Browsing by Subject "CX3CR1"

Now showing 1 - 5 of 5
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    CX3CR1 deficiency accelerates the development of retinopathy in a rodent model of type 1 diabetes
    (Springer, 2016-11) Beli, Eleni; Dominguez, James M.; Hu, Ping; Thinschmidt, Jeffrey S.; Caballero, Sergio; Calzi, Sergio Li; Luo, Defang; Shanmugam, Sumathi; Salazar, Tatiana; Duan, Yaqian; Boulton, Michael E.; Mohr, Susanna; Abcouwer, Steven F.; Saban, Daniel R.; Harrison, Jeffrey K.; Grant, Maria B.; Ophthalmology, School of Medicine
    In this study, the role of CX3CR1 in the progression of diabetic retinopathy (DR) was investigated. The retinas of wild type (WT), CX3CR1 null (CX3CR1gfp/gfp, KO) and heterozygous (CX3CR1+/gfp, Het) mice were compared in the presence and absence of streptozotocin (STZ) induced diabetes. CX3CR1 deficiency in STZ-KO increased vascular pathology at 4 months of diabetes, as a significant increase in acellular capillaries was observed only in the STZ-KO group. CX3CR1 deficiency and diabetes had similar effects on retinal neurodegeneration measured by an increase in DNA fragmentation. Retinal vascular pathology in STZ-KO mice was associated with increased numbers of monocyte-derived macrophages in the retina. Furthermore, compared to STZ-WT, STZ-KO mice exhibited increased numbers of inflammatory monocytes in the bone marrow and impaired homing of monocytes to the spleen. Induction of retinal IL-10 expression by diabetes was significantly less in KO mice, and when bone marrow-derived macrophages from KO mice were maintained in high glucose they expressed significantly less IL-10 and more TNF-α in response to LPS stimulation. These findings support that CX3CR1 deficiency accelerates the development of vascular pathology in DR through increased recruitment of proinflammatory myeloid cells that demonstrate reduced expression of anti-inflammatory IL-10.
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    CX3CR1 deficiency aggravates amyloid driven neuronal pathology and cognitive decline in Alzheimer's disease
    (BMC, 2022-06-28) Puntambekar, Shweta S.; Moutinho, Miguel; Lin, Peter Bor‑Chian; Jadhav, Vaishnavi; Tumbleson‑Brink, Danika; Balaji, Ananya; Benito, Martin Alvarado; Xu, Guixiang; Oblak, Adrian; Lasagna‑Reeves, Cristian A.; Landreth, Gary E.; Lamb, Bruce T.; Medical and Molecular Genetics, School of Medicine
    Background: Despite its identification as a key checkpoint regulator of microglial activation in Alzheimer's disease, the overarching role of CX3CR1 signaling in modulating mechanisms of Aβ driven neurodegeneration, including accumulation of hyperphosphorylated tau is not well understood. Methodology: Accumulation of soluble and insoluble Aβ species, microglial activation, synaptic dysregulation, and neurodegeneration is investigated in 4- and 6-month old 5xFAD;Cx3cr1+/+ and 5xFAD;Cx3cr1-/- mice using immunohistochemistry, western blotting, transcriptomic and quantitative real time PCR analyses of purified microglia. Flow cytometry based, in-vivo Aβ uptake assays are used for characterization of the effects of CX3CR1-signaling on microglial phagocytosis and lysosomal acidification as indicators of clearance of methoxy-X-04+ fibrillar Aβ. Lastly, we use Y-maze testing to analyze the effects of Cx3cr1 deficiency on working memory. Results: Disease progression in 5xFAD;Cx3cr1-/- mice is characterized by increased deposition of filamentous plaques that display defective microglial plaque engagement. Microglial Aβ phagocytosis and lysosomal acidification in 5xFAD;Cx3cr1-/- mice is impaired in-vivo. Interestingly, Cx3cr1 deficiency results in heighted accumulation of neurotoxic, oligomeric Aβ, along with severe neuritic dystrophy, preferential loss of post-synaptic densities, exacerbated tau pathology, neuronal loss and cognitive impairment. Transcriptomic analyses using cortical RNA, coupled with qRT-PCR using purified microglia from 6 month-old mice indicate dysregulated TGFβ-signaling and heightened ROS metabolism in 5xFAD;Cx3cr1-/- mice. Lastly, microglia in 6 month-old 5xFAD;Cx3cr1-/- mice express a 'degenerative' phenotype characterized by increased levels of Ccl2, Ccl5, Il-1β, Pten and Cybb along with reduced Tnf, Il-6 and Tgfβ1 mRNA. Conclusions: Cx3cr1 deficiency impairs microglial uptake and degradation of fibrillar Aβ, thereby triggering increased accumulation of neurotoxic Aβ species. Furthermore, loss of Cx3cr1 results in microglial dysfunction typified by dampened TGFβ-signaling, increased oxidative stress responses and dysregulated pro-inflammatory activation. Our results indicate that Aβ-driven microglial dysfunction in Cx3cr1-/- mice aggravates tau hyperphosphorylation, neurodegeneration, synaptic dysregulation and impairs working memory.
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    Genetically enhancing the expression of chemokine domain of CX3CL1 fails to prevent tau pathology in mouse models of tauopathy
    (Biomed Central, 2018-09-25) Maphis, Nicole M.; Formica, Shane V.; Wilson, Gina N.; Miller, Crystal M.; Xu, Guixiang; Kokiko-Cochran, Olga N.; Kim, Ki-Wook; Jung, Steffen; Cannon, Judy L.; Crish, Samuel D.; Cardona, Astrid E.; Lamb, Bruce T.; Bhaskar, Kiran; Bemiller, Shane M.; Medicine, School of Medicine
    BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Collectively, our data suggest that overexpression of only chemokine domain of CX3CL1 does not protect against tau pathology.
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    Integrative analysis of DNA methylation and gene expression identifies genes associated with biological aging in Alzheimer's disease
    (Wiley, 2022-09-20) Kim, Bo-Hyun; Vasanthakumar, Aparna; Li, Qingqin S.; Nudelman, Kelly N.H.; Risacher, Shannon L.; Davis, Justin W.; Idler, Kenneth; Lee, Jong-Min; Seo, Sang Won; Waring, Jeffrey F.; Saykin, Andrew J.; Nho, Kwangsik; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Radiology and Imaging Sciences, School of Medicine
    Introduction: The acceleration of biological aging is a risk factor for Alzheimer's disease (AD). Here, we performed weighted gene co-expression network analysis (WGCNA) to identify modules and dysregulated genes involved in biological aging in AD. Methods: We performed WGCNA to identify modules associated with biological clocks and hub genes of the module with the highest module significance. In addition, we performed differential expression analysis and association analysis with AD biomarkers. Results: WGCNA identified five modules associated with biological clocks, with the module designated as "purple" showing the strongest association. Functional enrichment analysis revealed that the purple module was related to cell migration and death. Ten genes were identified as hub genes in purple modules, of which CX3CR1 was downregulated in AD and low levels of CX3CR1 expression were associated with AD biomarkers. Conclusion: Network analysis identified genes associated with biological clocks, which suggests the genetic architecture underlying biological aging in AD. Highlights: Examine links between Alzheimer's disease (AD) peripheral transcriptome and biological aging changes. Weighted gene co-expression network analysis (WGCNA) found five modules related to biological aging. Among the hub genes of the module, CX3CR1 was downregulated in AD. The CX3CR1 expression level was associated with cognitive performance and brain atrophy.
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    Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling
    (Nature Research, 2019-06-17) Gunner, Georgia; Cheadle, Lucas; Johnson, Kasey M.; Ayata, Pinar; Badimon, Ana; Mondo, Erica; Nagy, M. Aurel; Liu, Liwang; Bemiller, Shane M.; Kim, Ki-Wook; Lira, Sergio A.; Lamb, Bruce T.; Tapper, Andrew R.; Ransohoff, Richard M.; Greenberg, Michael E.; Schaefer, Anne; Schafer, Dorothy P.; Psychiatry, School of Medicine
    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.