The Experts below are selected from a list of 751188 Experts worldwide ranked by ideXlab platform
Kiwook Kim - One of the best experts on this subject based on the ideXlab platform.
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sensory lesioning induces microglial synapse elimination via adam10 and fractalkine signaling
Nature Neuroscience, 2019Co-Authors: Georgia Gunner, Lucas Cheadle, Kasey M Johnson, Pinar Ayata, Ana Badimon, Erica Mondo, Aurel M Nagy, Shane M Bemiller, Liwang Liu, Kiwook KimAbstract:Microglia rapidly respond to changes in neural activity and inflammation to regulate synaptic connectivity. The extracellular signals, particularly neuron-derived molecules, that drive these microglial functions at synapses remain a key open question. Here we show that whisker lesioning, known to dampen cortical activity, induces microglia-mediated synapse elimination. This synapse elimination is dependent on signaling by CX3CR1, the receptor for microglial fractalkine (also known as CXCL1), but not complement receptor 3. Furthermore, mice deficient in CX3CL1 have profound defects in synapse elimination. Single-cell RNA sequencing revealed that Cx3cl1 is derived from cortical neurons, and ADAM10, a metalloprotease that cleaves CX3CL1 into a secreted form, is upregulated specifically in layer IV neurons and in microglia following whisker lesioning. Finally, inhibition of ADAM10 phenocopies CX3CR1-/- and Cx3cl1-/- synapse elimination defects. Together, these results identify neuron-to-microglia signaling necessary for cortical synaptic remodeling and reveal that context-dependent immune mechanisms are utilized to remodel synapses in the mammalian brain.
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sensory lesioning induces microglial synapse elimination via adam10 and fractalkine signaling
bioRxiv, 2019Co-Authors: Georgia Gunner, Lucas Cheadle, Kasey M Johnson, Pinar Ayata, Ana Badimon, Erica Mondo, Aurel M Nagy, Shane M Bemiller, Liwang Liu, Kiwook KimAbstract:Abstract Microglia rapidly respond to changes in neural activity and inflammation to regulate synaptic connectivity. The extracellular signals, particularly neuron-derived molecules, that drive these microglial functions at synapses remains a key open question. Here, whisker lesioning, known to dampen cortical activity, induces microglia-mediated synapse elimination. We show that this synapse elimination is dependent on the microglial fractalkine receptor, CX3CR1, but not complement receptor 3, signaling. Further, mice deficient in the CX3CR1 ligand (CX3CL1) also have profound defects in synapse elimination. Single-cell RNAseq then revealed that Cx3cl1 is cortical neuron-derived and ADAM10, a metalloprotease that cleaves CX3CL1 into a secreted form, is upregulated specifically in layer IV neurons and microglia following whisker lesioning. Finally, inhibition of ADAM10 phenocopies CX3CR1-/- and Cx3cl1-/- synapse elimination defects. Together, these results identify novel neuron-to-microglia signaling necessary for cortical synaptic remodeling and reveal context-dependent immune mechanisms are utilized to remodel synapses in the mammalian brain.
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genetically enhancing the expression of chemokine domain of cx3cl1 fails to prevent tau pathology in mouse models of tauopathy
Journal of Neuroinflammation, 2018Co-Authors: Kiwook Kim, Shane Bemiller, Nicole Maphis, Shane Formica, Gina N Wilson, Crystal M Miller, Olga N Kokikocochran, Steffen JungAbstract:Fractalkine (CX3CL1) and its receptor (CX3CR1) play an important role in regulating microglial function. We have previously shown that CX3CR1 deficiency exacerbated tau pathology and led to cognitive impairment. However, it is still unclear if the chemokine domain of the ligand CX3CL1 is essential in regulating neuronal tau pathology. We used transgenic mice lacking endogenous Cx3cl1 (Cx3cl1−/−) and expressing only obligatory soluble form (with only chemokine domain) and lacking the mucin stalk of CX3CL1 (referred to as Cx3cl1105Δ mice) to assess tau pathology and behavioral function in both lipopolysaccharide (LPS) and genetic (hTau) mouse models of tauopathy. First, increased basal tau levels accompanied microglial activation in Cx3cl1105Δ mice compared to control groups. Second, increased CD45+ and F4/80+ neuroinflammation and tau phosphorylation were observed in LPS, hTau/Cx3cl1−/−, and hTau/Cx3cl1105Δ mouse models of tau pathology, which correlated with impaired spatial learning. Finally, microglial cell surface expression of CX3CR1 was reduced in Cx3cl1105Δ mice, suggesting enhanced fractalkine receptor internalization (mimicking CX3CR1 deletion), which likely contributes to the elevated tau pathology. Collectively, our data suggest that overexpression of only chemokine domain of CX3CL1 does not protect against tau pathology.
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opposing effects of membrane anchored cx3cl1 on amyloid and tau pathologies via the p38 mapk pathway
The Journal of Neuroscience, 2014Co-Authors: Sungho Lee, Kiwook Kim, Steffen Jung, Richard M Ransohoff, Taylor R Jay, Sabina Bhatta, Gary E Landreth, Bruce T LambAbstract:Several Alzheimer's disease (AD) risk genes are specifically expressed by microglia within the CNS. However, the mechanisms by which microglia regulate the pathological hallmarks of AD—extracellular deposition of β-amyloid (Aβ) and intraneuronal hyperphosphorylation of microtubule-associated protein tau (MAPT)—remain to be established. Notably, deficiency for the microglial CX3CR1 receptor has opposing effects on Aβ and MAPT pathologies. CX3CL1, the neuronally derived cognate ligand for CX3CR1, signals both in membrane-anchored and soluble forms. In this study, we sought to determine the relative contribution on membrane-anchored versus soluble CX3CL1 in regulating the microglia-mediated amelioration of Aβ pathology, as well as provide insight into the potential downstream microglial-based mechanisms. As expected, CX3CL1 deficiency reduced Aβ deposition in APPPS1 animals in a similar manner to CX3CR1 deficiency. Surprisingly, however, CX3CL1-deficient APPPS1 animals exhibited enhanced neuronal MAPT phosphorylation despite reduced amyloid burden. Importantly, neither of these phenotypes was altered by transgenic expression of the soluble CX3CL1 isoform, suggesting that it is the membrane-anchored version of CX3CL1 that regulates microglial phagocytosis of Aβ and neuronal MAPT phosphorylation. Analysis of transcript levels in purified microglia isolated from APPPS1 mice with the various CX3CL1/CX3CR1 genotypes revealed increased expression of inflammatory cytokines and phagocytic markers, which was associated with activation of p38 mitogen-activated protein kinase and Aβ internalization within microglia. Together, these studies challenge the “frustrated phagocytosis” concept and suggest that neuronal–microglial communication link the two central AD pathologies.
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in vivo structure function and expression analysis of the cx3c chemokine fractalkine
Blood, 2011Co-Authors: Kiwook Kim, Sergio A Lira, Andreas Ludwig, Ehud Zigmond, Julia Farache, Elias Shezen, Guy Shakhar, Alexandra Valloneberhard, Steffen JungAbstract:The CX3C chemokine family is composed of only one member, CX3CL1, also known as fractalkine, which in mice is the sole ligand of the G protein-coupled, 7-transmembrane receptor CX3CR1. Unlike classic small peptide chemokines, CX3CL1 is synthesized as a membrane-anchored protein that can promote integrin-independent adhesion. Subsequent cleavage by metalloproteases, either constitutive or induced, can generate shed CX3CL1 entities that potentially have chemoattractive activity. To study the CX3C interface in tissues of live animals, we generated transgenic mice (CX3CL1cherry:CX3CR1gfp), which express red and green fluorescent reporter genes under the respective control of the CX3CL1 and CX3CR1 promoters. Furthermore, we performed a structure/function analysis to differentiate the in vivo functions of membrane-tethered versus shed CX3CL1 moieties by comparing their respective ability to correct established defects in macrophage function and leukocyte survival in CX3CL1-deficient mice. Specifically, expression of CX3CL1105Δ, an obligatory soluble CX3CL1 isoform, reconstituted the formation of transepithelial dendrites by intestinal macrophages but did not rescue circulating Ly6Clo CX3CR1hi blood monocytes in CX3CR1gfp/gfp mice. Instead, monocyte survival required the full-length membrane-anchored CX3CL1, suggesting differential activities of tethered and shed CX3CL1 entities.
Janet S Lee - One of the best experts on this subject based on the ideXlab platform.
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CX3CR1 lung mononuclear phagocytes spatially confined to the interstitium produce tnf α and il 6 and promote cigarette smoke induced emphysema
Journal of Immunology, 2011Co-Authors: Zeyu Xiong, Steven D Shapiro, Adriana S Leme, Prabir Ray, Janet S LeeAbstract:Increased numbers of macrophages are found in the lungs of smokers and those with chronic obstructive pulmonary disease. Experimental evidence shows the central role of macrophages in elaboration of inflammatory mediators such as TNF-α and the progression toward cigarette smoke-induced emphysema. We investigated the role of CX3CR1 in recruitment of mononuclear phagocytes, inflammatory cytokine responses, and tissue destruction in the lungs after cigarette smoke exposure. Using mice in which egfp is expressed at the locus of the CX3CR1 gene, we show that alveolar macrophages increased transmembrane ligand CX3CL1 expression and soluble CX3CL1 was detectable in the airspaces, but CX3CR1(GFP/GFP) and CX3CR1(GFP/+) mice failed to show recruitment of CX3CR1(+) cells into the airspaces with cigarette smoke. In contrast, cigarette smoke increased the accumulation of CX3CR1(+)CD11b(+) mononuclear phagocytes that were spatially confined to the lung interstitium and heterogenous in their expression of CD11c, MHC class II, and autofluorescent property. Although an intact CX3CL1-CX3CR1 pathway amplified the percentage of CX3CR1(+)CD11b(+) mononuclear phagocytes in the lungs, it was not essential for recruitment. Rather, functional CX3CR1 was required for a subset of tissue-bound mononuclear phagocytes to produce TNF-α and IL-6 in response to cigarette smoke, and the absence of functional CX3CR1 protected mice from developing tissue-destructive emphysema. Thus, CX3CR1(+) "tissue resident" mononuclear phagocytes initiate an innate immune response to cigarette smoke by producing TNF-α and IL-6 and are capable of promoting emphysema.
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cx3cl1 up regulation is associated with recruitment of CX3CR1 mononuclear phagocytes and t lymphocytes in the lungs during cigarette smoke induced emphysema
American Journal of Pathology, 2008Co-Authors: Jennifer Gonzalez Mccomb, Prabir Ray, Mrunalini Ranganathan, Xiang Hong Liu, Joseph M Pilewski, Simon C Watkins, Augustine M K Choi, Janet S LeeAbstract:CX3CR1 is expressed on monocytes, dendritic cells, macrophages, subsets of T lymphocytes, and natural killer cells and functions in diverse capacities such as leukocyte adhesion, migration, and cell survival on ligand binding. Expression of the CX3CL1 gene, whose expression product is the sole ligand for CX3CR1, is up-regulated in human lungs with chronic cigarette smoke-induced obstructive lung disease. At present, it is unknown whether CX3CL1 up-regulation is associated with the recruitment and accumulation of immune cells that express CX3CR1. We show that mice chronically exposed to cigarette smoke up-regulate CX3CL1 gene expression, which is associated with an influx of CX3CR1+ cells in the lungs. The increase in CX3CR1+ cells is primarily comprised of macrophages and T lymphocytes and is associated with the development of emphysema. In alveolar macrophages, cigarette smoke exposure increased the expression of both CX3CR1 and CX3CL1 genes. The inducibility of CX3CR1 expression was not solely dependent on a chronic stimulus because lipopolysaccharide up-regulated CX3CR1 in RAW264.7 cells in vitro and in mononuclear phagocytes in vivo. Our findings suggest a mechanism by which macrophages amplify and promote CX3CR1+ cell accumulation within the lungs during both acute and chronic inflammatory stress. We suggest that one function of the CX3CR1-CX3CL1 pathway is to recruit and sustain divergent immune cell populations implicated in the pathogenesis of cigarette smoke-induced emphysema.
Dana Gabuzda - One of the best experts on this subject based on the ideXlab platform.
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cd16 monocytes produce il 6 ccl2 and matrix metalloproteinase 9 upon interaction with cx3cl1 expressing endothelial cells
Journal of Leukocyte Biology, 2006Co-Authors: Petronela Ancuta, Jianbin Wang, Dana GabuzdaAbstract:The CD16+ subset of peripheral blood monocytes (Mo) is expanded dramatically during inflammatory conditions including sepsis, HIV-1 infection, and cancer. CD16+ express high levels of CX3CR1, which mediates arrest onto CX3CL1-expressing endothelial cells (EC) under flow conditions. In contrast, attachment of CD16- Mo onto cytokine-activated EC is independent of CX3CL1. Here, we investigate the ability of CD16+ and CD16- Mo to produce proinflammatory cytokines upon interaction with CX3CL1-expressing HUVEC. We demonstrate that CD16+ but not CD16- Mo produce high levels of IL-6, CCL2, and matrix metalloproteinase (MMP)-9 when cocultured with TNF/IFN-gamma-activated HUVEC or nonactivated HUVEC expressing CX3CL1. Furthermore, supernatants from Mo cocultured with cytokine-activated HUVEC induce neuronal death in vitro. These results suggest that membrane-bound CX3CL1 stimulates production of IL-6, CCL2, and MMP-9 by CD16+ Mo, likely via engagement of CX3CR1. Thus, expansion of CD16+ Mo and their accumulation onto CX3CL1-expressing EC may result in recruitment of Mo and T cell subsets at sites of inflammation in response to CCL2, IL-6-induced cell activation and/or differentiation, and MMP-9-mediated vascular and tissue injury.
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cd16 monocytes produce il 6 ccl2 and matrix metalloproteinase 9 upon interaction with cx3cl1 expressing endothelial cells
Journal of Leukocyte Biology, 2006Co-Authors: Petronela Ancuta, Jianbin Wang, Dana GabuzdaAbstract:The CD16 subset of peripheral blood monocytes (Mo) is expanded dramatically during inflammatory conditions including sepsis, HIV-1 infection, and cancer. CD16 express high levels of CX3CR1, which mediates arrest onto CX3CL1- expressing endothelial cells (EC) under flow condi- tions. In contrast, attachment of CD16 - Mo onto cytokine-activated EC is independent of CX3CL1. Here, we investigate the ability of CD16 and CD16 - Mo to produce proinflammatory cytokines upon interaction with CX3CL1-expressing HUVEC. We demonstrate that CD16 but not CD16 - Mo produce high levels of IL-6, CCL2, and matrix metalloproteinase (MMP)-9 when cocul- tured with TNF/IFN--activated HUVEC or nonac- tivated HUVEC expressing CX3CL1. Furthermore, supernatants from Mo cocultured with cytokine- activated HUVEC induce neuronal death in vitro. These results suggest that membrane-bound CX3CL1 stimulates production of IL-6, CCL2, and MMP-9 by CD16 Mo, likely via engagement of CX3CR1. Thus, expansion of CD16 Mo and their accumulation onto CX3CL1-expressing EC may re- sult in recruitment of Mo and T cell subsets at sites of inflammation in response to CCL2, IL-6-induced cell activation and/or differentiation, and MMP-9- mediated vascular and tissue injury. J. Leukoc. Biol. 80: 1156-1164; 2006.
Yasuni Nakanuma - One of the best experts on this subject based on the ideXlab platform.
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chemokine chemokine receptor ccl2 ccr2 and cx3cl1 CX3CR1 axis may play a role in the aggravated inflammation in primary biliary cirrhosis
Digestive Diseases and Sciences, 2014Co-Authors: Motoko Sasaki, Masami Miyakoshi, Yasunori Sato, Yasuni NakanumaAbstract:Senescent cells can alter local tissue environments by secretion of various senescence-associated secretory phenotypes (SASP), such as cytokines and chemokines. Given senescent biliary epithelial cells (BECs) in damaged small bile ducts in primary biliary cirrhosis (PBC) show increased expression of chemokines CCL2 and CX3CL1 as SASP, we further examined an involvement of CCL2/CCR2 and CX3CL1/CX3CR1 systems in the pathogenesis of PBC. We examined immunohistochemically the expression of CCR2, CX3CR1, CCL2 and CX3CL1 in livers taken from the patients with PBC (n = 45) and control livers (n = 78), such as chronic viral hepatitis (CVH; n = 39). CCR2 or CX3CR1-expressing cells were characterized by double immunofluorescence with CD3, CD4, CD8, CD56 or CD68. CCR2 is expressed in round cells, epithelioid cells and dendritic cells and most CCR2-positive cells were CD68-positive. Infiltration of CCR2-positive cells in the intraepithelial layer or around small bile ducts was significantly more extensive in PBC than CVH and normal liver (p CD4). Infiltration of CX3CR1-positive cells in the intraepithelial layer and around small bile ducts was significantly more extensive in PBC than control livers (p < 0.05) and was significantly correlated with the expression of CX3CL1 in BECs (p < 0.05). CCL2 and CX3CL1 produced by senescent BECs may promote infiltration of corresponding CCR2 and CX3CR1-expressing cells and further aggravate inflammation in bile duct lesion in PBC.
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chemokine chemokine receptor ccl2 ccr2 and cx3cl1 CX3CR1 axis may play a role in the aggravated inflammation in primary biliary cirrhosis
Digestive Diseases and Sciences, 2014Co-Authors: Motoko Sasaki, Masami Miyakoshi, Yasunori Sato, Yasuni NakanumaAbstract:Background and Aims Senescent cells can alter local tissue environments by secretion of various senescence-associated secretory phenotypes (SASP), such as cytokines and chemokines. Given senescent biliary epithelial cells (BECs) in damaged small bile ducts in primary biliary cirrhosis (PBC) show increased expression of chemokines CCL2 and CX3CL1 as SASP, we further examined an involvement of CCL2/CCR2 and CX3CL1/CX3CR1 systems in the pathogenesis of PBC.
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participation of natural killer cells in the pathogenesis of bile duct lesions in biliary atresia
Journal of Clinical Pathology, 2013Co-Authors: Kenichi Harada, Atsushi Okamura, Masaki Nio, Yasuni NakanumaAbstract:Aims Immunological disturbances including innate immunity after a suspected viral infection are considered important to the pathogenesis of bile duct lesions in cases of biliary atresia (BA). In this study, we tried to evaluate whether natural killer (NK) cells and CX3CL1 (Fractalkine) and its receptor (CX3CR1) are involved in the bile duct injury. Methods Using the section of BA (22 cases) and controls, immunohistochemistry for CD56, CD16, CD68, CX3CL1 and CX3CR1 was performed. Moreover, using cultured biliary epithelial cells (BECs) and NK cells, the production of CX3CL1 in BECs and the migration of NK cells were evaluated. Results It was found that CD56(−)CD16(+)CD68(−) NK cells were increased around the damaged small and large bile ducts in BA and hepatitis C virus-related chronic hepatitis in comparison with other controls. CX3CL1 was strongly expressed on the damaged bile ducts in BA, while this expression was relatively weak or absent in the bile ducts of normal liver. The results suggest the CD56(−)CD16(+) NK cells to be involved in the development of bile duct injuries in BA. These CD16(+) NK cells were positive for CX3CR1, and attracted by CX3CL1 expressed on bile ducts. Further study revealed that stimulation with poly(I:C) (a synthetic analogue of viral dsRNA) increased the expression of CX3CL1 on cultured BECs followed by increased migrational activity of cultured NK cells. Conclusions CD56(−)CD16(+) NK cells with reduced NK activity may be involved in the bile duct damage in BA, and CD16(+) NK cells expressing CX3CR1 may be attracted by and interact with bile ducts expressing CX3CL1.
Gang Chen - One of the best experts on this subject based on the ideXlab platform.
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cx3cl1 CX3CR1 axis attenuates early brain injury via promoting the delivery of exosomal microrna 124 from neuron to microglia after subarachnoid hemorrhage
Journal of Neuroinflammation, 2020Co-Authors: Xiao Chen, Ming Jiang, Yang Wang, Haitao Shen, Yunhai Zhang, Gang ChenAbstract:Background Microglial activation-mediated neuroinflammation is a major contributor to early brain injury (EBI) after subarachnoid hemorrhage (SAH). MicroRNA-124 (miR-124) is the most abundant miRNAs in the central nervous system (CNS) and plays a vital role in microglial activation by targeting protein CCAAT-enhancer-binding protein α (C/EBPα). It has been reported that the CX3CL1/CX3CR1 axis is involved in the delivery of miR-124 from neurons to microglia. Methods An experimental rat SAH model was established by injecting autologous arterial blood into the prechiasmatic cistern, and cultured primary neurons and microglia were exposed to oxyhemoglobin to mimic SAH in vitro. We additionally exploited specific expression plasmids encoding CX3CL1 and CX3CR1. Results We observed significant decreases in CX3CL1 and CX3CR1 in the brain tissues of SAH patients. We also observed decreases in the levels of CX3CL1 in neurons and CX3CR1 in microglia after SAH in rats. Moreover, microglia exhibited an activated phenotype with macrophage-like morphology and high levels of CD45 and major histocompatibility complex (MHC) class II after SAH. After overexpression of CX3CL1/CX3CR1, the level of CD45 and MHC class II and the release of inflammatory factors tumor necrosis factor α, interleukin 1α and complement 1q were significantly decreased. There was also increased neuronal degeneration and behavior dysfunction after SAH, both of which were inhibited by CX3CL1/CX3CR1 overexpression. Additionally, we found that the delivery of exosomal miR-124 from neurons to microglia was significantly reduced after SAH, accompanied by an increase in C/EBPα expression, and was inhibited by CX3CL1/CX3CR1 overexpression. In conclusion, the CX3CL1/CX3CR1 axis may play protective roles after SAH by promoting the delivery of exosomal miR-124 to microglia and attenuate microglial activation and neuroinflammation. Conclusions CX3CL1/CX3CR1 axis may be a potential intervention target for the inhibition of SAH-induced EBI by promoting exosome transport of miR-124 to microglia.
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cx3cl1 CX3CR1 axis attenuates early brain injury via promoting the delivery of exosomal microrna 124 from neuron to microglia after subarachnoid hemorrhage
Journal of Neuroinflammation, 2020Co-Authors: Xiao Chen, Ming Jiang, Yang Wang, Haitao Shen, Yunhai Zhang, Gang ChenAbstract:Microglial activation-mediated neuroinflammation is a major contributor to early brain injury (EBI) after subarachnoid hemorrhage (SAH). MicroRNA-124 (miR-124) is the most abundant miRNAs in the central nervous system (CNS) and plays a vital role in microglial activation by targeting protein CCAAT-enhancer-binding protein α (C/EBPα). It has been reported that the CX3CL1/CX3CR1 axis is involved in the delivery of miR-124 from neurons to microglia. An experimental rat SAH model was established by injecting autologous arterial blood into the prechiasmatic cistern, and cultured primary neurons and microglia were exposed to oxyhemoglobin to mimic SAH in vitro. We additionally exploited specific expression plasmids encoding CX3CL1 and CX3CR1. We observed significant decreases in CX3CL1 and CX3CR1 in the brain tissues of SAH patients. We also observed decreases in the levels of CX3CL1 in neurons and CX3CR1 in microglia after SAH in rats. Moreover, microglia exhibited an activated phenotype with macrophage-like morphology and high levels of CD45 and major histocompatibility complex (MHC) class II after SAH. After overexpression of CX3CL1/CX3CR1, the level of CD45 and MHC class II and the release of inflammatory factors tumor necrosis factor α, interleukin 1α and complement 1q were significantly decreased. There was also increased neuronal degeneration and behavior dysfunction after SAH, both of which were inhibited by CX3CL1/CX3CR1 overexpression. Additionally, we found that the delivery of exosomal miR-124 from neurons to microglia was significantly reduced after SAH, accompanied by an increase in C/EBPα expression, and was inhibited by CX3CL1/CX3CR1 overexpression. In conclusion, the CX3CL1/CX3CR1 axis may play protective roles after SAH by promoting the delivery of exosomal miR-124 to microglia and attenuate microglial activation and neuroinflammation. CX3CL1/CX3CR1 axis may be a potential intervention target for the inhibition of SAH-induced EBI by promoting exosome transport of miR-124 to microglia.
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cx3cl1 CX3CR1 regulates nerve injury induced pain hypersensitivity through the erk5 signaling pathway
Journal of Neuroscience Research, 2013Co-Authors: Jianliang Sun, Gang Chen, Chun Xiao, Juan Zhang, Xiaozong Yuan, Wei Chen, Fengjiang Zhang, Min YanAbstract:Peripheral nerve injury induces the cleavage of CX3CL1 from the membrane of neurons, where the soluble CX3CL1 subsequently plays an important role in the transmission of nociceptive signals between neurons and microglia. Here we investigated whether CX3CL1 regulates microglia activation through the phosphorylation of extracellular signal-regulated protein kinase 5 (ERK5) in the spinal cord of rats with spinal nerve ligation (SNL). ERK5 and microglia were activated in the spinal cord after SNL. The knockdown of ERK5 by intrathecal injection of antisense oligonucleotides suppressed the hyperalgesia and nuclear impact of nuclear factor-κB induced by SNL. The blockage of CX3CR1, the receptor of CX3CL1, significantly reduced the level of ERK5 activation following SNL. In addition, the antisense knockdown of ERK5 reversed the CX3CL1-induced hyperalgesia and spinal microglia activation. Our study suggests that CX3CL1/CX3CR1 regulates nerve injury-induced pain hypersensitivity through the ERK5 signaling pathway.
