Ischemia-induced Neuronal Cell Death Is Mediated by Chemokine Receptor CX3CR1
Open accessAbstract
The chemokine fractalkine (CX3CL1) and its receptor CX3CR1 play a fundamental role in the pathophysiology of stroke. Previous studies have focused on a paracrine interaction between neurons that produce fractalkine and microglia that express CX3CR1 receptors in the central nervous system. Recent findings have demonstrated the functional expression of CX3CR1 receptors by hippocampal neurons, suggesting their involvement in neuroprotective and neurodegenerative actions. To elucidate the roles of neuronal CX3CR1 in neurodegeneration induced by ischemic stroke, a mouse model of permanent middle cerebral artery occlusion (pMCAO) was employed. In the pMCAO mice, increased CX3CR1 levels, apoptosis-associated morphological changes, and Caspase 3-positive neuronal cells were observed in the striatum and in the hippocampus 24 hours after occlusion. Upregulation of CX3CR1 in ischemic neurons is associated with neuronal apoptotic cell death. In contrast, ischemia-induced apoptotic neuronal cell death was decreased in CX3CR1 deficient mice. Cultured primary hippocampal neurons obtained from CX3CR1 deficient mice were more resistant to glutamate-induced excitotoxicity by blocking calcium influx than those from wild-type mice. For the first time, we reported that neuronal CXCR1 mediates neuronal apoptotic cell death in ischemia. Our results suggest that modulating CXCR1 activity offers a novel therapeutic strategy for stroke.
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Wang et al. reported that transient expression of Cx3cr1 in neurons is neuronal protective in an ischemic model.
“Wang et al., reported that transient expression of Cx3cr1 in neurons is neuronal protective in an ischemic model (Wang et al., 2018).”
From Targeting Microglia Using Cx3cr1-Cre Lines: Revisiting the Specificity (2019) · cites this paper as Wang et al., 2018
The Discussion states the opposite: elevated neuronal CX3CR1 is associated with apoptotic death, while CX3CR1 deficiency protects against ischemic brain damage. The study used a permanent, not transient, ischemia model. The supplied passages have section labels but no page numbers. (LLM, conf=0.94)
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Experimental — accuracy not yet measuredIn Wang et al., the IHC data showed that the majority of Cx3cr1-positive cells were neurons and very few, if any, were microglia.
“However, oddly, the IHC data showed that the majority of Cx3cr1-positive cells were neurons and very few, if any, were microglia.”
From Targeting Microglia Using Cx3cr1-Cre Lines: Revisiting the Specificity (2019) · cites this paper as Wang et al., 2018
In Results, Figure 2, the double staining is described as showing CX3CR1 mainly in ischemic neurons, supporting the majority-neuronal part of the claim. The same Results section reports CX3CR1 upregulation in microglia at a relatively lower level at 24 hours, but does not establish that very few, if any, CX3CR1-positive cells were microglia. (LLM, conf=0.86)
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Cites
Jung, S., Aliberti, J., Graemmel, P., Sunshine, M. J., Kreutzberg, G. W., Sher, A., & Littman, D. R. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.11.4106-4114.2000 · Cited by 2,632 · see citing works
A new class of membrane-bound chemokine with a CX3C motif
Bazan, J. F., Bacon, K. B., Hardiman, G., Wang, W., Soo, K., Rossi, D., Greaves, D. R., Zlotnik, A., & Schall, T. J. (1997) · Nature · doi:10.1038/385640a0 · Cited by 2,013 · see citing works
Harrison, J. K., Jiang, Y., Chen, S., Xia, Y., Maciejewski, D., McNamara, R. K., Streit, W. J., Salafranca, M. N., Adhikari, S., Thompson, D. A., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.18.10896 · Cited by 1,176 · cited 1× · see citing works
“(5) Neutralizing the CX3CR1 with anti-CX3CR1 antibody could attenuate the damage of glutamate, (6) while the same animal source of anti-IgG antibody could not attenuate the damage.”
BackgroundNational Vital Statistics Reports NCHS.pdf
Hoyert, D. (2012) · Medical Entomology and Zoology · Cited by 984 · see citing works
Murphy, S. L., Xu, J., & Kochanek, K. D. (2013) · PubMed · Cited by 894 · see citing works
Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity
Meucci, O., Fatatis, A., Simen, A. A., Bushell, T. J., Gray, P. W., & Miller, R. J. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.24.14500 · Cited by 692 · see citing works
Use of structural magnetic resonance imaging to predict who will get Alzheimer's disease
Killiany, R., Gómez‐Isla, T., Moss, M. B., Kikinis, R., Sándor, T., Jolesz, F. A., Tanzi, R. E., Jones, K. J., Hyman, B. T., & Albert, M. (2000) · Annals of Neurology · doi:10.1002/1531-8249(200004)47:4 · Cited by 659 · see citing works
Culturing pyramidal neurons from the early postnatal mouse hippocampus and cortex
Beaudoin, G. M. J., Lee, S.-H., Singh, D., Yuan, Y., Ng, Y., Reichardt, L. F., & Arikkath, J. (2012) · Nature Protocols · doi:10.1038/nprot.2012.099 · Cited by 655 · see citing works
Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation
Pan, Y., Lloyd, C. M., Zhou, H., Dolich, S., Deeds, J., Gonzalo, J.-Á., Vath, J., Gosselin, M., Ma, J., Dussault, B. J., et al. (1997) · Nature · doi:10.1038/42491 · Cited by 643 · see citing works
Expression of CX <sub>3</sub> CR1 chemokine receptors on neurons and their role in neuronal survival
Meucci, O., Fatatis, A., Simen, A. A., & Miller, R. J. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.090017497 · Cited by 385 · see citing works
Nishiyori, A., Minami, M., Ohtani, Y., Takami, S., Yamamoto, J., Kawaguchi, N., Kume, T., Akaike, A., & Satoh, M. (1998) · FEBS Letters · doi:10.1016/s0014-5793(98)00583-3 · Cited by 367 · cited 1× · see citing works
“(5) Neutralizing the CX3CR1 with anti-CX3CR1 antibody could attenuate the damage of glutamate, (6) while the same animal source of anti-IgG antibody could not attenuate the damage.”
BackgroundMaciejewski-Lenoir, D., Chen, S., Feng, L., Maki, R. A., & Bacon, K. B. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.163.3.1628 · Cited by 357 · see citing works
Production and neuroprotective functions of fractalkine in the central nervous system.
Mizuno, T., Kawanokuchi, J., Numata, K., & Suzumura, A. (2003) · Brain Research · doi:10.1016/s0006-8993(03)02867-1 · Cited by 352 · cited 2× · see citing works
“Our principal findings are: (1) CX3CR1 is unregulated in ischemic neurons in vitro and in a mouse model of permanent focal ischemia; (2) neuronal CX3CR1 elevation is associated with apoptotic neuronal death; (3) CX3CR1 deficiency protects mice from ischemic brain damage in vivo; (4) CX3CR1 deficiency reduces glutamate…”
BackgroundCa 2+ Signals and Neuronal Death in Brain Ischemia
Bano, D., & Nicotera, P. (2007) · Stroke · doi:10.1161/01.str.0000256294.46009.29 · Cited by 309 · see citing works
Chen, J., Zacharek, A., Zhang, C., Jiang, H., Li, Y., Roberts, C., Lu, M., Kapke, A., & Chopp, M. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.5071-04.2005 · Cited by 287 · see citing works
Dénes, Á., Ferenczi, S., Halász, J., Környei, Z., & Kovács, K. J. (2008) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2008.64 · Cited by 276 · see citing works
Ischemic neurons recruit natural killer cells that accelerate brain infarction
Gan, Y. X., Liu, Q., Wu, W., Yin, J., Bai, X., Shen, R. Z., Wang, Y., Chen, J., Cava, A. L., Poursine‐Laurent, J., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1315943111 · Cited by 275 · see citing works
Self-citationHughes, P. M., Botham, M. S., Frentzel, S., Mir, A., & Perry, V. H. (2002) · Glia · doi:10.1002/glia.10037 · Cited by 252 · see citing works
Donnelly, D. J., Longbrake, E. E., Shawler, T. M., Kigerl, K. A., Lai, W., Tovar, C. A., Ransohoff, R. M., & Popovich, P. G. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.2114-11.2011 · Cited by 219 · see citing works
Tang, Z., Gan, Y. X., Liu, Q., Yin, J., Liu, Q., Shi, J., & Shi, F. (2014) · Journal of Neuroinflammation · doi:10.1186/1742-2094-11-26 · Cited by 192 · see citing works
Self-citationTüreyen, K., Vemuganti, R., Sailor, K. A., & Dempsey, R. J. (2004) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2004.04.029 · Cited by 180 · see citing works
CX3CR1 deficiency induces an early protective inflammatory environment in ischemic mice
Fumagalli, S., Perego, C., Ortolano, F., & Simoni, M. G. D. (2013) · Glia · doi:10.1002/glia.22474 · Cited by 179 · see citing works
Isolation and Culture of Hippocampal Neurons from Prenatal Mice
Seibenhener, M. L., & Wooten, M. W. (2012) · Journal of Visualized Experiments · doi:10.3791/3634 · Cited by 178 · see citing works
Chemokine CX3CL1 protects rat hippocampal neurons against glutamate-mediated excitotoxicity
Limatola, C., Lauro, C., Catalano, M., Ciotti, M. T., Bertollini, C., Di Angelantonio, S., Ragozzino, D., & Eusebi, F. (2005) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2005.03.023 · Cited by 153 · see citing works
Chemokines and chemokine receptors: multipurpose players in neuroinflammation.
Ransohoff, R., Liu, L.-P., & Cardona, A. (2007) · International review of neurobiology · doi:10.1016/s0074-7742(07)82010-1 · Cited by 151 · see citing works
Taoufik, E., & Probert, L. (2008) · Current Pharmaceutical Design · doi:10.2174/138161208786848748 · Cited by 146 · see citing works
Heiss, W., Kracht, L., Grond, M., Rudolf, J., Bauer, B., Wienhard, K., & Pawlik, G. (2000) · Stroke · doi:10.1161/01.str.31.2.366 · Cited by 143 · see citing works
Mitsios, N., Gaffney, J. J., Kumar, P., Krupiński, J., Kumar, S., & SLEVIN, M. A. (2006) · Pathobiology · doi:10.1159/000096017 · Cited by 73 · cited 3× · see citing works
“Our principal findings are: (1) CX3CR1 is unregulated in ischemic neurons in vitro and in a mouse model of permanent focal ischemia; (2) neuronal CX3CR1 elevation is associated with apoptotic neuronal death; (3) CX3CR1 deficiency protects mice from ischemic brain damage in vivo; (4) CX3CR1 deficiency reduces glutamate…”
BackgroundMethodExpression of functional chemokine receptors by rat cerebellar neurons
Gillard, S. E., Lü, M., Mastracci, R. M., & Miller, R. J. (2002) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(02)00005-x · Cited by 64 · see citing works
Zhao, Y., Fu, B., Zhang, X., Zhao, T., Chen, L., Zhang, J., & Wang, X. (2014) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2014.09.008 · Cited by 58 · see citing works
Yeo, S.-I., Kim, J.-E., Ryu, H. J., Seo, C. H., Lee, B. C., Choi, I.-G., Kim, D.-S., & Kang, T.-C. (2011) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2011.03.005 · Cited by 55 · see citing works
Neuronal Cx3cr1 Deficiency Protects against Amyloid β-Induced Neurotoxicity
Dworzak, J., Renvoisé, B., Habchi, J., Yates, E. V., Combadière, C., Knowles, T. P., Dobson, C. M., Blackstone, C., Paulsen, O., & Murphy, P. M. (2015) · PLOS ONE · doi:10.1371/journal.pone.0127730 · Cited by 30 · see citing works
Pickering, M., Pickering, B., Murphy, K. J., & O'Connor, J. J. (2008) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2008.05.014 · Cited by 17 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Neuroinflammation: friend and foe for ischemic stroke
Jayaraj, R. L., Azimullah, S., Beiram, R., Jalal, F. Y., & Rosenberg, G. A. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1516-2 · Cited by 1,438 · see citing works
Immune responses to stroke: mechanisms, modulation, and therapeutic potential.
Iadecola, C., Buckwalter, M. S., & Anrather, J. (2020) · Journal of Clinical Investigation · doi:10.1172/jci135530 · Cited by 853 · see citing works
Recent advancements in the use of exosomes as drug delivery systems
Bunggulawa, E. J., Wang, W., Yin, T., Wang, N., Durkan, C., Wang, Y., & Wang, G. (2018) · Journal of Nanobiotechnology · doi:10.1186/s12951-018-0403-9 · Cited by 590 · see citing works
Glutamate excitotoxicity: Potential therapeutic target for ischemic stroke
Shen, Z., Xiang, M., Chen, C., Ding, F., Wang, Y., Shang, C., Xin, L., Zhang, Y., & Cui, X. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113125 · Cited by 236 · see citing works
CX3CL1/CX3CR1 signaling targets for the treatment of neurodegenerative diseases
Subbarayan, M. S., Joly‐Amado, A., Bickford, P. C., & Nash, K. R. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107989 · Cited by 204 · see citing works
Przykaza, Ł. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.782569 · Cited by 177 · see citing works
NG2 glia regulate brain innate immunity via TGF-β2/TGFBR2 axis
Zhang, S.-Z., Wang, Q., Yang, Q., Gu, H., Yin, Y., Li, Y., Hou, J., Chen, R., Sun, Q., Sun, Y., et al. (2019) · BMC Medicine · doi:10.1186/s12916-019-1439-x · Cited by 138 · see citing works
Rivas-Fuentes, S., Salgado-Aguayo, A. R., Arratia-Quijada, J., & Gorocica-Rosete, P. (2020) · Journal of Cancer · doi:10.7150/jca.47022 · Cited by 101 · see citing works
“In the murine model of stroke by occlusion of the middle cerebral artery, it was observed that 24 hours after the stroke, there was a positive regulation of CX3CR1 expression in hippocampal neurons and an increase in neuronal apoptosis, but in CX3CR1 mice, apoptosis was diminished [59] so the disruption of the CX3CL1-…”
BackgroundTargeting Microglia Using Cx3cr1-Cre Lines: Revisiting the Specificity
Zhao, X.-F., Alam, M. M., Liao, Y., Huang, T., Mathur, R., Zhu, X., & Huang, Y. (2019) · eneuro · doi:10.1523/eneuro.0114-19.2019 · Cited by 92 · see citing works
“Transient Cx3cr1 activity in neurons and astrocytes following excitatory injury Cx3cr1 was reported to be expressed in cultured neurons and induced in neurons and astrocytes following brain ischemia and severe seizures, respectively (Meucci et al., 2000; Yeo et al., 2011; Dworzak et al., 2015; Wang et al., 2018).”
BackgroundSenescence as an Amyloid Cascade: The Amyloid Senescence Hypothesis
Walton, C. C., Begelman, D. V., Nguyen, W., & Andersen, J. K. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00129 · Cited by 61 · see citing works
Wu, C., Duan, F., Yang, R., Dai, Y., Chen, X., & Li, S. (2023) · Phytomedicine · doi:10.1016/j.phymed.2023.154790 · Cited by 53 · see citing works
Zhang, B., Zou, J., Han, L., Beeler, B., Friedman, J. L., Griffin, E., Piao, Y., Rensing, N. R., & Wong, M. (2018) · Epilepsia · doi:10.1111/epi.14526 · Cited by 50 · see citing works
Modulation of Neural Networks by Interleukin-1
Nemeth, D. P., & Quan, N. (2020) · Brain Plasticity · doi:10.3233/bpl-200109 · Cited by 44 · see citing works
“The loss of neurons via necrosis and apoptosis occur following traumatic brain injuries [42], excitotoxic injuries [43], substance abuse [44], and ischemia [45].”
BackgroundYu, L., Jin, Z., Li, M., Liu, H., Tao, J., Xu, C. L., Wang, L., & Zhang, Q. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1063035 · Cited by 43 · see citing works
“…in OGD/R-insulted BMECs and MCAO rats, which is inconsistent with the observation of Qi et al. A body of studies has demonstrated that autophagy increases in cerebral I/R injury, and both harmful and protective potentials of autophagy have been reported (Wang et al., 2013; Luo et al., 2014).”
ResultStructure and Function of Ligand CX3CL1 and its Receptor CX3CR1 in Cancer
Lu, X. (2022) · Current Medicinal Chemistry · doi:10.2174/0929867329666220629140540 · Cited by 39 · see citing works
Barkaway, A., Attwell, D., & Korte, N. (2022) · Neurophotonics · doi:10.1117/1.nph.9.3.031914 · Cited by 37 · see citing works
“In the healthy brain, FKN promotes synaptic strength, neurogenesis, and memory formation and may act as a “find me” signal for microglia to clear neuronal debris,(201,235,236) but, after stroke, signaling via FKN reduces CBF, enhances neuronal apoptosis and worsens neurological outcome in mice.(120,237,238) In the mou…”
BackgroundDrivers of Chronic Pathology Following Ischemic Stroke: A Descriptive Review
Goodman, G. W., Do, T. H., Tan, C., & Ritzel, R. M. (2023) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-023-01437-2 · Cited by 35 · see citing works
“For instance, disturbances in microglial CX3CR1, the receptor for the neuronal ligand CX3CL1, were shown to attenuate stroke-induced apoptosis and infarct volume (Tang et al. 2014; Wang et al. 2018).”
Guo, X., Rao, Y., Mao, R., Cui, L., & Fang, Y. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.108336 · Cited by 35 · see citing works
Fractalkine signaling regulates oligodendroglial cell genesis from SVZ precursor cells
Watson, A. E. S., de Almeida, M. M. A., Dittmann, N. L., Li, Y., Torabi, P., Footz, T. K., Vetere, G., Galleguillos, D., Sipione, S., Cardona, A. E., et al. (2021) · Stem Cell Reports · doi:10.1016/j.stemcr.2021.06.010 · Cited by 34 · see citing works
“Intriguingly, NPCs and OPCs express chemokine receptors in the developing and adult CNS (reviewed in Watson et al., 2020).”
BackgroundInfluentialJin, T., & Leng, B. (2022) · Applied Biochemistry and Biotechnology · doi:10.1007/s12010-022-04060-x · Cited by 32 · see citing works
“After the completion of the experiment, the brain tissues were collected and processed by immersing the collected tissues of 2 mm thickness in 2% tetrazolium chloride solution for 10 min at room temperature and analyzed for CIR [15, 17].”
MethodRole of CXCR1 and Interleukin-8 in Methamphetamine-Induced Neuronal Apoptosis
Du, S., Zhang, W., Yue, X., Luo, X., Tan, X.-H., Liu, C., Qiao, D., & Wang, H. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00230 · Cited by 30 · see citing works
“The pro-inflammatory IL-8 is a multi-functional CXC chemokine of about 75 amino acids in length (Waugh and Wilson, 2008; Citro et al., 2015).”
BackgroundMichalettos, G., & Ruscher, K. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.807911 · Cited by 30 · see citing works
The effect of CX3CL1/ CX3CR1 signal axis on microglia in central nervous system diseases
Zhao, J., Li, Q., Ouyang, X., Wang, F., Li, Q., Xu, Z., Ji, D., Wu, Q., Zhang, J., Lu, C., et al. (2023) · Journal of Neurorestoratology · doi:10.1016/j.jnrt.2023.100042 · Cited by 29 · see citing works
Blood-spinal cord barrier disruption in degenerative cervical myelopathy
Kim, H. W., Hu, Y. S., & Shea, G. K. (2023) · Fluids and Barriers of the CNS · doi:10.1186/s12987-023-00463-y · Cited by 28 · see citing works
“In animal models, CNS hypoxia induces neuroglia to release proinflammatory cytokines such as IL-1β, IL-6, IL-8, FasL, and TNF-α [90, 95–97].”
BackgroundThe roles of chemokines following intracerebral hemorrhage in animal models and humans
Wang, J., Bian, L., Du, Y., Wang, D., Jiang, R., Lu, J., & Zhao, X. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.1091498 · Cited by 27 · see citing works
Self-citationMicroglia–neuron–vascular interactions in ischemia
Lénárt, N., Cserép, C., Császár, E., Pósfai, B., & Dénes, Á. (2023) · Glia · doi:10.1002/glia.24487 · Cited by 27 · see citing works
“…et al., 2015), while CX3CR1 GFP/GFP mice, which have altered microglial phenotypes and microglia – neuron – vascular interactions, showed decreased lesion volume and BBB injury in several studies (Table 1) (Denes et al., 2008; Fumagalli et al., 2013; Jolivel et al., 2015; Wang et al., 2018).”
BackgroundLin, X., Zhan, J., Jiang, J., & Ren, Y. (2021) · Journal of Inflammation Research · doi:10.2147/jir.s307841 · Cited by 25 · see citing works
Cichoń, N., Synowiec, E., Miller, E. D., Śliwiński, T., Ceremuga, M., Saluk, J., & Bijak, M. (2020) · Brain Sciences · doi:10.3390/brainsci10050266 · Cited by 21 · see citing works
“There are many factors that can induce apoptosis of cells after ischaemia, such as inflammation, cytokine activation, cascade of free radicals, and induction of thrombin [6].”
BackgroundLi, H., Li, D., Zhang, Y.-L., Ding, X.-F., Gao, H., Zhu, Y., Liu, J., Zhang, L., Chen, J., Chen, G., et al. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1123387 · Cited by 20 · see citing works
Age-dependent changes on fractalkine forms and their contribution to neurodegenerative diseases
Eugenín, J. L., Bernhardi, L. E.-V., & Rommy von Bernhardi, M. (2023) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2023.1249320 · Cited by 17 · see citing works
“That is, CX 3 CR1 deletion can endow neuroprotection in mouse models of brain ischemia (Denes et al., 2008; Wang et al., 2018).”
InfluentialCX3CL1 Regulation of Gliosis in Neuroinflammatory and Neuroprotective Processes
Gutiérrez, I. L., Martín‐Hernández, D., MacDowell, K. S., García‐Bueno, B., Caso, J. R., Leza, J. C., & Madrigal, J. L. M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26030959 · Cited by 17 · see citing works
“In these cells, CX3CR1 expression has been associated with a larger degree of neuronal apoptosis in models of permanent middle cerebral artery occlusion [9].”
Ahn, J., Kim, D., Park, J. H., Lee, T., Lee, H., Won, M., & Lee, C. H. (2019) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2019.4273 · Cited by 16 · see citing works
“That study has suggested that neuronal cX3cR1 elevation might be associated with ischemia-induced apoptotic neuronal death (22).”
BackgroundMechanisms of glutamate metabolic function and dysfunction in vascular dementia
Wang, J., Zhang, Y., Tian, N., Ya, D., Yang, J., Jiang, Y., Li, X., Lin, X. S., Yang, B., Li, Q., et al. (2024) · Neuroprotection/Neuroprotection (Chichester, England. Print) · doi:10.1002/nep3.32 · Cited by 16 · see citing works
Self-citationCharacteristics and pathogenesis of chemokines in the post-stroke stage
Lin, Y.-T., Chen, H.-D., Ai, Q., Yang, Y., Zhang, Z., Chu, S., & Chen, N. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.109781 · Cited by 12 · see citing works
Zhan, L., Qiu, M., Zheng, J., Lai, M., Lin, K., Dai, J., Sun, W., & Xu, E. (2024) · Cell Communication and Signaling · doi:10.1186/s12964-024-01830-4 · Cited by 11 · see citing works
“Wang et al. observed in permanent MCAO model, elevated neuronal CX3CR1 expression in the peri-infarct, hippocampus and striatum after ischemia [53].”
BackgroundDrug delivery based exosomes uptake pathways
Dowaidar, M. (2024) · Neurochemistry International · doi:10.1016/j.neuint.2024.105835 · Cited by 10 · see citing works
Potential significance of CX3CR1 dynamics in stress resilience against neuronal disorders
Inoue, K. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.335831 · Cited by 10 · see citing works
“For example, inflammation-induced neurotoxicity in stroke models is reduced in CX3CR1deficient mice, whereas neurotoxicity appears to be increased by CX3CR1deficiency in Parkinson’s disease and amyotrophic lateral sclerosis (ALS) models (Cardona et al., 2006; Tang et al., 2014; Wang et al., 2018).”
BackgroundZhang, Y., Liu, Q., Zhang, T., et al. (2022) · Pharmaceutical Biology · doi:10.1080/13880209.2022.2134430 · Cited by 10 · see citing works
“The rat model of permanent middle cerebral artery occlusion (pMCAO) The pMCAO model was established by modified Longa method (Ma et al. 2018; Wang et al. 2018).”
MethodSelf-citationCX3CR1 mediates motor dysfunction in mice through 5-HTR2a
Pei, J., Zou, Y., Wan, C., Liu, S., Hu, B., Li, Z., & Tang, Z. (2023) · Behavioural Brain Research · doi:10.1016/j.bbr.2023.114837 · Cited by 9 · see citing works
“Studies have found that CX3CR1 is expressed in other cells, including neurons and astrocytes [4,5].”
BackgroundResultSelf-citationPertussis Toxin Ameliorates Microglial Activation Associated With Ischemic Stroke
Zhou, F., Liu, R., Han, P., Zhang, X., Li, Z., Zhang, S., Liu, C., Xia, Y., & Tang, Z. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00152 · Cited by 8 · see citing works
“The procedure for transient middle cerebral artery occlusion (tMCAO) model was described previously (Chen et al., 2005; Liesz et al., 2009; Wang et al., 2018).”
BackgroundMethodInfluentialSelf-citationYilmazer‐Hanke, D., Alami, N. O., Fang, L., Klotz, S., Kovács, G. G., Pankratz, H., Weis, J., Katona, I., Scheuerle, A., Streit, W. J., et al. (2022) · Neuroscience · doi:10.1016/j.neuroscience.2022.10.018 · Cited by 6 · see citing works
He, Q., Zhou, T., & He, Q. (2025) · Brain Sciences · doi:10.3390/brainsci15070759 · Cited by 5 · see citing works
“Chronic pro-inflammatory microenvironment: CX3CR1 drives persistent microglial pro-inflammatory polarization [51,91,92], establishing self-perpetuating neurotoxic microenvironments that amplify neural damage.”
Sambataro, M. P., Sambado, L., Colardo, M., Furlan, A., Stefani, P. M., Durante, E., Antico, A., Conte, S., Bella, S. D., Nollino, L., et al. (2025) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2025.109176 · Cited by 5 · see citing works
Septyaningtrias, D. E., Sholikah, T. A., Suhda, S., Sumiwi, Y. A. A., & Susilowati, R. (2025) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-025-10245-y · Cited by 2 · see citing works
“…expression may exert neuroprotective effects by preventing neuronal loss (Dworzak et al. 2015; Tang et al. 2014), inhibiting glutamate excitotoxicity (Wang et al. 2018), and decreasing the production of reactive oxygen species and proinflammatory cytokines by microg - lia (Tang et al. 2014 ).”
Zainuri, M., Purba, J. S., Jusman, S. W. A., et al. (2022) · The Saudi Dental Journal · doi:10.1016/j.sdentj.2022.08.005 · Cited by 2 · see citing works
“Other studies have reported that the addition of CM-SHED might inhibit apoptosis, reduce tissue loss in the brain, and improve neurological function in mice with ischemic hypoxia (Mita et al., 2015, Wang et al., 2018).”
Acute and Long-Term Consequences of Neonatal NMDA Blockade in the Cx3cr1 Knock-Out Mouse
Salcido, F. A. M., Torres-Flores, M. I., Ordaz, B., & Peña‐Ortega, F. (2025) · Inflammation · doi:10.1007/s10753-025-02272-x · Cited by 1 · see citing works
“…and psychiatric disorders including Parkinson’s [26], Alzheimer’s [27, 28], schizophrenia [29, 30], epilepsy [12, 31, 32], and ischemia [33–35], among others, with contrasting results ranging from protective to damaging depending on the nature of the insult and the stage of progression.”
Li, Y., & Wang, J. (2025) · European Journal of Neuroscience · doi:10.1111/ejn.70345 · Cited by 1 · see citing works
“The neuronal chemokine fractalkine receptor mediates apoptotic cell death during ischemia, while excessive glutamate release can overwhelm synaptic receptors, causing neuronal damage or death (Wang et al. 2018).”
Self-citationLi, R., Zhang, J., Wang, Q., Fan, J.-Q., & Lin, B. (2026) · Experimental & Molecular Medicine · doi:10.1038/s12276-025-01618-7 · Cited by 1 · see citing works
Rahman, M., Akter, K., Rani, A., Park, M. N., & Kim, B. (2026) · Nutrients · doi:10.3390/nu18111796 · Cited by 1 · see citing works
Hatayama, K., Kim, B., Chen, X. F., Lim, Y., Davidson, J. O., Bennet, L., Gunn, A. J., & Stonestreet, B. S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221910751 · Cited by 1 · see citing works
Duque, É. D. A. (2019) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.42.2019.tde-15102019-100704
“Entretanto, um estudo recente mostrou a expressão de CX3CR1 em neurônios de hipocampo de camundongos e uma relação direta entre presença deste receptor e morte neuronal por apoptose induzida por isquemia (58).”
Shevelev, A. A., Сороковиков, В. А., Larionov, S. N., et al. (2026) · Бюллетень Восточно-Сибирского научного центра Сибирского отделения Российской академии медицинских наук · doi:10.29413/abs.2025-10.6.11
Tiliwaerde, M., Dong, Z., Jingjing, L., Qi, L., Hongxian, J., Huan, G., Shen, W., Wei, G., & Jin, Z. (2026) · British Journal of Pharmacology · doi:10.1111/bph.70359
“In parallel, CX 3 CR1 , the receptor for the chemokine CX 3 CL1 (fractalkine ), substantially curtails the Ca 2 + inflow into ischaemic neurons in mice, serving to avert the neurotoxic impact of Ca 2 + overload (Wang et al., 2018).”
Najib, N., Wasinger, V. C., Doig, R. O., et al. (2026) · Redox Report · doi:10.1080/13510002.2026.2649669
Bryniarska, N., Kubiak, A., Trojan, E., et al. (2026) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.6c00005
Bioactive Food Ingredients in the Treatment of Neuroinflmammatory Disorders
Sehar, N., & Sehar, S. (2026) · Food bioactive ingredients · doi:10.1007/978-3-032-23814-6_11
Microglial CX3CR1 signaling mediates synaptic pruning in degenerative cervical myelopathy
Zhou, C. M., Asgarihafshejani, A., Hong, J., Brockie, S. T., Movahed, M., Sadat, S., Kouhzaei, S., & Fehlings, M. G. (2026) · Neurobiology of Disease · doi:10.1016/j.nbd.2026.107567
- Authors
- Wang, J., Gan, Y., Han, P., Yin, J., Liu, Q., Ghanian, S., Gao, F., Gong, G., & Tang, Z.
- Affiliations
- First Affiliated Hospital of Kunming Medical University (CN)
- Barrow Neurological Institute (US)
- Corresponding author
- Tang, Zhiwei
- Venue
- Scientific Reports
- Published
- 2018-01-11
- Volume
- 8
- Issue
- 1
- Pages
- 556-556
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5765008
- OpenAlex
- W2782347637
- Cited by
- 58
- References
- 33
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 3 · 2023: 10 · 2022: 10 · 2021: 5 · 2020: 7 · 2019: 6 · 2018: 3
- FWCI
- 2.36
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Natural Science Foundation of China (2017FE467, 81360204, 81760220)
- Kunming Medical University (2017FE467-)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Keywords
- CX3CR1, fractalkine, ischemic stroke, neuronal apoptosis, hippocampal neurons, middle cerebral artery occlusion, excitotoxicity, glutamate, caspase-3, neuroprotection, stroke treatment
- MeSH terms
- CX3C Chemokine Receptor 1, Animals, Calcium, Cells, Cultured, Corpus Striatum, Hippocampus, Male, Mice, Inbred C57BL, Neurons, Up-Regulation, Apoptosis, Glutamic Acid, Infarction, Middle Cerebral Artery, Mice
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