CX3CL1
Fractalkine precursor (C-X3-C motif chemokine 1) (CX3C membrane-anchored chemokine) (Neurotactin) (Small-inducible cytokine D1) [Contains: Processed fractalkine] [FKN] [NTT] [SCYD1] [A-152E5.2]
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Fractalkine (CX3CL1; FKN) is a chemokine expressed by neurons that mediates communication between neurons and microglia. By regulating microglial activity, CX3CL1 can mitigate the damaging effects of chronic microglial inflammation within the brain, a state that plays a major role in aging and neurodegeneration. CX3CL1 is present in two forms, a full-length membrane-bound form and a soluble cleaved form (sFKN), generated by a disintegrin and metalloproteinase (ADAM) 10 or 17. Levels of sFKN decrease with aging, which could lead to enhanced inflammation, deficits in synaptic remodeling, and subsequent declines in cognition. Recently, the idea that these two forms of CX3CL1 may display differential activities within the CNS has garnered increased attention, but remains unresolved. Here, we assessed the consequences of CX3CL1 knockout (CX3CL1 ) on cognitive behavior as well as the functional rescue with the two different forms of CX3CL1 in mice. CX3CL1 mice were treated with adeno-associated virus (AAV) expressing either green fluorescent protein (GFP), sFKN, or an obligate membrane-bound form of CX3CL1 (mFKN) and then subjected to behavioral testing to assess cognition and motor function. Following behavioral analysis, brains were collected and analyzed for markers of neurogenesis, or prepared for electrophysiology to measure long-term potentiation (LTP) in hippocampal slices. CX3CL1 mice showed significant deficits in cognitive tasks for long-term memory and spatial learning and memory in addition to demonstrating enhanced basal motor performance. These alterations correlated with deficits in both hippocampal neurogenesis and LTP. Treatment of CX3CL1 mice with AAV-sFKN partially corrected changes in both cognitive and motor function and restored neurogenesis and LTP to levels similar to wild-type animals. Treatment with AAV-mFKN partially restored spatial learning and memory in CX3CL1 mice, but did not rescue long-term memory, or neurogenesis. These results are the first to demonstrate that CX3CL1 knockout causes significant cognitive deficits that can be rescued by treatment with sFKN and only partially rescued with mFKN. This suggests that treatments that restore signaling of soluble forms of CX3CL1 may be a viable therapeutic option for aging and disease.
Keywords
- Aging
- CX3CL1
- Cognition
- Fractalkine
- Long-term potentiation
- Microglia
- Neurodegeneration
- Neurogenesis
- Neuroinflammation
A hexanucleotide repeat expansion on chromosome 9 open reading frame 72 (C9orf72) is associated with familial amyotrophic lateral sclerosis (ALS) and a subpopulation of patients with sporadic ALS and frontotemporal dementia. We used inducible pluripotent stem cells from neurotypic and C9orf72 (C9 ) ALS patients to derive neuronal progenitor cells. We demonstrated that C9 and neurotypic neuronal progenitor cells differentiate into neurons. The C9 neurons, however, spontaneously re-expressed cyclin D1 after 12 weeks, suggesting cell cycle re-engagement. Gene profiling revealed significant increases in senescence-associated genes in C9 neurons. Moreover, C9 neurons expressed high levels of mRNA for CXCL8, a chemokine overexpressed by senescent cells, while media from C9 neurons contained significant levels of CXCL8, CXCL1, IL13, IP10, CX3CL1, and reactive oxygen species, which are components of the senescence-associated secretory phenotype. Thus, re-engagement of cell cycle-associated proteins and a senescence-associated secretory phenotype could be fundamental components of neuronal dysfunction in ALS and frontotemporal dementia.
MeSH Terms
- Amyotrophic Lateral Sclerosis
- C9orf72 Protein
- Cell Cycle
- Cells, Cultured
- Cellular Senescence
- DNA Repeat Expansion
- Frontotemporal Dementia
- Gene Expression
- Gene Expression Regulation, Developmental
- Humans
- Induced Pluripotent Stem Cells
- Interleukin-8
- RNA, Messenger
- Stem Cells
Keywords
- Amyotrophic lateral sclerosis
- Cell cycle re-entry
- Frontotemporal dementia
- Senescence
- Senescence-associated secretory phenotype
The aim of this study was to examine whether cytokines and chemokines expressed in the uterine mucosa play a role in the process of eggshell formation in the chicken uterus. Changes in the expression levels of pro- and anti-inflammatory cytokines and chemokines in the uterine mucosa during an ovulatory cycle (experiment 1) and effects of aging on their expression (experiment 2) were examined. In experiment 1, the expression of the pro-inflammatory cytokines IL1β, IL6, TNFSF15, and IFNγ, and a chemokine CX3CL1 was found to increase during eggshell biomineralization (16 h following oviposition), while anti-inflammatory TGFβ2 expression was found to increase at 4 h following oviposition. In experiment 2, a higher expression of the anti-inflammatory cytokines TGFβ2 and TGFβ3, and chemokines CXCLi2 and CX3CL1, was observed in aged hens than in young hens. A significantly higher number of macrophages and CD8 T cells were observed in the uterine tissue of aged hens than in young hens. Furthermore, the expression of adhesion molecules associated with leukocytic infiltration was found to be higher in aged hens than in young hens. We conclude that the eggshell formation process may be affected by the pro- and anti-inflammatory cytokines and chemokines. The balanced expressions of these molecules might be disrupted in aged hens.
MeSH Terms
- Aging
- Animals
- Chemokines
- Chickens
- Cytokines
- Female
- Inflammation
- Mucous Membrane
- Oviducts
- Oviposition
- Ovulation
- Uterus
Keywords
- Aging
- Chemokines
- Cytokines
- Eggshell
- Laying hens
- Mucosal homeostasis
Use of the frailty index to measure an accumulation of deficits has been proven a valuable method for identifying elderly people at risk for increased vulnerability, disease, injury, and mortality. However, complementary molecular frailty biomarkers or ideally biomarker panels have not yet been identified. We conducted a systematic search to identify biomarker candidates for a frailty biomarker panel. Gene expression databases were searched (http://genomics.senescence.info/genes including GenAge, AnAge, LongevityMap, CellAge, DrugAge, Digital Aging Atlas) to identify genes regulated in aging, longevity, and age-related diseases with a focus on secreted factors or molecules detectable in body fluids as potential frailty biomarkers. Factors broadly expressed, related to several "hallmark of aging" pathways as well as used or predicted as biomarkers in other disease settings, particularly age-related pathologies, were identified. This set of biomarkers was further expanded according to the expertise and experience of the authors. In the next step, biomarkers were assigned to six "hallmark of aging" pathways, namely (1) inflammation, (2) mitochondria and apoptosis, (3) calcium homeostasis, (4) fibrosis, (5) NMJ (neuromuscular junction) and neurons, (6) cytoskeleton and hormones, or (7) other principles and an extensive literature search was performed for each candidate to explore their potential and priority as frailty biomarkers. A total of 44 markers were evaluated in the seven categories listed above, and 19 were awarded a high priority score, 22 identified as medium priority and three were low priority. In each category high and medium priority markers were identified. Biomarker panels for frailty would be of high value and better than single markers. Based on our search we would propose a core panel of frailty biomarkers consisting of (1) CXCL10 (C-X-C motif chemokine ligand 10), IL-6 (interleukin 6), CX3CL1 (C-X3-C motif chemokine ligand 1), (2) GDF15 (growth differentiation factor 15), FNDC5 (fibronectin type III domain containing 5), vimentin (VIM), (3) regucalcin (RGN/SMP30), calreticulin, (4) PLAU (plasminogen activator, urokinase), AGT (angiotensinogen), (5) BDNF (brain derived neurotrophic factor), progranulin (PGRN), (6) α-klotho (KL), FGF23 (fibroblast growth factor 23), FGF21, leptin (LEP), (7) miRNA (micro Ribonucleic acid) panel (to be further defined), AHCY (adenosylhomocysteinase) and KRT18 (keratin 18). An expanded panel would also include (1) pentraxin (PTX3), sVCAM/ICAM (soluble vascular cell adhesion molecule 1/Intercellular adhesion molecule 1), defensin α, (2) APP (amyloid beta precursor protein), LDH (lactate dehydrogenase), (3) S100B (S100 calcium binding protein B), (4) TGFβ (transforming growth factor beta), PAI-1 (plasminogen activator inhibitor 1), TGM2 (transglutaminase 2), (5) sRAGE (soluble receptor for advanced glycosylation end products), HMGB1 (high mobility group box 1), C3/C1Q (complement factor 3/1Q), ST2 (Interleukin 1 receptor like 1), agrin (AGRN), (6) IGF-1 (insulin-like growth factor 1), resistin (RETN), adiponectin (ADIPOQ), ghrelin (GHRL), growth hormone (GH), (7) microparticle panel (to be further defined), GpnmB (glycoprotein nonmetastatic melanoma protein B) and lactoferrin (LTF). We believe that these predicted panels need to be experimentally explored in animal models and frail cohorts in order to ascertain their diagnostic, prognostic and therapeutic potential.
MeSH Terms
- Aged
- Aging
- Amyloid beta-Peptides
- Amyloid beta-Protein Precursor
- Animals
- Apoptosis
- Biomarkers
- Fibronectins
- Frailty
- Genetic Association Studies
- Growth Differentiation Factor 15
- Humans
- Insulin-Like Growth Factor I
- Interleukin-1 Receptor-Like 1 Protein
- Membrane Glycoproteins
- MicroRNAs
- Signal Transduction
Keywords
- Age-related diseases
- Biomarker panel
- Frailty
- Hallmark of aging pathways
Age is the most prominent risk factor for the development of postoperative cognitive dysfunction. The present study investigated the role of CX3CL1-CX3CR1 signaling in age-related differences in surgery-induced cognitive deficits and neuroinflammation. Adult and aged male Sprague-Dawley rats were subjected to partial hepatectomy or partial hepatectomy with intracerebroventricular infusion of CX3CL1. On postoperative days 3, 7, and 14, the rats were subjected to an open field test and the Morris water maze test. Hippocampal interleukin-1β, CX3CL1, CX3CR1, brain derived neurotrophic factor (BDNF), ionized calcium-binding adapter molecule 1 (Iba-1), and Arginase-1 (Arg1) levels were measured. Age exacerbated cognitive impairment and increased neuroinflammation following surgery. Surgery-induced decreases in CX3CL1 and CX3CR1 proteins were accompanied by increased microglial activation, as indicated by increased Iba-1 expression. Corresponding decline in Arg1 and BDNF levels were observed. Treatment with CX3CL1 decreased proinflammatory cytokines expression, increased BDNF and Arg1 levels in the brain, and enhanced behavioral recovery. The surgery-induced decreases in CX3CL1 and CX3CR1 expression exacerbated postoperative cognitive deficits and exaggerated neuroinflammatory responses in this rodent model. Treatment with CX3CL1 attenuated these effects, at least partly by inhibiting microglial activation, decreasing the associated production of proinflammatory cytokines, and enhancing BDNF expression.
MeSH Terms
- Aging
- Animals
- Brain
- CX3C Chemokine Receptor 1
- Chemokine CX3CL1
- Cognitive Dysfunction
- Hepatectomy
- Liver
- Male
- Maze Learning
- Random Allocation
- Rats
- Rats, Sprague-Dawley
- Signal Transduction
Microglia have been discovered to undergo repopulation following ablation. However, the functionality of repopulated microglia and the mechanisms regulating microglia repopulation are unknown. We examined microglial homeostasis in the adult mouse retina, a specialized neural compartment containing regular arrays of microglia in discrete synaptic laminae that can be directly visualized. Using in vivo imaging and cell-fate mapping techniques, we discovered that repopulation originated from residual microglia proliferating in the central inner retina that subsequently spread by centrifugal migration to fully recapitulate pre-existing microglial distributions and morphologies. Repopulating cells fully restored microglial functions including constitutive "surveying" process movements, behavioral and physiological responses to retinal injury, and maintenance of synaptic structure and function. Microglial repopulation was regulated by CX3CL1-CX3CR1 signaling, slowing in CX3CR1 deficiency and accelerating with exogenous CX3CL1 administration. Microglial homeostasis following perturbation can fully recover microglial organization and function under the regulation of chemokine signaling between neurons and microglia.
MeSH Terms
- Aging
- Animals
- CX3C Chemokine Receptor 1
- Calcium-Binding Proteins
- Cell Movement
- Cell Proliferation
- Chemokine CX3CL1
- Mice, Transgenic
- Microfilament Proteins
- Microglia
- Retina
- Signal Transduction
Depending on the species, microglial cells represent 5-20% of glial cells in the adult brain. As the innate immune effector of the brain, microglia are involved in several functions: regulation of inflammation, synaptic connectivity, programmed cell death, wiring and circuitry formation, phagocytosis of cell debris, and synaptic pruning and sculpting of postnatal neural circuits. Moreover, microglia contribute to some neurodevelopmental disorders such as Nasu-Hakola disease (NHD), and to aged-associated neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and others. There is evidence that human and rodent microglia may become senescent. This event determines alterations in the microglia activation status, associated with a chronic inflammation phenotype and with the loss of neuroprotective functions that lead to a greater susceptibility to the neurodegenerative diseases of aging. In the central nervous system (CNS), Triggering Receptor Expressed on Myeloid Cells 2-DNAX activation protein 12 (TREM2-DAP12) is a signaling complex expressed exclusively in microglia. As a microglial surface receptor, TREM2 interacts with DAP12 to initiate signal transduction pathways that promote microglial cell activation, phagocytosis, and microglial cell survival. Defective TREM2-DAP12 functions play a central role in the pathogenesis of several diseases. The CX3CL1 (fractalkine)-CX3CR1 signaling represents the most important communication channel between neurons and microglia. The expression of CX3CL1 in neurons and of its receptor CX3CR1 in microglia determines a specific interaction, playing fundamental roles in the regulation of the maturation and function of these cells. Here, we review the role of the TREM2-DAP12 and CX3CL1-CX3CR1 axes in aged microglia and the involvement of these pathways in physiological CNS aging and in age-associated neurodegenerative diseases.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Aging
- Animals
- Brain
- CX3C Chemokine Receptor 1
- Central Nervous System
- Chemokine CX3CL1
- Gene Expression Regulation
- Humans
- Membrane Glycoproteins
- Membrane Proteins
- Microglia
- Neurodegenerative Diseases
- Receptors, Immunologic
- Signal Transduction
Keywords
- CX3CL1
- CX3CR1
- DAP12
- TREM2
- aged microglia
- aging
Alzheimer's disease (AD) brains exhibit plaques and tangles in association with inflammation. The non-receptor tyrosine kinase Abl is linked to neuro-inflammation in AD. Abl inhibition by nilotinib or bosutinib facilitates amyloid clearance and may decrease inflammation. Transgenic mice that express Dutch, Iowa and Swedish APP mutations (TgAPP) and display progressive Aβ plaque deposition were treated with tyrosine kinase inhibitors (TKIs) to determine pre-plaque effects on systemic and CNS inflammation using milliplex® ELISA. Plaque Aβ was detected at 4months in TgAPP and pre-plaque intracellular Aβ accumulation (2.5months) was associated with changes of cytokines and chemokines prior to detection of glial changes. Plaque formation correlated with increased levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-1α, IL-1β) and markers of immunosuppressive and adaptive immunity, including, IL-4, IL-10, IL-2, IL-3, Vascular Endothelial Growth Factor (VEGF) and IFN-γ. An inverse relationship of chemokines was observed as CCL2 and CCL5 were lower than WT mice at 2months and significantly increased after plaque appearance, while soluble CX3CL1 decreased. A change in glial profile was only robustly detected at 6months in Tg-APP mice and TKIs reduced astrocyte and dendritic cell number with no effects on microglia, suggesting alteration of brain immunity. Nilotinib decreased blood and brain cytokines and chemokines and increased CX3CL1. Bosutinib increased brain and blood IL-10 and CX3CL1, suggesting a protective role for soluble CX3CL1. Taken together these data suggest that TKIs regulate systemic and CNS immunity and may be useful treatments in early AD through dual effects on amyloid clearance and immune modulation.
MeSH Terms
- Aging
- Amyloid beta-Peptides
- Amyloid beta-Protein Precursor
- Aniline Compounds
- Animals
- Astrocytes
- Brain
- Cytokines
- Disease Models, Animal
- Enzyme Inhibitors
- Female
- Humans
- Intracellular Space
- Male
- Mice, Inbred C57BL
- Mice, Transgenic
- Microglia
- Neuroimmunomodulation
- Nitriles
- Peptide Fragments
- Plaque, Amyloid
- Protein-Tyrosine Kinases
- Pyrimidines
- Quinolines
Keywords
- CX3CL1
- bosutinib
- inflammation
- nilotinib
- plaque
Microglia develop an inflammatory phenotype during normal aging. The mechanism by which this occurs is not well understood, but might be related to impairments in several key immunoregulatory systems. Here we show that micro-RNA (miR)-29a and miR-29b, 2 immunoregulatory micro-RNAs, were increased in the brain of aged BALB/c mice compared with adults. Insulin-like growth factor-1 (IGF-1) and fractalkine ligand (CX3CL1) are negative modulators of microglial activation and were identified as targets of miR-29a and miR-29b using luciferase assay and primary microglia transfection. Indeed, higher expression of miR-29b in the brain of aged mice was associated with reduced messenger RNA (mRNA) levels of IGF-1 and CX3CL1. Parallel to these results in mice, miR-29a and miR-29b were also markedly increased in cortical brain tissue of older individuals (mean, 77 years) compared with middle-aged adults (mean, 45 years). Moreover, increased expression of miR-29b in human cortical tissue was negatively correlated with IGF-1 and CX3CL1 expression. Collectively, these data indicate that an age-associated increase in miR-29 corresponded with the reduction of 2 important regulators of microglia, IGF-1 and CX3CL1.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Animals
- CX3C Chemokine Receptor 1
- Cerebral Cortex
- Chemokine CX3CL1
- Humans
- Insulin-Like Growth Factor I
- Ligands
- Male
- Mice, Inbred BALB C
- MicroRNAs
- Microglia
- Middle Aged
- RNA, Messenger
- Receptors, Chemokine
- Young Adult
Keywords
- Aging
- Fractalkine
- Insulin-like growth factor
- Microglia
- Neuroinflammation
- miR-29a
- miR-29b
Chronic obstructive pulmonary disease (COPD) is associated with lung fibroblast senescence, a process characterized by the irreversible loss of replicative capacity associated with the secretion of inflammatory mediators. However, the mechanisms of this phenomenon remain poorly defined. The aim of this study was to analyze the role of prostaglandin E2 (PGE2), a prostaglandin known to be increased in COPD lung fibroblasts, in inducing senescence and related inflammation in vitro in lung fibroblasts and in vivo in mice. Fibroblasts were isolated from patients with COPD and from smoker and nonsmoker control subjects. Senescence markers and inflammatory mediators were investigated in fibroblasts and in mice. Lung fibroblasts from patients with COPD exhibited higher expression of PGE2 receptors EP2 and EP4 as compared with nonsmoker and smoker control subjects. Compared with both nonsmoker and smoker control subjects, during long-term culture, COPD fibroblasts displayed increased senescent markers (increased senescence associated-β galactosidase activity, p16, and p53 expression and lower proliferative capacity), and an increased PGE2, IL-6, IL-8, growth-regulated oncogene (GRO), CX3CL1, and matrix metalloproteinase-2 protein and cyclooxygenase-2 and mPGES-1 mRNA expression. Using in vitro pharmacologic approaches and in vivo experiments in wild-type and p53(-/-) mice we demonstrated that PGE2 produced by senescent COPD fibroblasts is responsible for the increased senescence and related inflammation. PGE2 acts either in a paracrine or autocrine fashion by a pathway involving EP2 and EP4 prostaglandin receptors, cyclooxygenase-2-dependent reactive oxygen species production and signaling, and consecutive p53 activation. PGE2 is a critical component of an amplifying and self-perpetuating circle inducing senescence and inflammation in COPD fibroblasts. Modulating the described PGE2 signaling pathway could provide a new basis to dampen senescence and senescence-associated inflammation in COPD.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Animals
- Autocrine Communication
- Case-Control Studies
- Cells, Cultured
- Cyclooxygenase 2
- Dinoprostone
- Female
- Fibroblasts
- Genes, p53
- Humans
- Lung
- Male
- Mice
- Mice, Inbred C57BL
- Middle Aged
- Paracrine Communication
- Pulmonary Disease, Chronic Obstructive
- Reactive Oxygen Species
- Receptors, Prostaglandin E, EP2 Subtype
- Receptors, Prostaglandin E, EP4 Subtype
- Statistics, Nonparametric
Ageing is accompanied by a decline in cognitive functions; along with a variety of neurobiological changes. The association between inflammation and ageing is based on complex molecular and cellular changes that we are only just beginning to understand. The hippocampus is one of the structures more closely related to electrophysiological, structural and morphological changes during ageing. In the present study we examined the effect of normal ageing and LPS-induced inflammation on astroglia-neuron interaction in the rat hippocampus of adult, normal aged and LPS-treated adult rats. Astrocytes were smaller, with thicker and shorter branches and less numerous in CA1 Str. radiatum of aged rats in comparison to adult and LPS-treated rats. Astrocyte branches infiltrated apoptotic neurons of aged and LPS-treated rats. Cellular debris, which were more numerous in CA1 of aged and LPS-treated rats, could be found apposed to astrocytes processes and were phagocytated by reactive microglia. Reactive microglia were present in the CA1 Str. Radiatum, often in association with apoptotic cells. Significant differences were found in the fraction of reactive microglia which was 40% of total in adult, 33% in aged and 50% in LPS-treated rats. Fractalkine (CX3CL1) increased significantly in hippocampus homogenates of aged and LPS-treated rats. The number of CA1 neurons decreased in aged rats. In the hippocampus of aged and LPS-treated rats astrocytes and microglia may help clearing apoptotic cellular debris possibly through CX3CL1 signalling. Our results indicate that astrocytes and microglia in the hippocampus of aged and LPS-infused rats possibly participate in the clearance of cellular debris associated with programmed cell death. The actions of astrocytes may represent either protective mechanisms to control inflammatory processes and the spread of further cellular damage to neighboring tissue, or they may contribute to neuronal damage in pathological conditions.
MeSH Terms
- Aging
- Animals
- Apoptosis
- Astrocytes
- Chemokine CX3CL1
- Disease Models, Animal
- Hippocampus
- Immunohistochemistry
- Inflammation
- Lipopolysaccharides
- Male
- Microglia
- Microscopy, Confocal
- Neurons
- Phagocytosis
- Rats
- Rats, Wistar
- Signal Transduction