Depression is a prevalent and debilitating mental disorder, and the underlying mechanisms of depression remain unclear. Emerging evidence highlights the importance of chemokines, particularly CX3CL1/CX3CR1 signaling, in the pathophysiology of depression. CX3CL1 (Fractalkine, CX3C chemokine ligand 1) is an essential chemokine and exerts its biological effects by binding to its receptor, CX3CR1. This interaction plays a pivotal role in mediating communication between microglia and neurons within the central nervous system. Numerous studies have suggested that CX3CL1/CX3CR1 signaling is a critical regulator of neuroinflammation and synaptic plasticity. Therefore, this narrative review provides a comprehensive overview of the role of CX3CL1/CX3CR1 signaling in neuroinflammation, synaptic plasticity, and cognition. In addition, we discuss the critical role of this signaling pathway in the pathophysiology of depression and antidepressant treatments and highlight its significance in the field of neuropsychopharmacology.
AlamoCGarcía-GarciaPLopez-MuñozF, et al. (2019) Tianeptine, an atypical pharmacological approach to depression. Revista de Psiquiatria y Salud Mental (English Edition)12(3): 170–186.
2.
AlboniSBenattiCMontanariC, et al. (2013) Chronic antidepressant treatments resulted in altered expression of genes involved in inflammation in the rat hypothalamus. European Journal of Pharmacology721(1–3): 158–167.
3.
AlboniSPogginiSGarofaloS, et al. (2016) Fluoxetine treatment affects the inflammatory response and microglial function according to the quality of the living environment. Brain, Behavior, and Immunity58: 261–271.
4.
AntoniukSBijataMPonimaskinE, et al. (2019) Chronic unpredictable mild stress for modeling depression in rodents: Meta-analysis of model reliability. Neuroscience & Biobehavioral Reviews99: 101–116.
5.
ArnouxIAudinatE (2015) Fractalkine signaling and microglia functions in the developing brain. Neural Plasticity2015: 689404.
6.
BajettoABonaviaRBarberoS, et al. (2001) Chemokines and their receptors in the central nervous system. Front Neuroendocrinol22(3): 147–184.
7.
BajettoABonaviaRBarberoS, et al. (2002) Characterization of chemokines and their receptors in the central nervous system: physiopathological implications. Journal of Neurochemistry82(6): 1311–1329.
8.
BanisadrGRostèneWKitabgiP, et al. (2005) Chemokines and brain functions. Current Drug Targets – Inflammation & Allergy4(3): 387–399.
9.
BazanJFBaconKBHardimanG, et al. (1997) A new class of membrane-bound chemokine with a CX3C motif. Nature385(6617): 640–644.
10.
BertolliniCRagozzinoDGrossC, et al. (2006) Fractalkine/CX3CL1 depresses central synaptic transmission in mouse hippocampal slices. Neuropharmacology51(4): 816–821.
11.
BeurelEToupsMNemeroffCB (2020) The bidirectional relationship of depression and inflammation: Double trouble. Neuron107(2): 234–256.
12.
BlankTDetjeCNSpießA, et al. (2016) Brain endothelial- and epithelial-specific interferon receptor chain 1 drives virus-induced sickness behavior and cognitive impairment. Immunity44(4): 901–912.
13.
BollingerJLBergeon BurnsCMWellmanCL (2016) Differential effects of stress on microglial cell activation in male and female medial prefrontal cortex. Brain, Behavior, and Immunity52: 88–97.
14.
BolósMPereaJRTerreros-RoncalJ, et al. (2018) Absence of microglial CX3CR1 impairs the synaptic integration of adult-born hippocampal granule neurons. Brain, Behavior, and Immunity68: 76–89.
15.
Borroto-EscuelaDOAmbroginiPChruścickaB, et al. (2021) The role of central serotonin neurons and 5-HT heteroreceptor complexes in the pathophysiology of depression: A historical perspective and future prospects. International Journal of Molecular Science22(4): 1927.
16.
BymasterFPMcNamaraRKTranPV (2003) New approaches to developing antidepressants by enhancing monoaminergic neurotransmission. Expert Opinion on Investigational Drugs12(4): 531–543.
17.
CallewaereCBanisadrGRostèneW, et al. (2007) Chemokines and chemokine receptors in the brain: Implication in neuroendocrine regulation. Journal of Molecular Endocrinology38(3): 355–363.
18.
Camacho-HernándezNPPeña-OrtegaF (2023) Fractalkine/CX3CR1-dependent modulation of synaptic and network plasticity in health and disease. Neural Plasticity2023: 4637073.
19.
CardinaliDPSrinivasanVBrzezinskiA, et al. (2012) Melatonin and its analogs in insomnia and depression. Journal of Pineal Research52(4): 365–375.
20.
CardonaAEPioroEPSasseME, et al. (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nature Neuroscience9(7): 917–924.
21.
CardonaAESasseMELiuL, et al. (2008) Scavenging roles of chemokine receptors: chemokine receptor deficiency is associated with increased levels of ligand in circulation and tissues. Blood112(2): 256–263.
22.
CarvalhoLAGorensteinCMorenoR, et al. (2009) Effect of antidepressants on melatonin metabolite in depressed patients. Journal of Psychopharmacology23(3): 315–321.
23.
CazarethJGuyonAHeurteauxC, et al. (2014) Molecular and cellular neuroinflammatory status of mouse brain after systemic lipopolysaccharide challenge: Importance of CCR2/CCL2 signaling. Journal of Neuroinflammation11: 132.
24.
ChaiHHFuXCMaL, et al. (2019) The chemokine CXCL1 and its receptor CXCR2 contribute to chronic stress-induced depression in mice. FASEB Journal33(8): 8853–8864.
25.
ChameraKTrojanESzuster-GłuszczakM, et al. (2020) The potential role of dysfunctions in neuron-microglia communication in the pathogenesis of brain disorders. Current Neuropharmacology18(5): 408–430.
26.
ChandrasekarBMummidiSPerlaRP, et al. (2003) Fractalkine (CX3CL1) stimulated by nuclear factor kappaB (NF-kappaB)-dependent inflammatory signals induces aortic smooth muscle cell proliferation through an autocrine pathway. Biochemical Journal373(Pt 2): 547–558.
27.
CornellJSalinasSHuangHY, et al. (2022) Microglia regulation of synaptic plasticity and learning and memory. Neural Regeneration Research17(4): 705–716.
28.
CoronaAWHuangYO’ConnorJC, et al. (2010) Fractalkine receptor (CX3CR1) deficiency sensitizes mice to the behavioral changes induced by lipopolysaccharide. Journal of Neuroinflammation7: 93.
29.
DamianFSantomauroAMMHShadidJZhengP, et al. (2021) Global prevalence and burden of depressive and anxiety disorders in 204 countries and territories in 2020 due to the COVID-19 pandemic. The Lancet398(10312): 1700–1712.
30.
de BodinatCGuardiola-LemaitreBMocaërE, et al. (2010) Agomelatine, the first melatonergic antidepressant: Discovery, characterization and development. Nature Reviews Drug Discovery9(8): 628–642.
31.
DelgadoPL (2000) Depression: The case for a monoamine deficiency. Journal of Clinical Psychiatry61(Suppl 6): 7–11.
32.
Dell’OssoLCarmassiCMucciF, et al. (2016) Depression, serotonin and tryptophan. Current Pharmaceutical Design22(8): 949–954.
33.
Di FilippoMSarchielliPPicconiB, et al. (2008) Neuroinflammation and synaptic plasticity: Theoretical basis for a novel, immune-centred, therapeutic approach to neurological disorders. Trends in Pharmacological Sciences29(8): 402–412.
34.
DiazGranadosNIbrahimLABrutscheNE, et al. (2010) Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. Journal of Clinical Psychiatry71(12): 1605–1611.
35.
DorfmanMDKrullJEDouglassJD, et al. (2017) Sex differences in microglial CX3CR1 signalling determine obesity susceptibility in mice. Nature Communications8: 14556.
36.
EdinoffANSallSBeckmanSP, et al. (2023) Tianeptine, an antidepressant with opioid agonist effects: Pharmacology and abuse potential, a narrative review. Pain and Therapy12(5): 1121–1134.
37.
FrickLRWilliamsKPittengerC (2013) Microglial dysregulation in psychiatric disease. Clinical and Developmental Immunology2013: 608654.
38.
García-MarchenaNBarreraMMestre-PintóJI, et al. (2019) Inflammatory mediators and dual depression: Potential biomarkers in plasma of primary and substance-induced major depression in cocaine and alcohol use disorders. PLoS One14(3): e0213791.
39.
GartonKJGoughPJBlobelCP, et al. (2001) Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1). Journal of Biological Chemistry276(41): 37993–38001.
40.
GunnerGCheadleLJohnsonKM, et al. (2019) Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling. Nature Neuroscience22(7): 1075–1088.
41.
GuoBZhangMHaoW, et al. (2023) Neuroinflammation mechanisms of neuromodulation therapies for anxiety and depression. Translational Psychiatry13(1): 5.
42.
HagenaHManahan-VaughanD (2024) Interplay of hippocampal long-term potentiation and long-term depression in enabling memory representations. Philosophical Transactions of the Royal Society of London B Biological Sciences379(1906): 20230229.
43.
HammenC (2005) Stress and depression. Annu Rev Clin Psychol1: 293–319.
HeinischSKirbyLG (2009) Fractalkine/CX3CL1 enhances GABA synaptic activity at serotonin neurons in the rat dorsal raphe nucleus. Neuroscience164(3): 1210–1223.
46.
HellwigSBrioschiSDieniS, et al. (2016) Altered microglia morphology and higher resilience to stress-induced depression-like behavior in CX3CR1-deficient mice. Brain, Behavior, and Immunity55: 126–137.
47.
HodzicAGesslbauerBBochkovV, et al. (2024) Cooperative induction of CXCL chemokines by inflammatory cytokines and oxidized phospholipids. Immunology173(2): 286–295.
48.
HughesCENibbsRJB (2018) A guide to chemokines and their receptors. FEBS Journal285(16): 2944–2971.
49.
ImaiTHieshimaKHaskellC, et al. (1997) Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion. Cell91(4): 521–530.
50.
JeonSWKimYK (2023) Neuron-microglia crosstalk in neuropsychiatric disorders. Advances in Experimental Medicine and Biology1411: 3–15.
51.
JiangXYiSLiuQ, et al. (2022) Asperosaponin VI ameliorates the CMS-induced depressive-like behaviors by inducing a neuroprotective microglial phenotype in hippocampus via PPAR-γ pathway. Journal of Neuroinflammation19(1): 115.
52.
KawamuraNKatsuuraGYamada-GotoN, et al. (2020) Reduced brain fractalkine-CX3CR1 signaling is involved in the impaired cognition of streptozotocin-treated mice. IBRO Reports9: 233–240.
53.
KoperOMKamińskaJSawickiK, et al. (2018) CXCL9, CXCL10, CXCL11, and their receptor (CXCR3) in neuroinflammation and neurodegeneration. Advances in Clinical and Experimental Medicine27(6): 849–856.
54.
LauroCCiprianiRCatalanoM, et al. (2010) Adenosine A1 receptors and microglial cells mediate CX3CL1-induced protection of hippocampal neurons against Glu-induced death. Neuropsychopharmacology35(7): 1550–1559.
55.
LeiWJiaLWangZ, et al. (2023) CC chemokines family in fibrosis and aging: From mechanisms to therapy. Ageing Research Reviews87: 101900.
56.
LeightonSPNerurkarLKrishnadasR, et al. (2018) Chemokines in depression in health and in inflammatory illness: A systematic review and meta-analysis. Molecular Psychiatry23(1): 48–58.
57.
LimatolaCLauroCCatalanoM, et al. (2005) Chemokine CX3CL1 protects rat hippocampal neurons against glutamate-mediated excitotoxicity. Journal of Neuroimmunology166(1–2): 19–28.
58.
LiuYWuXMLuoQQ, et al. (2015) CX3CL1/CX3CR1-mediated microglia activation plays a detrimental role in ischemic mice brain via p38MAPK/PKC pathway. Journal of Cerebral Blood Flow & Metabolism35(10): 1623–1631.
59.
LiuYZhangTMengD, et al. (2020) Involvement of CX3CL1/CX3CR1 in depression and cognitive impairment induced by chronic unpredictable stress and relevant underlying mechanism. Behavioural Brain Research381: 112371.
60.
LuoPChuSFZhangZ, et al. (2019) Fractalkine/CX3CR1 is involved in the cross-talk between neuron and glia in neurological diseases. Brain Research Bulletin146: 12–21.
61.
MaddukuriRKHemaCSri TejaswiK, et al. (2021) Antidepressant efficacy of Agomelatine: Meta-analysis of placebo controlled and active comparator studies. Asian Journal of Psychiatry65: 102866.
62.
MageeJCGrienbergerC (2020) Synaptic plasticity forms and functions. Annual Review of Neuroscience43: 95–117.
63.
MaggiLScianniMBranchiI, et al. (2011) CX(3)CR1 deficiency alters hippocampal-dependent plasticity phenomena blunting the effects of enriched environment. Frontiers in Cellular Neuroscience5: 22.
64.
MaggiLTrettelFScianniM, et al. (2009) LTP impairment by fractalkine/CX3CL1 in mouse hippocampus is mediated through the activity of adenosine receptor type 3 (A3R). Journal of Neuroimmunology215(1–2): 36–42.
65.
MalhiGSMannJJ (2018) Depression. The Lancet392(10161): 2299–2312.
66.
MarciniakEFaivreEDutarP, et al. (2015) The Chemokine MIP-1α/CCL3 impairs mouse hippocampal synaptic transmission, plasticity and memory. Science Reports5: 15862.
67.
MarsdenWN (2013) Synaptic plasticity in depression: Molecular, cellular and functional correlates. Progress in Neuro-Psychopharmacology and Biological Psychiatry43: 168–184.
68.
MerendinoRADi PasqualeGDe LucaF, et al. (2004) Involvement of fractalkine and macrophage inflammatory protein-1 alpha in moderate-severe depression. Mediators of Inflammation13(3): 205–207.
69.
MeucciOFatatisASimenAA, et al. (2000) Expression of CX3CR1 chemokine receptors on neurons and their role in neuronal survival. Proceedings of the National Academy of Sciences of the United States of America97(14): 8075–8080.
70.
MiliorGLecoursCSamsonL, et al. (2016) Fractalkine receptor deficiency impairs microglial and neuronal responsiveness to chronic stress. Brain, Behavior, and Immunity55: 114–125.
71.
MillerRJRosteneWApartisE, et al. (2008) Chemokine action in the nervous system. Journal of Neuroscience28(46): 11792–11795.
72.
MizunoTKawanokuchiJNumataK, et al. (2003) Production and neuroprotective functions of fractalkine in the central nervous system. Brain Research979(1–2): 65–70.
73.
MizutaniMPinoPASaederupN, et al. (2012) The fractalkine receptor but not CCR2 is present on microglia from embryonic development throughout adulthood. Journal of Immunology188(1): 29–36.
74.
MuWOuyangXAgarwalA, et al. (2005) IL-10 suppresses chemokines, inflammation, and fibrosis in a model of chronic renal disease. Journal of the American Society of Nephrology16(12): 3651–3660.
75.
PabonMMBachstetterADHudsonCE, et al. (2011) CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson’s disease. Journal of Neuroinflammation8: 9.
76.
PanYLloydCZhouH, et al. (1997) Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation. Nature387(6633): 611–617.
77.
PengQShiLKongY, et al. (2020) CX3CL1 rs170364 gene polymorphism has a protective effect against major depression by enhancing its transcriptional activity. Brain Research1738: 146801.
78.
QinMChenCWangN, et al. (2023) Total saponins of panax ginseng via the CX3CL1/CX3CR1 axis attenuates neuroinflammation and exerted antidepressant-like effects in chronic unpredictable mild stress in rats. Phytotherapy Research37(5): 1823–1838.
79.
RagozzinoDDi AngelantonioSTrettelF, et al. (2006) Chemokine fractalkine/CX3CL1 negatively modulates active glutamatergic synapses in rat hippocampal neurons. Journal of Neuroscience26(41): 10488–10498.
80.
RameshGMacLeanAGPhilippMT (2013) Cytokines and chemokines at the crossroads of neuroinflammation, neurodegeneration, and neuropathic pain. Mediators of Inflammation2013: 480739.
81.
RansohoffRM (2009) Chemokines and chemokine receptors: Standing at the crossroads of immunobiology and neurobiology. Immunity31(5): 711–721.
82.
ReshefRKreiselTBeroukhim KayD, et al. (2014) Microglia and their CX3CR1 signaling are involved in hippocampal- but not olfactory bulb-related memory and neurogenesis. Brain, Behavior, and Immunity41: 239–250.
83.
RimmermanNSchottlenderNReshefR, et al. (2017) The hippocampal transcriptomic signature of stress resilience in mice with microglial fractalkine receptor (CX3CR1) deficiency. Brain, Behavior, and Immunity61: 184–196.
84.
RogersJTMorgantiJMBachstetterAD, et al. (2011) CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. Journal of Neuroscience31(45): 16241–16250.
85.
RossettiACPappMGrucaP, et al. (2016) Stress-induced anhedonia is associated with the activation of the inflammatory system in the rat brain: Restorative effect of pharmacological intervention. Pharmacological Research103: 1–12.
86.
RostèneWGuyonAKularL, et al. (2011) Chemokines and chemokine receptors: New actors in neuroendocrine regulations. Frontiers in Neuroendocrinology32(1): 10–24.
87.
RostèneWKitabgiPParsadaniantzSM (2007) Chemokines: A new class of neuromodulator?Nature Reviews Neuroscience8(11): 895–903.
88.
ScianniMAntonilliLCheceG, et al. (2013) Fractalkine (CX3CL1) enhances hippocampal N-methyl-D-aspartate receptor (NMDAR) function via D-serine and adenosine receptor type A2 (A2AR) activity. Journal of Neuroinflammation10: 108.
89.
SheridanGKWdowiczAPickeringM, et al. (2014) CX3CL1 is up-regulated in the rat hippocampus during memory-associated synaptic plasticity. Frontiers in Cellular Neuroscience8: 233.
90.
ŚlusarczykJTrojanEGłombikK, et al. (2015) Prenatal stress is a vulnerability factor for altered morphology and biological activity of microglia cells. Frontiers in Cellular Neuroscience9: 82.
91.
ŚlusarczykJTrojanEWydraK, et al. (2016) Beneficial impact of intracerebroventricular fractalkine administration on behavioral and biochemical changes induced by prenatal stress in adult rats: Possible role of NLRP3 inflammasome pathway. Biochemical Pharmacology113: 45–56.
92.
SunXWangMWangY, et al. (2017) Melatonin produces a rapid onset and prolonged efficacy in reducing depression-like behaviors in adult rats exposed to chronic unpredictable mild stress. Neuroscience Letters642: 129–135.
93.
SzepesiZManouchehrianOBachillerS, et al. (2018) Bidirectional microglia-neuron communication in health and disease. Frontiers in Cellular Neuroscience12: 323.
94.
TangMMLinWJPanYQ, et al. (2018) Fibroblast growth factor 2 modulates hippocampal microglia activation in a neuroinflammation induced model of depression. Frontiers in Cellular Neuroscience12: 255.
95.
TangMMLinWJZhangJT, et al. (2017) Exogenous FGF2 reverses depressive-like behaviors and restores the suppressed FGF2-ERK1/2 signaling and the impaired hippocampal neurogenesis induced by neuroinflammation. Brain, Behavior, and Immunity66: 322–331.
96.
TarozzoGBortolazziSCrochemoreC, et al. (2003) Fractalkine protein localization and gene expression in mouse brain. Journal of Neuroscience Research73(1): 81–88.
97.
TrojanEŚlusarczykJChameraK, et al. (2017) The modulatory properties of chronic antidepressant drugs treatment on the brain chemokine–chemokine receptor network: A molecular study in an animal model of depression. Frontiers in Pharmacology8: 779.
98.
TroubatRBaronePLemanS, et al. (2021) Neuroinflammation and depression: A review. European Journal of Neuroscience53(1): 151–171.
99.
TsaiWHShihCHFengSY, et al. (2014) Role of CX3CL1 in the chemotactic migration of all-trans retinoic acid-treated acute promyelocytic leukemic cells toward apoptotic cells. Journal of the Chinese Medical Association77(7): 367–373.
100.
Vega-RiveraNMOrtiz-LópezLGranados-JuárezA, et al. (2020) Melatonin reverses the depression-associated behaviour and regulates microglia, fractalkine expression and neurogenesis in adult mice exposed to chronic mild stress. Neuroscience440: 316–336.
101.
VoseLRStantonPK (2017) Synaptic plasticity, metaplasticity and depression. Current Neuropharmacology15(1): 71–86.
102.
WangHHeYSunZ, et al. (2022) Microglia in depression: An overview of microglia in the pathogenesis and treatment of depression. Journal of Neuroinflammation19(1): 132.
103.
WilliamsJLHolmanDWKleinRS (2014) Chemokines in the balance: Maintenance of homeostasis and protection at CNS barriers. Frontiers in Cellular Neuroscience8: 154.
104.
WilliamsonLLBilboSD (2013) Chemokines and the hippocampus: A new perspective on hippocampal plasticity and vulnerability. Brain, Behavior, and Immunity30: 186–194.
105.
WohlebESPowellNDGodboutJP, et al. (2013) Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior. Journal of Neuroscience33(34): 13820–13833.
106.
WojdasiewiczPPoniatowskiŁAKotelaA, et al. (2020) Comparative analysis of the occurrence and role of CX3CL1 (Fractalkine) and its receptor CX3CR1 in hemophilic arthropathy and osteoarthritis. Journal of Immunology Research2020: 2932696.
107.
WuAZhangJ (2023) Neuroinflammation, memory, and depression: New approaches to hippocampal neurogenesis. Journal of Neuroinflammation20(1): 283.
108.
WuJBieBYangH, et al. (2013) Suppression of central chemokine fractalkine receptor signaling alleviates amyloid-induced memory deficiency. Neurobiology of Aging34(12): 2843–2852.
109.
YinYYWangYHLiuWG, et al. (2021) The role of the excitation: Inhibition functional balance in the mPFC in the onset of antidepressants. Neuropharmacology191: 108573.
110.
YirmiyaR (2024) The inflammatory underpinning of depression: An historical perspective. Brain, Behavior, and Immunity122: 433–443.
111.
ZanierERMarchesiFOrtolanoF, et al. (2016) Fractalkine receptor deficiency is associated with early protection but late worsening of outcome following brain trauma in mice. Journal of Neurotrauma33(11): 1060–1072.
112.
ZhangJYiSLiY, et al. (2020) The antidepressant effects of asperosaponin VI are mediated by the suppression of microglial activation and reduction of TLR4/NF-κB-induced IDO expression. Psychopharmacology (Berl)237(8): 2531–2545.
113.
ZhangYJinYLiJ, et al. (2024) CXCL14 as a key regulator of neuronal development: Insights from its receptor and multi-omics analysis. International Journal of Molecular Science25(3): 1651.
114.
ZhouYWangCLanX, et al. (2021) Plasma inflammatory cytokines and treatment-resistant depression with comorbid pain: improvement by ketamine. Journal of Neuroinflammation18(1): 200.
115.
ZujovicVBenavidesJVigéX, et al. (2000) Fractalkine modulates TNF-alpha secretion and neurotoxicity induced by microglial activation. Glia29(4): 305–315.
116.
ZujovicVSchusslerNJourdainD, et al. (2001) In vivo neutralization of endogenous brain fractalkine increases hippocampal TNFalpha and 8-isoprostane production induced by intracerebroventricular injection of LPS. Journal of Neuroimmunology115(1–2): 135–143.
