MOLECULES
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2023
·Vol. 28
·期 11
·4501
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IF 4.6
Xiaohui Liu,Ning Jiang,Wenxia Zhou
The activation of the microglia plays an important role in the neuroinflammation induced by different stimulations associated with Alzheimer’s disease (AD). Different stimulations, such as pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) and cytokines, trigger a consequence of activation in the microglia with diverse changes of the microglial cell type response in AD. The activation of the microglia is often accompanied by metabolic changes in response to PAMPs, DAMPs and cytokines in AD. Actually, we do not know the distinct differences on the energetic metabolism of microglia when subject to these stimuli. This research assessed the changes of the cell type response and energetic metabolism in mouse-derived immortalized cells (BV-2 cells) induced by a PAMP (LPS), DAMPs (Aβ and ATP) and a cytokine (IL-4) in mouse-derived immortalized cells (BV-2 cells) and whether the microglial cell type response was improved by targeting the metabolism. We uncovered that LPS, a proinflammatory stimulation of PAMPs, modified the morphology from irregular to fusiform, with stronger cell viability, fusion rates and phagocytosis in the microglia accompanied by a metabolic shift to the promotion of glycolysis and the inhibition of oxidative phosphorylation (OXPHOS). Aβ and ATP, which are two known kinds of DAMPs that trigger microglial sterile activation, induced the morphology from irregular to amoebic, and significantly decreased others in the microglia, accompanied by boosting or reducing both glycolysis and OXPHOS. Monotonous pathological changes and energetic metabolism of microglia were observed under IL-4 exposure. Further, the inhibition of glycolysis transformed the LPS-induced proinflammatory morphology and decreased the enhancement of LPS-induced cell viability, the fusion rate and phagocytosis. However, the promotion of glycolysis exerted a minimal effect on the changes of morphology, the fusion rate, cell viability and phagocytosis induced by ATP. Our study reveals that microglia induced diverse pathological changes accompanied by various changes in the energetic metabolism in response to PAMPs, DAMPs and cytokines, and it may be a potential application of targeting the cellular metabolism to interfere with the microglia-mediated pathological changes in AD.Keywords:Alzheimer’s disease;microglia;DAMPs;PAMPs;cytokines;energetic metabolism
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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代谢
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DOI
PubMed
高影响因子
BIOMATERIALS
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2023
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IF 14
Xiao Wang,Yang Liu,Mingxi Li,Yongxu Ju,Jian Tang,Tiandong Chen,Xubo Lin,Ning Gu,Fang Yang
Epilepsy is a common neurological disease caused by synchronous firing of hyperexcitable neurons. Currently, patients with epilepsy are typically treated with antiseizure medicines that work by interrupting the hyperexcitability or hypersynchrony of localized neurons or by inhibiting excitatory neurotransmission. However, these drugs do not treat the underlying causes of epilepsy, and nearly one-third of patients have seizures that cannot be controlled by these medications. Animal and clinical evidence suggests that inflammation caused by neuronal and non-neuronal cells within the epilepsy lesion could play a central role in seizure disorders. Here we report a gas-filled nanobubble (NB) conjugated with diammonium glycyrrhizinate (DG) drugs and sphingosine-1-phosphate (S1P) molecules (S1P@DG–NBs) on the lipid shell for targeted therapy and real-time ultrasound visualization applications against neuroinflammatory injury. Affinity of S1P@DG-NBs for the S1P receptor endows these NBs with enhanced targeting capability to the neuroinflammatory microenvironment of epilepsy, where the DG drugs modulate endothelium-microglia-neuron inflammation by inhibiting high-mobility group box 1 molecules and downregulating the Toll-like receptor 4 signaling pathway, resulting in anti-inflammatory M2 microglia that exert anti-epilepsy effects. Our results show that this technology can enhance visualization of epileptic brain and deliver drugs with anti-inflammatory and immunomodulatory properties to ameliorate seizures symptoms.
研究领域:
神经科学
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药理学
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生物医学工程
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神经病学
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
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2026
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IF 10.4
Liu An,Zhang Ming-jun,Guo Jin-rong,Chu Han,Liu Song-bin,Chen Dan-yang,Kai Yuan-zhong,Cao Peng,Zhang Zhi
Although pain sensitization is among the most common conditions affecting the elderly, its underlying neural mechanisms remain unclear. Here, we found that mechanical hypersensitivity arises from enhanced glutamatergic excitability in primary somatosensory cortex due to bradykinin receptor B2 (BDKRB2) upregulation by dystrophic microglia during aging. Specifically, in vivo fiber photometry in aged mice revealed hyperactivity of glutamatergic neurons in primary somatosensory cortex of hindlimb (S1HL Glu ), while chemogenetic inhibition of these neurons reverses pain hypersensitivity in aged mice. BDKRB2 expression on S1HL Glu neurons is significantly increased in aged mice, whereas its conditional knockdown restores pain sensitization, and its overexpression leads to nociceptive hypersensitivity in young mice. Moreover, chemogenetic or pharmacological inhibition of dystrophic microglia in aged mice reduces BDKRB2 levels, alleviating pain hypersensitivity. The present study thus demonstrates that microglia-mediated S1HL Glu hyperactivity drives development of aging-related pain via BDKRB2 signaling, suggesting several potentially effective therapeutic targets for treating geriatric pain.
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DOI
高影响因子
SCIENCE
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2025
·Vol. 389
·期 6756
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IF 45.8
Jingying Wu,Yafei Wang,Xiaoyu Li,Pei Ouyang,Yuanyuan Cai,Yang He,Mengyuan Zhang,Xinghua Luan,Yuxiao Jin,Jie Wang,Yujie Xiao,Yuqing Liang,Fang Xie,Yousheng Shu,Jiong Hu,Chunkang Chang,Jieling Jiang,Dong Wu,Youshan Zhao,Taohui Liu,Yuxin Li,Xiaojun Huang,Yao Li,Junfang Zhang,Yuwen Cao,Xin Cheng,Ying Mao,Yanxia Rao,Li Cao,Bo Peng
Colony-stimulating factor 1 receptor ( CSF1R ) is primarily expressed in microglia. Its monoallelic mutation causes CSF1R-associated microgliopathy (CAMP), a major form of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and a fatal neurological disease without clinical cure. We developed mouse models harboring human hotspot mutations of CAMP and replaced CSF1R-deficient microglia with CSF1R-normal cells through microglia replacement by bone marrow transplantation (Mr BMT), which attenuated pathology in mice. We further demonstrated that, in the context of CSF1R deficiency, traditional bone marrow transplantation (tBMT) in ALSP functions similarly to Mr BMT, efficiently replacing microglia and reducing disease progression. We then replaced CSF1R-deficient microglia in eight patients by tBMT. The disease progression was halted during the 24-month follow-up. Together, microglia replacement corrects pathogenic mutations and halts disease progression in mice and humans.
研究领域:
神经生物学
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免疫学
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遗传学
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转化医学
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血液病学
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产品关联
DOI
PubMed
高影响因子
MATERIALS & DESIGN
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2025
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IF 7.9
Siyu Wu,Di You,Ying Chen,Hongqi Meng,Huidong Zhou,Guokun Zhang,Mikhail I. Voevoda,Rui Li,Wenlai Guo,Wenrui Qu
Diabetic peripheral neuropathy (DPN) causes persistent pain and sensory dysfunction due to neuroinflammation, where pro-inflammatory microglial polarization is a key therapeutic target. ARA290, a peptide derived from erythropoietin with non-hematopoietic activity, offers neuroprotection and pain relief. However, its clinical utility has been constrained by intrinsic peptide limitations in administration and pharmacokinetics. To overcome this, we developed a biocompatible polymeric microneedle (MN) patch. This patch features hydrogel-forming tips loaded with ARA290 and a soluble backing, enabling sustained drug release upon dermal insertion with minimal irritation. In DPN model rats, the MN patches induced significantly early reductions in allodynia and hyperalgesia. Electrophysiological and histological assessments showed improved nerve conduction velocity and intraepidermal nerve density, respectively. Notably, sustained release promoted anti-inflammatory (M2) microglial polarization, reducing central neuroinflammation. Collectively, this MN patch-based strategy effectively alleviates peripheral neuropathy and inhibits central sensitization, offering a promising approach for advanced DPN treatment
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高影响因子
Journal of Neuroinflammation
·
2023
·Vol. 20
·期 1
·1-16
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IF 9.3
Long Dan-dan,Zhang Yu-zhuo,Liu An,Shen Liang,Wei Hong-rui,Lou Qian-qian,Hu Shan-shan,Chen Dan-yang,Chai Xiao-qing,Wang Di
Background Long-term smoking is a risk factor for chronic pain, and chronic nicotine exposure induces pain-like effects in rodents. The anterior cingulate cortex (ACC) has been demonstrated to be associated with pain and substance abuse. This study aims to investigate whether ACC microglia are altered in response to chronic nicotine exposure and their interaction with ACC neurons and subsequent nicotine-induced allodynia in mice.Methods We utilized a mouse model that was fed nicotine water for 28 days. Brain slices of the ACC were collected for morphological analysis to evaluate the impacts of chronic nicotine on microglia. In vivo calcium imaging and whole-cell patch clamp were used to record the excitability of ACC glutamatergic neurons.Results Compared to the vehicle control, the branch endpoints and the length of ACC microglial processes decreased in nicotine-treated mice, coinciding with the hyperactivity of glutamatergic neurons in the ACC. Inhibition of ACC glutamatergic neurons alleviated nicotine-induced allodynia and reduced microglial activation. On the other hand, reactive microglia sustain ACC neuronal excitability in response to chronic nicotine, and pharmacological inhibition of microglia by minocycline or liposome-clodronate reduces nicotine-induced allodynia. The neuron-microglia interaction in chronic nicotine-induced allodynia is mediated by increased expression of neuronal CX3CL1, which activates microglia by acting on CX3CR1 receptors on microglial cells.Conclusion Together, these findings underlie a critical role of ACC microglia in the maintenance of ACC neuronal hyperactivity and resulting nociceptive hypersensitivity in chronic nicotine-treated mice.
研究领域:
神经科学
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疼痛研究
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药理学
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产品关联
DOI
PubMed
高影响因子
NEUROTOXICITY RESEARCH
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2021
·Vol. 39
·期 6
·1800-1811
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IF 3.911
Zhou Wei,Hu Mengmeng,Hu Jingrong,Du Zhiyun,Su Qing,Xiang Zhangmin
Microglia-mediated neuroinflammation in response to injurious self and non-self-stimuli exerts detrimental effects on neurons, which may lead to cognitive impairment. Luteolin, a typical kind of natural flavonoid in honeysuckle, chrysanthemum, and Herba Schizonepetae , is widely recognized to be anti-inflammatory and antioxidant against peripheral inflammation. However, its protective effect against inflammation-induced cognitive impairment is currently unknown. In this paper, we investigated the relief potential of luteolin against lipopolysaccharide (LPS)-induced cognitive impairment and neuroinflammation and its possible anti-inflammatory mechanisms in lipopolysaccharide-stimulated BV2 microglia cells. In this study, luteolin ameliorated LPS-induced cognitive impairments, indicated by behavioral performance of neuroinflammatory model mice in Morris water maze tests. Protein analyses and histological examination also revealed protective effect of luteolin against neuronal damage, through inhibiting overproduction of inflammatory cytokines in both hippocampus and cortex of mice. We also observed luteolin in vitro significantly suppressed the levels of pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-1 β (IL-1β), and inflammatory mediators like nitric oxide. Taken together, these results demonstrated luteolin was effective in alleviating cognitive impairment and limited neuronal damage via inhibiting the release of inflammatory mediators, suggesting luteolin is potential for further therapeutic research of neuroinflammation-related neurodegenerative diseases.
研究领域:
神经科学
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药理学
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免疫学
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神经退行性疾病
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产品关联
DOI
PubMed
高影响因子
MOLECULAR PSYCHIATRY
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2023
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IF 11
Sun Jia,Wang Xinyuan,Sun Rui,Xiao Xiaoao,Wang Yu,Peng Yu,Gao Yuanqing
The hypothalamus plays a crucial role in controlling metabolism and energy balance, with Agouti-related protein (AgRP) neurons and proopiomelanocortin (POMC) neurons being essential components of this process. The proper development of these neurons is important for metabolic regulation in later life. Microglia, the resident immune cells in the brain, have been shown to significantly influence neurodevelopment. However, their role in shaping the postnatal development of hypothalamic neural circuits remains underexplored. In this study, we investigated the dynamic changes of microglia in the hypothalamic arcuate nucleus (ARC) during lactation and their impact on the maturation of AgRP and POMC neurons. We demonstrated that microglial depletion during a critical period of ARC neuron maturation increases the number of AgRP neurons and fiber density, with less effect on POMC neurons. This depletion also resulted in increased neonatal feeding behavior. Mechanistically, microglia can engulf perineuronal net (PNN) components surrounding AgRP neurons both in vivo and ex vivo. The absence of microglia leads to increased PNN formation and enhanced leptin sensitivity in ARC. Our findings suggest that microglia participate in the postnatal development of AgRP neurons by regulating the plasticity of PNN formation. This study contributes to a better understanding of microglia’s role in shaping hypothalamic neural circuits during postnatal development and their impact on metabolism regulation.
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DOI
PubMed
高影响因子
BIOMATERIALS
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2026
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IF 13.6
Xinzhu Sun,Yilong Xi,Yun Chen,Jianping Zhou,Jiang Ni,Yang Ding,Huaqing Zhang
Amyloid-β (Aβ) clearance holds promise in Alzheimer's disease (AD) treatment, but the clinical application is limited by poor clearance efficacy and microglial inflammatory cascade caused by overloaded Aβ degradation. In this study, a polymeric lipoprotein-curcumin nanoscavenger (CP/ Man Disc-Cur) with dysfunctional microglia-specific targeting capability is designed to synergistically promote Aβ clearance and inhibit microglial inflammatory cascade. For preparation, curcumin is post-encapsulated into mannose-modified Disc ( Man Disc-Cur), followed by assembly with chitosan derivatives (CP) to obtain CP/ Man Disc-Cur. After intranasal administration and triggered by the nasal acidic microenvironment, CP/ Man Disc-Cur is depolymerized into Man Disc-Cur and protonated CP that adheres to reversibly open the tight junctions, promoting Man Disc-Cur penetration into the brain via the olfactory pathway. Thereafter, Man Disc-Cur captures Aβ oligomer with a high binding affinity (K D = 5.90 × 10 −8 M) and selectively targets dysfunctional microglia where Aβ catabolism is accelerated with inflammation inhibition by curcumin. After nasal treatment of CP/ Man Disc-Cur for 4 weeks, Aβ burden, microglial inflammation, and memory deficits of APPswe/PS1dE9 transgenic AD mice are significantly attenuated without the obvious side effects. Collectively, this study provides a promising strategy for synergistically improving Aβ clearance and inhibiting microglial inflammatory cascade for enhanced AD treatment.
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DOI
PubMed
高影响因子
NEURON
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2026
·
IF 16.9
Haoran Zhang,Zhen Liu,Bijia Chen,Guangxin Zhang,Longteng Wang,Changsheng Wei,Xiaohui Zhang,Yuxiang Luo,Ting Peng,Qing Fang,Lei Gu,Ruicheng Ge,Jiangning Zhu,Ruiying Yang,Weiguo Shen,Zhujun Jiang,Yufang Sun,Weixun Duan,Jincheng Liu,Tingting Li,Jing Wang,Zhihua Gao,Xiang Yu,Hebing Chen,Zilu Ye,Xiaomeng Shi,Cheng Li
Microglia are brain-resident immune cells with complex physiological functions. Exploring their proteomic heterogeneity at the single-cell level has remained technically challenging. Here, we optimized a label-free single-cell proteomics (SCP) workflow using Orbitrap Astral mass spectrometry (MS) and applied it to fluorescence-activated cell sorting (FACS)-sorted microglia from the hippocampus and prefrontal cortex of young, middle-aged, and aged mice. This yielded one of the largest SCP datasets to date, comprising 3,085 single cells, with an average of 1,153 protein groups identified per cell. Compared with single-cell transcriptomic data, the SCP dataset showed higher expression completeness and moderate cross-modality correlation. This dataset revealed spatiotemporal proteomic heterogeneity of microglia during aging. Notably, we defined the microglial “phagoproteome,” uncovering state-specific phagocytic preferences, and verified these results by imaging. This study underscores the potential of SCP to reveal subpopulation-specific proteomic dynamics and provides a new resource for studying microglial state transitions during aging.
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
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2025
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IF 8.2
Zhipeng Li,Wenyu Wang,Liping Zhu,Zhiqiang Wang,Chaolong Liu,Yong Sun,Jingliang Wu,Qing Wang
Diabetic retinopathy (DR), as the most common microvascular complication of diabetes, seriously threatens the vision of diabetic patients. As the resident phagocytes of the retina, microglia participate in inflammation, neovascularization, and neurodegeneration of DR. Herein, apoptotic retinal cell membrane-coated, rapamycin-loaded mesoporous Prussian blue NPs as immunomodulators for ameliorating DR by modulating microglial polarization are reported. The apoM@mPB@Ra NPs exhibited favorable stability and biocompatibility and achieved active targeted delivery due to the specific recognition between “eat me” signal expressed on apoptotic membrane and microglia. In an LPS-induced cellular inflammation model, apoM@mPB@Ra NPs effectively promoted microglial polarization toward the anti-inflammatory phenotype (M2) by scavenging intracellular reactive oxygen species (ROS) combined with affecting the mTOR signaling pathway, leading to downregulation of pro-inflammatory cytokines IL-6 and TNF-α. Meanwhile, owing to the multienzyme-like activities of mPB in nanoparticles, apoM@mPB@Ra NPs obviously alleviated cellular hypoxia, thereby decreasing the expression of VEGF. Notably, in a mouse model of DR, intravitreally injected apoM@mPB@Ra NPs significantly improved the severity of the abnormal retinal vascular network and inflammatory microenvironment of retinopathy by down-regulating the expression of HIF-1α, VEGF, and inflammatory-related cytokines. Collectively, these findings demonstrate that apoM@mPB@Ra NPs provide a promising and effective approach for the treatment of DR.
研究领域:
医学
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药学
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生物材料学
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产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
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2025
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IF 8.2
Xiaomeng Ji,Jingquan Dong,Wenting Zhu,Shasha Zhang,Yaru Chen,Xiao Liu,Yan Cao,Panpan Zhao,Zibo Dong
Background Sepsis-associated encephalopathy (SAE) represents one of the most common neurological complications observed in sepsis patients, contributing to both increased mortality and long-term cognitive impairment. Microglial mitochondrial reactive oxygen species (mtROS) overproduction and NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation were key pathological drivers of SAE. Although PIM-1, a serine/threonine kinase, was known to regulate both mtROS generation and NLRP3 signaling, its specific contribution to SAE remained poorly defined. Methods This study established a SAE mouse model using cecal ligation and puncture (CLP) surgery, and screened the differentially expressed gene PIM-1 through immunohistochemistry, GEO database analysis, and etc. An in vitro model was established using Lipopolysaccharide + Adenosine(LPS + ATP) Triphosphate stimulated Mouse Microglia (BV-2), and the regulation mechanism of PIM-1 was analyzed through siRNA interference, RNA-seq, and etc. Potential drug Urolithin B (UB) targeting PIM-1 inhibition was screened through molecular docking, and its inhibitory effect on PIM-1 and therapeutic potential in SAE were evaluated through thermal stability experiments, behavioral experiments, etc. Results PIM-1 was upregulated in SAE, which was associated with brain damage. PIM-1 knockdown suppressed microglial activation and reduced inflammatory cytokines release. Further investigation indicated that PIM-1 modulated mtROS generation and facilitated NLRP3 inflammasome activation. Notably, pharmacological inhibition of PIM-1 by UB alleviated SAE both in vivo and in vitro , resulting in improved neuronal damage and cognitive impairment. Conclusion PIM-1 played a critical role in SAE progression, potentially through its mediation of microglial activation and neuroinflammation via the mtROS/NLRP3 axis. Notably, pharmacological inhibition of PIM-1 with urolithin B significantly alleviated SAE.
研究领域:
神经免疫学
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重症医学
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分子神经生物学
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炎症与感染
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转化神经科学
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药理学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）