gene expression, and C-C chemokine receptor 4 (CCR4) was identified as a key regulator of this process. IAA could inhibit the expression level of CCR4, and siRNAs CCR4 markedly inhibited microglia-mediated phagocytosis of synapse. We further demonstrated that microglial CCR4 interacts with aryl hydrocarbon receptor (AHR), a key receptor of IAA, and proposed the hypothesis that AHR binds to the CCR4 promoter, thereby inhibiting its transcriptional activity. Moreover, we further revealed that bacteria producing IAA supplementation inhibited microglia-mediated synaptic loss by down-regulating CCR4, thus delaying Alzheimer’s progression. These findings elucidate the mechanisms underlying microbial metabolite IAA’s impact on AD, highlighting that targeting CCR4 inhibition in microglia-mediated synaptic phagocytosis represents a promising therapeutic strategy for AD.
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高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2026
·
IF 4.7
Li Qianyu,Wang Huiyue,Chen Nan,Liu Xue,Li Yongle,Chen Lei,Gan Lu,Luan Yong
Postoperative cognitive dysfunction (POCD) is a common complication following surgery, particularly in elderly patients, and is closely linked to neuroinflammation driven by microglial activation. While dexmedetomidine (Dex) has shown neuroprotective potential in clinical settings, the molecular mechanisms underlying its beneficial effects—particularly in relation to RNA epigenetic regulation and metabolic reprogramming in microglia—remain poorly understood. Here, we uncover a novel mechanism by which Dex alleviates POCD through modulation of N6-methyladenosine (m 6 A)–dependent post-transcriptional regulation of pyruvate kinase M2 (PKM2). We demonstrate that Dex enhances the expression of the m 6 A reader protein YTHDF2, which recognizes m 6 A-modified PKM2 mRNA and promotes its degradation, thereby suppressing microglial glycolysis and neuroinflammation. In both in vitro and in vivo models, Dex treatment reversed surgery- or LPS-induced cognitive deficits, reduced pro-inflammatory cytokine production, and normalized metabolic shifts in microglia—effects that were dependent on YTHDF2-mediated PKM2 downregulation. Our findings uncovered a novel epigenetic mechanism by which Dex exerts neuroprotection and highlight YTHDF2-mediated PKM2 regulation as a potential therapeutic target for POCD.
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高影响因子
Neural Regeneration Research
·
2024
·Vol. 21
·期 1
·365
·
IF 5.9
Zeng Fanzhuo,Li Yuxin,Li Xiaoyu,Gu Xinyang,Cao Yue,Cheng Shuai,Tian He,Mei Rongcheng,Mei Xifan
Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited. Microglia is the resident immune cells of the central nervous system, play a critical role in spinal cord injury. Previous studies have shown that microglia can promote neuronal survival by phagocytosing dead cells and debris and by releasing neuroprotective and anti-inflammatory factors. However, excessive activation of microglia can lead to persistent inflammation and contribute to the formation of glial scars, which hinder axonal regeneration. Despite this, the precise role and mechanisms of microglia during the acute phase of spinal cord injury remain controversial and poorly understood. To elucidate the role of microglia in spinal cord injury, we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia. We observed that sustained depletion of microglia resulted in an expansion of the lesion area, downregulation of brain-derived neurotrophic factor, and impaired functional recovery after spinal cord injury. Next, we generated a transgenic mouse line with conditional overexpression of brain-derived neurotrophic factor specifically in microglia. We found that brain-derived neurotrophic factor overexpression in microglia increased angiogenesis and blood flow following spinal cord injury and facilitated the recovery of hindlimb motor function. Additionally, brain-derived neurotrophic factor overexpression in microglia reduced inflammation and neuronal apoptosis during the acute phase of spinal cord injury. Furthermore, through using specific transgenic mouse lines, TMEM119, and the colony-stimulating factor 1 receptor inhibitor PLX73086, we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages. In conclusion, our findings suggest the critical role of microglia in the formation of protective glial scars. Depleting microglia is detrimental to recovery of spinal cord injury, whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury.
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Cancer Management and Research
·
2020
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IF 2.886
Weixu Luo,Yuanshan Han,Pan Meng,Qin Yang,Hongqing Zhao,Jia Ling,Yuhong Wang
Background Breast cancer is one of the most common cancer with high risk in females all over the world. It is usually complicated with depression, which can further accelerate the development and progression of breast tumors. We aim to identify a new drug and identify its functional mechanism in the regulation of hippocampal microglia (MG) in breast cancer complicated with depression (BCCD). Methods The activation model of MG was established by treatments from corticosterone (CORT) or lipopolysaccharides (LPS). The inhibitory effects of resatorvid on MG were investigated by CCK-8, ROS, immunofluorescence, TUNEL, scratch test, ELISA, RT-qPCR and Western blot. BCCD animal model was established using 4T1 inflammatory breast cancer cells and CORT treatment in vitro. Open field experiment (OFE), tail suspension test (TST), ELISA, RT-qPCR and Western blot experiments were utilized to examine the effects of resatorvid on the animal model in vivo. Results The cell viability and migration ability of the BCCD model group were suppressed. The expressions of inflammatory factors, ROS, and the apoptotic rate of the BCCD model group were up-regulated, in contrast to the control group. The expressions related to the TLR4/NF-κB/NLRP3 signaling in the BCCD model group were also elevated. Resatorvid reversed the above changes, which showed good therapeutic effects in depression-related behavioral changes, tumor treatment, and blood–brain barrier function. Conclusion In summary, resatorvid inhibited the activation of hippocampal MG in BCCD by regulating TLR4/NF-κB/NLRP3 signaling pathway.
研究领域:
肿瘤学
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神经科学
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药理学
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高影响因子
NEUROPHARMACOLOGY
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2017
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IF 5.012
Jun Tang,Hongping Miao,Bing Jiang,Qianwei Chen,Liang Tan,Yihao Tao,Jianbo Zhang,Fabao Gao,Hua Feng,Gang Zhu,Zhi Chen
Microglia play dual roles after germinal matrix hemorrhage, and the neurotrophic phenotype maybe neuroprotective . However, the phenotype transformation and the way by which neuron-microglia dialogue remain unclear. We raise the hypothesis that a cannabinoid receptor2 agonist (JWH133) accelerates the CX3CR1 + microglia secreting neurotrophic factors and restores damaged neuronal circuit. Here, we report a novel function of JWH133 in transforming the microglia CX3CR1 positive that secrete brain-derived neurotrophic factor (BDNF), which triggers neuron proliferation and neuronal restoration. Using a collagen VII-induced GMH model in rat pups postnatal day 7 (P7), we found that the drug showed robust activity in neuronal precursors. Moreover, the FA value of DTI in the internal zone revealed the positive effects of JWH133 on neural restoration. CX3CR1, a critical modulating molecule expressed in microglia, was upregulated after treatment with JWH133 and the corresponding shRNA (NM_133534.1) was used to silence the expression of CX3CR1. 3 days after treatment with JWH133, we detected reduced expression of biomarkers for neural progenitor cells (NPCs) in pups pre-injected in the lateral ventricular tissue with CX3CR1 shRNA, but not in pups injected with control shRNA. Overall, this study provides evidence that JWH133 promoted a neurotrophic phenotype of microglia (CX3CR1 + microglia), beyond merely alleviating microglial proliferation and inflammation. Moreover, JWH133 restored impaired neuronal circuit, which represent a novel therapeutic strategy following GMH in clinic.
研究领域:
神经科学
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药理学
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神经生物学
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高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2021
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IF 4.432
Feng Zhang,Keqing Zhao,Tao Tang,Yan Deng,Yun Zhang,Shuo Feng,Pu Feng,Mengyuan Guo,Xiaohui Li,Juan Cen
Neuroinflammation is considered as an important mechanism of vascular dementia (VaD). Our primary study showed that the bisindole analogue (2-(2-(bis(5-chloro-1H-indol-3-yl)methyl)phenoxy)aniline, compound 4ae ) had great anti-inflammation in zebrafish. Rat model of permanent occlusion of the bilateral common carotid arteries (2-vessel occlusion, 2VO) was utilized to evaluate the neuroprotective effect of 4ae . Our results showed that 4ae treatment effectively reduced Iba-1 positive microglia cells in cerebral cortex and hippocampus after cerebral ischemia . Compared with the model group, neuroinflammation characterized by Interleukin (IL)-6 and tumor necrosis factor (TNF)-α, oxidative stress characterized by reactive oxygen species (ROS) and superoxide dismutase (SOD) were both improved significantly after treatment with 4ae. Moreover, 4ae treatment significantly reversed ischemia-induced ACE enhancement, while notably increased the level of ACE2. To further elucidate the role of 4ae on neuroinflammation, we investigated the effects of 4ae on lipopolysaccharide (LPS)-induced inflammation in BV2 microglia cells, a kind of innate immune cells in central nervous system . The results demonstrated that the expressions of CD11b, TNFα and IL-6 and the level of ROS were up-regulated after treatment with LPS. More importantly, 4ae was able to block the activation of BV2 by reducing ROS production and the expression of inflammatory cytokines. In addition, our results suggested that 4ae inhibited the inflammatory response mediated by microglia cells by inhibiting NF-κB. This anti-inflammatory effect on microglia may be a potential mechanism for the neuroprotective effect of 4ae in VaD.
研究领域:
神经科学
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药理学
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炎症
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痴呆症
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神经保护
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PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2023
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IF 5.6
Zhihong Zhuo,Yao Wang,Huimin Kong,Tianjiao Fu
Neuroinflammation is a major component of epilepsy. Gut-enriched Kruppel-like factor (GKLF), a transcription factor of Kruppel-like factor family, has been reported to promote microglia activation and mediate neuroinflammation. However, the role of GKLF in epilepsy remains poorly characterized. This study focused on the function of GKLF in neuron loss and neuroinflammation in epilepsy and the molecular mechanism underlying microglia activation induced by GKLF upon lipopolysaccharides (LPS) treatment. An experimental epileptic model was induced by an intraperitoneal injection of 25 mg/kg kainic acid (KA). Lentivirus vectors (Lv) carrying Gklf CDS or short hairpin RNA targeting Gklf (shGKLF) was injected into the hippocampus, resulting in Gklf overexpression or knockdown in the hippocampus. BV-2 cells were co-infected with Lv-shGKLF or/and Lv carrying thioredoxin interacting protein ( Txnip ) CDS for 48 h and treated with 1 μg/mL LPS for 24 h. Results showed that GKLF enhanced KA-induced neuronal loss, pro-inflammatory cytokine secretion, activation of NOD-like receptor protein-3 (NLRP3) inflammasomes and microglia, and TXNIP expression in the hippocampus. GKLF inhibition showed negative effects on LPS-induced microglia activation, as evidenced by reduced pro-inflammatory cytokine secretion and activation of NLRP3 inflammasomes. GKLF bound to Txnip promoter and increased TXNIP expression in LPS-activated microglia. Interestingly, Txnip overexpression reversed the inhibitory effect of Gklf knockdown on microglia activation. These findings indicated that GKLF was involved in microglia activation via TXNIP. This study demonstrates the underlying mechanism of GKLF in the pathogenesis of epilepsy and uncovers that GKLF inhibition may be a therapeutic strategy for epilepsy treatment.
研究领域:
神经科学
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分子生物学
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免疫学
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高影响因子
Journal of Translational Internal Medicine
·
2023
·Vol. 11
·期 2
·156-168
·
IF 4.9
Mengdi Guo,Qian Cao,Shengnan Xia,Xiang Cao,Jian Chen,Yi Qian,Xinyu Bao,Yun Xu
Background and Objectives
Overactivated glial cells, especially microglia, are core components in the progression of pathologic neuroinflammation, and the application of anti-inflammatory reagents has been regarded as a potential therapy in the management of infarction/reperfusion (I/R) brain injury. This research aims to clarify the anti-inflammatory efect of a novel lipophilic compound N-(2-[4-tert-butylphenyl]-2-[pyrrolidine-1-yl]ethyl)-7-methyl-4-oxo-4H-chromene-2-carboxamide (named CP-07 in this study) in LPS-stimulated BV2 cell line and primary mouse microglia, and its therapeutic effect on I/R brain injury.
Method
Cell Counting Kit-8 assay was used to determine the maximal nontoxic dose of CP-07. The mRNA levels of representative proinflammatory cytokines were determined by quantitative real-time polymerase chain reaction both in vitro and in vivo . TTC staining was performed to calculate infarct volumes while behavioral tests were used to assess the neurological deficits at 24 h after middle cerebral artery occlusion (MCAO). Flow cytometry analysis and immunofluorescence staining were performed to calculate the percentage of pro-inflammatory microglia in vivo .A selective JAK2/STAT3 pathway inhibitor, AG490 was used to block STAT3 phosphorylation before the CP-07 anti-inflammation tests in vitro .
Results
CP-07 could effectively suppress the mRNA levels of IL-6, IL-1β, iNOS and TNF-α induced by lipopolysaccharide (LPS) in vitro , and markedly block the evaluation of the fluorescence intensity of Iba-1 in primary mouse microglia. In middle cerebral arteryocclusion models, intraperitoneal injection with 1 mg/kg CP-07 significantly reduced cerebral infarct volumes at 24 h after surgery compared with vehicle treatment group, and promoted the recovery of neurological functions in MCAO mice. Further studies validated that CP-07 administration reduced the percentage of CD86 positive microglia after I/R injury, and the expression level of p-STAT3 was also markedly reduced in both microglial cells and the penumbra tissues. Blocking STAT3 phosphorylation with AG490 could completely eliminate the anti-inflammatory effects of CP-07, at least in vitro .
Conclusion
We showed that a newly synthesized compound, CP-07, could effectively reduce the inflammatory responses in LPS-stimulated BV2 cells and primary mouse microglia, and overproduction of cytokines in middle cerebral artery occlusion mouse models by inhibiting STAT3 phosphorylation, leading to a neuroprotective effect on I/R brain injury.
研究领域:
神经科学
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药理学
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炎症
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神经保护
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PubMed
高影响因子
Cell Communication and Signaling
·
2026
·Vol. 24
·期 1
·322
·
IF 11.6
Chen Jiancong,Hu Yanhong,Xie Jiaxin,Zhou Haiping,Yang Tingting,Yu Mingjia,Wu Jingwen,Pan Suyue,Huang Kaibin
Background Status epilepticus (SE) is a life-threatening neurological emergency with high mortality, often leading to acute cerebral edema and chronic cognitive impairment. Its pathology involves both immune and vascular dysfunction. The complement C3/C3a receptor (C3/C3aR) signaling pathway has recently emerged as a key regulator of immune activation and blood-brain barrier (BBB) permeability. This study investigates whether bindarit, a potent anti-inflammatory drug, mitigates SE-induced brain injury through modulation of the C3/C3aR pathway. Methods SE modeling mice were randomized to receive daily bindarit or vehicle. To explore underlying mechanisms, C3aR antagonist (C3aRA) and recombinant C3a were used in additional groups. Post-SE brain injuries were assessed, including survival, memory performance, histopathology, brain edema, BBB integrity, neurovascular inflammation, microglia-astrocyte interactions, and microglial synaptic engulfment. Results We found that bindarit treatment improved survival and memory, reduced histological damage, alleviated brain edema, preserved BBB integrity, and attenuated endothelial inflammation in SE mice. It promoted a shift in microglia from a pro-inflammatory to an anti-inflammatory-associated features, reversed pathological microglia-astrocyte crosstalk, limited synaptic elimination, and restored microglial morphology. Mechanistically, bindarit inhibited neurotoxic astrocyte-derived C3 production and reduced C3aR expression in both microglia and endothelial cells. C3aRA produced comparable protective effects, whereas co-administration of C3a partially negated bindarit’s benefits. Conclusions Bindarit confers robust neuroprotection in SE by preserving BBB integrity, attenuating neurovascular inflammation, reducing synaptic loss, and improving cognitive outcomes. These effects are mediated predominantly through inhibition of the C3/C3aR pathway, highlighting bindarit as a promising therapeutic candidate for SE.
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高影响因子
AGING CELL
·
2026
·Vol. 25
·期 10
·e70732
·
IF 7.7
Lixing Zhou,Ying Cheng,Wanyu Zhao,Xuelian Sun,Fengjuan Hu,Meiling Ge,Yan Zhang,Gongchang Zhang,Birong Dong,Xiaolei Liu
Cognitive impairment (CI) associated with aging and immunosenescence is linked to metabolic alterations. Microglial senescence and dysregulated autophagy have been implicated as major contributors to this process, but the underlying metabolic regulators remain unclear. This study aimed to identify key metabolic regulators of CI and elucidate their underlying mechanisms. Human cohort analyses, older and D‐galactose (D‐gal)‐induced mouse models, and microglial cell models were integrated to investigate the metabolic regulation of CI. Clinical analyses identified ghrelin as the factor most strongly associated with CI. Older and D‐gal mice exhibited CI, microglial senescence, enhanced inflammation, and elevated ghrelin. Ghrelin treatment improved cognitive function, attenuated microglial senescence, and suppressed inflammation, whereas high‐dose ghrelin induced growth hormone secretagogue receptor (GHSR) desensitization. Sex hormone‐binding globulin (SHBG) showed mainly cytoplasmic localization, was identified as a potential mediator of ghrelin signaling in microglia, and its expression was downregulated following ghrelin treatment. Transcriptomic profiling revealed significant enrichment of autophagy‐related pathways in ghrelin‐treated microglia. Ghrelin altered autophagy‐related markers, as indicated by increased Beclin1 and LC3 and decreased p62. SHBG overexpression or JNK1 inhibition attenuated the ghrelin‐induced alterations in autophagy‐related markers and anti‐senescent effects, whereas Beclin1 overexpression partially rescued these inhibitory effects caused by SHBG overexpression. In conclusion, ghrelin alleviated aging‐related CI, with mechanistic evidence indicating that the modulation of microglial autophagy‐related mechanisms through the SHBG/JNK1/Beclin1 axis may contribute to its protective effects, thereby providing a potential therapeutic strategy for aging‐related CI. This study found that aging‐related cognitive impairment is accompanied by hippocampal microglial senescence. Ghrelin suppresses microglial senescence by promoting autophagy through the SHBG/JNK1/Beclin1 axis, thereby alleviating aging‐related cognitive impairment. The graphical abstract was drawn using the Figdraw.
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高影响因子
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