Ann. N.Y. Acad. Sci. ISSN 0077-8923
A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Neuroimmunomodulation in Health and Disease
Fractalkine in the nervous system: neuroprotective or neurotoxic molecule? Clotilde Lauro,1 Myriam Catalano,1,2 Flavia Trettel,1 and Cristina Limatola1,2 1
Department of Physiology and Pharmacology, Istituto Pasteur Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy. 2 IRCCS NeuroMed, Pozzilli, Italy Address for correspondence: Clotilde Lauro, Department of Physiology and Pharmacology, Istituto Pasteur Fondazione Cenci Bolognetti, Sapienza University of Rome, Piazzale Aldo Moro 5, Rome 00185, Italy. [email protected]
Fractalkine (CX3CL1) is an intriguing chemokine that plays a central role in the nervous system. The expression of CX3CL1 on neurons and of its receptor CX3CR1 on microglia facilitates a privileged interaction, playing important roles in regulating the function and maturation of these cells. CX3CL1 is reported to have neuroprotective and antiinflammatory activities in several experimental systems and animal models of disease, and its expression correlates with positive outcomes in human neuropathologies. However, a comparable amount of evidence shows that CX3CL1 sustains neuroinflammatory conditions and contributes to neurotoxicity. This review discusses the evidence in favor of the CX3CL1/CX3CR1 pair being neuroprotective and other evidence that it is neurotoxic. Our aim is to stimulate future research examining the molecular and cellular determinants responsible for this unique functional switch, which could be important for several neuropathologies. Keywords: fractalkine; neuroprotection; inflammation; brain disease; microglia
Introduction: the CX3CL1/CX3CR1 system Many aspects of brain functioning are the result of complex and concerted interactions between neurons and neighboring glial cells, and in recent years, numerous studies have aimed to understand how the cells of the central nervous system (CNS) communicate in order to maintain brain homeostasis. In this view, the fractalkine (CX3CL1)/CX3CR1 pair represents an interesting path of signaling between neurons, microglia, and astrocytes in different aspects of CNS function. CX3CL1 is the sole member of the CX3C chemokine family; in the CNS, it is constitutively and abundantly expressed on neurons,1 while in astrocytes it can be induced by tumor necrosis factor (TNF)-␣ and interferon (IFN)-␥ treatment.2 CX3CL1 is expressed as a transmembrane protein that can be cleaved in a soluble form, consisting of the extracellular N-terminal chemokine domain, by the activity of the lysosomal cysteine protease cathepsin S (CatS) or by members of the disintegrin and metalloproteinase (ADAM) family, ADAM-10 and ADAM-17.3–5 Both
membrane-bound and soluble CX3CL1 bind a unique G protein–coupled receptor, CX3CR1, that in the brain is restricted to microglial cells.1 The discovery that CX3CL1 can be expressed on the cell surface as a membrane-bound protein and in a soluble form prompted the identification of possible distinct functions, such as adhesion and chemotaxis, for the two forms, at least in circulating cells.6–8 In the nervous system, clear indications of distinctive functions for the two molecular forms were lacking until there was evidence that, in the APP/PS1 mouse model of Alzheimer’s disease (AD), different effects of the soluble and membrane-bound forms of CX3CL1 were obtained for amyloid beta (A) deposition and phagocytosis and for microtubule-associated protein tau (MAPT) phosphorylation.9 Distinctive functions have also been reported recently in the MPTP mouse model of Parkinson’s disease (PD) where, with adenovirus-mediated gene expression, Morganti described selective neuroprotective effects of the soluble CX3CL1, able to reduce motor coordination impairment, decrease dopaminergic neuron
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loss, and modify microglial activation and release of proinflammatory cytokines.10 In physiological conditions, CX3CL1/CX3CR1 signaling is involved in different brain functions both in development and adulthood. During development, the CX3CL1/CX3CR1 pair participates in functional maturation of neuronal circuits driving cell positioning. In particular, the pair plays a role in (1) determining a correct neuronal network, as reported for the survival of layer V cortical neurons during the first postnatal week;11 (2) driving correct functional maturation of synapsis in the somatosensory cortex where CX3CL1 signaling controls microglial entry in the barrel centers and the proper functional maturation of thalamocortical synapses;12 and (3) controlling the recruitment of microglia for the correct recognition of synaptic boutons during pruning, since a lack of CX3CR1 in mice has been shown to result in transiently reduced microglial cell number and delayed synaptic pruning in the developing brain, with a consequent excess of dendritic spines, immature synapses, and a persistence of electrophysiological and pharmacological hallmarks of immature brain circuitry.13 In the adult brain, CX3CL1/CX3CR1 signaling regulates synaptic plasticity and cognitive functions. In particular, in the hippocampus, CX3CL1 is a potent modulator of glutamatergic synaptic transmission by (1) operating a reversible depression of the field excitatory postsynaptic potential (fEPSP) in acute slices;14 (2) regulating AMPA receptor–mediated currents through phosphatasedependent GluR1 dephosphorylation;15 and (3) inhibiting long-term potentiation (LTP) induction at CA3–CA1 synapses.16 Moreover, CX3CL1 upregulation, observed in experiments of postspatial learning,17 supports a direct role for CX3CL1 in memory-associated synaptic plasticity; in fact, genetic disruption of CX3CR1 impairs motor learning and associative and spatial memory. More importantly, these deficits appear to be gene dose dependent and related to increased levels of interleukin (IL)-1.18,19 An interesting observation is that CX3CL1 expression is abundant in the brains of young, but decreased in those of aged, rodents; reduced hippocampal neurogenesis is also reported, likely due to age-dependent neuronal loss. The genetic deletion or pharmacological block of CX3CR1 leads to reduced neurogenesis in the dentate gyrus of 142
mouse hippocampus,18–20 and the disruption of microglia-driven CX3CR1 signaling decreases both the survival and proliferation rate of neuronal progenitors, with a mechanism requiring IL-1.20 In aged mice, together with a reduced expression of CX3CL1, there is a reduction of microglia ramification, an increase of neuroinflammatory markers,20 and an amplified microglia response to peripheral lipopolysaccharide (LPS) injection,20–22 suggesting an anti-inflammatory role of CX3CL1. Several studies have demonstrated that CX3CL1 suppresses LPS-induced microglia activation by reducing the production of nitric oxide (NO), IL-6, and TNF-␣21,23 and inhibits neuronal cell death due to LPS-activated microglia in vitro, limiting the release of inflammatory factors.23,24 These data suggest that the high level of endogenous CX3CL1 expressed on neurons in the adult CNS leads to a tonic activation of CX3CR1 on microglia, and acts as a neuronal off signal maintaining microglia in a quiescent state,25,26 thus mediating a neuroprotective role for CX3CL1/CX3CR1 signaling. However, recently, Mattison demonstrated that in mixed neuron–glia cultures derived from CX3CR1 knockout (KO) mice, as well as in BV-2 cells silenced for CX3CR1 by small interfering RNA (siRNA) technology, LPS-induced release of TNF-␣, NO, and superoxide is reduced compared to wild-type (WT) cells,27 proposing instead that CX3CL1 is involved in the release of proinflammatory substances by activated microglia. The situation is even more confounding when studies on the effects of CX3CL1 in pathological conditions are taken into account. While there is a consensus with respect to a neuroprotective role of CX3CL1 in in vitro studies, in vivo studies of CX3CR1-KO mice have produced conflicting results. A neuroprotective role of CX3CL1/CX3CR1 signaling was demonstrated in CX3CR1-KO models of amyotrophic lateral sclerosis (ALS), PD,28 and multiple sclerosis (MS),29 while a neurotoxic role emerged in CX3CR1-KO models for AD30 and stroke.31 Accordingly, CX3CL1 may have dual functions, being neuroprotective and anti-inflammatory in some contexts, while proinflammatory and contributing to neuronal damage in others. Neuroprotective profile of CX3CL1 Neurons respond to potentially toxic insults by releasing soluble factors that can be sensed by
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surrounding cells to induce a broad range of cellular responses directed at protecting, and eventually repairing, tissue damage. Among the protective factors released by injured neurons is CX3CL1, which is upregulated,32,33 cleaved, and released upon ischemia or excitotoxic insult.34–36 CX3CL1 is neuroprotective in a variety of hypoxic and excitotoxic in vitro and in vivo models; a key mechanism underlying CX3CL1 neuroprotection is its ability to trigger the release of soluble factors that orchestrate a neuroprotective response, acting on surrounding microglia, astrocytes, and neurons. One of these soluble factors is adenosine. Stimulation of microglia with CX3CL1 induces an increase in extracellular adenosine, most likely derived from ATP,37,38 whose action on specific receptors counteracts the excitotoxic cell damage triggered by the activation of different glutamate (Glu) receptors. Specifically, activation of the adenosine receptors A1 R and A3 R modulates CX3CL1 neuroprotection against Glu excitoxicity,38,39 while A2A R is involved in neuroprotection against N-methyl-d-aspartate receptor (NMDAR) overactivation.40 CX3CL1 neuroprotection against Glu challenge requires the activity of A1 R expressed on astrocytes, which is necessary for increased expression and upregulation of the excitatory amino acid transporter GLT-1 and thereby leads to a more efficient removal of glutamate from the synaptic cleft.41 Moreover, CX3CL1 acts synergistically with other chemokines to promote neuroprotection. Recent data have shown that CX3CL1 elicits from glia the release of CXCL1639 that, in turn, contributes to neuronal survival via a mechanism that involves the activation of astrocytic A3 R and the release of CCL2.42 CX3CL1 also induces the release of d-serine from glia, via an A2A Rmediated mechanism,43 that, besides modulating the NMDAR response, contributes to the neuroprotective effect by mediating the phosphorylation of cyclic AMP response element–binding protein (CREB).40 Among the factors released upon CX3CL1 stimulation is brain-derived neurotrophic factor (BDNF); hippocampal cultures treated with CX3CL1 showed increased BDNF expression and TrkB phosphorylation levels,40 both of which are correlated to phosphorylation of CREB and neuroprotection. These data corroborate the idea that, together with a direct action on microglia, the neuroprotective effect of CX3CL1 requires an intense dialogue
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among different cells of brain parenchyma that cooperate to limit brain damage by modulating the activity of neurotrophic factors and glutamate receptors, as well as the phagocytic capacity of microglia cells. In this regard, the phagocytic activity of microglia could be beneficial for tissue repair, since the clearing of cellular debris after brain injury represents an important mechanism in regaining tissue homeostasis and promoting functional recovery.44 One molecule that regulates microglia phagocytosis is milk fat globule–EGF factor 8 (MFG-E8), which recognizes the phosphatidylserine (PS) receptor on injured neurons and mediates phagocytosis of damaged cells, thereby dampening neuroinflammatory responses.45 CX3CL1 secreted from damaged neurons promotes microglia phagocytosis of neuronal debris through increased expression of MFG-E8,46 and activates anti-inflammatory and neuroprotective signals by inducing activation of c-Jun N-terminal kinases (JNK) and, consequently, nuclear translocation of the erythroidrelated transcription factor 2 (Nrf2); the latter occurs together with the expression of the antioxidant enzyme heme oxygenase-1 (HO-1) that, in turn, reduces Glu neurotoxicity.36 Another key event in CX3CL1 neuroprotection following stroke is the acute recruitment into a damaged area of Iba1+ /NG2+ progenitor cells (BINCs) and bone marrow–derived mesenchymal stem cells (BMSCs), which participate in tissue protection.33,47 BINCs contribute to neuroprotection by producing neuroprotective factors, such as insulin-like growth factor-1 (IGF-1) and hepatocyte growth factor (HGF), and by removing debris of damaged tissue.48 BMSCs exert neuroprotective action through their ability to display multilineage differentiation and to improve functional outcomes via a mechanism dependent on the stromal cell–derived factor-1␣ (SDF-1␣)–CXCR4 axis.49 CX3CL1 is neuroprotective against brain ischemia in animals with a normal CX3CR1/CX3CL1 axis. Intracerebroventricular injections of CX3CL1 result in a smaller infarct size and milder neurological deficits compared to untreated animals, both in in vivo murine models of permanent middle cerebral artery occlusion (pMCAO)50 and transient MCAO.51 Similar results have been reported in a model of transient global cerebral ischemia in rats, in which CX3CR1 inhibition by siRNA increased the activation of microglia and the release
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of proinflammatory cytokines, resulting in a general worsening of neurological deficits.52 Evidence for neuroprotective activity of CX3CL1 has also been reported in different mouse models of chronic neurodegenerative diseases, such as AD; for example, in hAPP-J20 transgenic mice, the deletion of CX3CR1 enhanced tau pathology and increased microglia activation.53 In line with these results, in a mouse model of tauopathy CX3CL1 limited the overactivation of microglia and attenuated tau-induced microgliosis by activating Nrf2 signaling.54 CX3CL1 also reduced neuronal loss in a rat model of PD produced by intrastriatal injection of 6-hydroxydopamine (6-OHDA).55 In epileptic human tissues, CX3CL1 reduced the usedependent impairment of gamma-aminobutyric acid (GABA) currents, suggesting a protective effect in this pathology, with a possible reduction of excitatory neurotransmission.56 CX3CL1/CX3CR1 axis activity has also been shown to be neuroprotective in CX3CR1-deficient mice, at least in some disease models, such as ALS,28 experimental autoimmune encephalomyelitis (EAE),29 and MPTP-induced PD.10,28 Neurotoxic profile of CX3CL1 An early event in brain inflammatory responses, the release of soluble factors from damaged neurons in response to neurotoxic insults can lead to the recruitment of reactive immune cells. Among these soluble factors, CX3CL1, acting on CX3CR1, selectively modulates microglia activity1 and regulates recruitment of circulating leucocytes to sites of injury.7,8 CX3CR1-deficient mice have reduced damage upon cerebral ischemia, showing less inflammatory infiltrate and proinflammatory cytokines, together with reduced ischemic volume, leukocyte infiltration, and blood–brain barrier (BBB) damage.31,50 MCAO ischemic Cx3cr1–/– mice have smaller infarcts than WT mice, together with reduced microglia activation (defined by a lower expression of CD11b and CD68), and mainly express M2-specific anti-inflammatory markers, such as Ym1.57 These findings suggest that in Cx3cr1–/– mice the reduced damage observed upon cerebral ischemia can be explained by a lower recruitment of peripheral macrophages along with an increased anti-inflammatory state of microglia,58 thus indicating a toxic role for CX3CL1 signaling. 144
A neurotoxic role for CX3CL1 has also been hypothesized for AD pathology. Data obtained in CX3CR1-deficient mice crossed with different mouse models of AD, such as APP/PS1 and R1.40 mice, showed reduced A deposition, and fewer dystrophic neurons and plaque-associated microglia,59 not dissimilar from what was reported in 3xTg-AD-thy1-YFP-CX3CR1GFP/GFP mice.60 In CRND8/CX3CR1GFP/GFP mice, the authors reported increased microglia phagocytic activity and reduced A deposition,61 further suggesting that CX3CL1 can exert a toxic effect, acting as a repressor of microglia phagocytic activity. In another model of a chronic neurodegenerative disorder, namely PD, a toxic effect for CX3CL1 has been shown: in rats, 1-methyl-4-phenylpyridinium (MPP) treatment increased the expression of CX3CL1/CX3CR1 in the substantia nigra (SN), and CX3CL1 injection in the SN of MPP-treated rats induced microglia activation, dopaminergic cell depletion, and motor dysfunction.62 All these effects were abolished by intracerebroventricular administration of a neutralizing antibody against CX3CR1, indicating that CX3CL1-induced microglia activation plays an important role in the development of PD, at least in this experimental model. Recent evidence suggests that CX3CL1/CX3CR1 signaling also plays a role in cell death associated with epilepsy;63,64 in particular, the expression of CX3CR1 was shown to be increased in the hippocampus of adult rats one week following status epilepticus (SE); and intracerebroventricular injection of an anti-CX3CR1 antibody diminished SE-induced microglial activation and neurodegeneration.65 Translation to human brain diseases In this complex view, it is clear that CX3CL1/ CX3CR1 signaling is crucial for neuron–microglia communication, but whether CX3CL1 can be considered a bona fide neuroprotective or neurotoxic molecule remains controversial. Although most of the studies have been performed on animal models, recent data on patients suggested that CX3CL1 could play an active role in traumatic and inflammatory neurological diseases. In patients affected by viral or bacterial meningitis or traumatic brain injury, a significant increase in CX3CL1 was reported in the cerebrospinal fluid (CSF);66–68 in MS and systemic lupus erythematosus (SLE), CX3CL1
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levels were elevated in both CSF and serum.67,69 Furthermore, a positive correlation was reported between CX3CL1 plasma levels and a better outcome in ischemic patients; high CX3CL1 levels were also associated with low percentages of white blood cells, polymorphonuclear cells, monocytes, and reduced levels of the high-sensitivity C-reactive protein at several time points after stroke.70 Similar results were recently shown in an association study between the temporal pattern of CX3CL1 expression, stroke severity, and outcome in humans.71 These data would indicate that, in humans as well, CX3CL1 limits the inflammatory response and tissue damage upon stroke, improving long-term outcomes. In accordance with the evidence of a protective function of CX3CL1, patients with mild cognitive impairment (MCI), a clinical condition that often precedes AD, have higher circulating levels of CX3CL1 in comparison with AD patients; and the level of CX3CL1 is inversely correlated to AD severity.72 CX3CL1 could also play an important protective role in human epilepsy, as shown by studies that reported increased levels of CX3CL1 in the CSF of patients with mesial temporal lobe epilepsy (MTLE)64 and increased CX3CL1 and CX3CR1 expression in brain tissue from MTLE patients.56 Electrophysiological recordings in freshly resected human brain slices from MTLE patients evidenced the ability of CX3CL1 to reduce the use-dependent decrease of GABA-evoked currents, possibly limiting the deregulation of excitatory neurotransmission that underlies SE-induced neuronal damage.56
activation state of microglia in the different phases of acute and chronic brain diseases. The message that emerges from the experimental evidence over the past 15 years is that the effects of the activation of CX3CL1/CX3CR1 signaling are context dependent: CX3CL1 might promote the brain recruitment of different innate immune cells expressing CX3CR1, but the combination of CX3CL1 expression with particular sets of cytokines, growth factors, and other soluble factors (i.e., the local microenvironment where CX3CL1 operates) may promote an imbalance between neuroprotective or neurotoxic signals, depending on the strength, duration, and nature of the toxic stimulus. This is especially true when using genetically modified mice, where the activation state of microglia might be modified by the absence of constitutive CX3CL1/CX3CR1 signaling. In this view it is clear that, to better approach the study of CX3CL1 in the nervous system, the use of conditional transgenic or viral-mediated knockdown models should be considered, since it would allow a reduced alteration of the activation state of microglia and artificial modification of the brain microenvironment. In light of the many and multifaceted potential roles of CX3CL1 in the nervous system, results obtained with these approaches might be informative for developing new therapeutic strategies for different brain diseases.
Conclusions
References
CX3CL1 is a molecule that may have dual activities, with either beneficial or destructive potential in the CNS, likely depending on the activation state of its main target, the microglia cell population. Microglia have different intermediate activation states between a pro- (M1) and anti-inflammatory phenotype (M2), the former characterized by the release of NO, reactive oxygen products, and proinflammatory cytokines, and the latter characterized by the release of anti-inflammatory cytokines and growth factors.73 Evidence suggests that microglia phenotype changes from M2 to M1 with the progression of brain diseases such as AD, traumatic brain injury, and ischemia.74–76 In this context, the ability of CX3CL1 to be either neuroprotective or neurotoxic might depend on the M1 or M2
Conflicts of interest The authors declare no conflicts of interest.
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53. Cho, S.H., B. Sun, Y. Zhou, et al. 2011. CX3CR1 protein signaling modulates microglial activation and protects against plaque-independent cognitive deficits in a mouse model of Alzheimer disease. J. Biol. Chem. 286: 32713–22. 54. Lastres-Becker, I., N.G. Innamorato, T. Jaworski, et al. 2014. Fractalkine activates NRF2/NFE2L2 and heme oxygenase 1 to restrain tauopathy-induced microgliosis. Brain 137: 78–91. 55. Pabon, M.M., A.D. Bachstetter, C.E. Hudson, et al. 2011. CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson’s disease. J. Neuroinflammation 8: 9. 56. Roseti, C., S. Fucile, C. Lauro, et al. 2013. Fractalkine/ CX3CL1 modulates GABAA currents in human temporal lobe epilepsy. Epilepsia 54: 1834–1844. 57. Fumagalli, S., C. Perego, F. Ortolano, et al. 2013. CX3CR1 deficiency induces an early protective inflammatory environment in ischemic mice. Glia 61: 827–842. 58. Tang, Z., Y. Gan, Q. Liu, et al. 2014. CX3CR1 deficiency suppresses activation and neurotoxicity of microglia/ macrophage in experimental ischemic stroke. J. Neuroinflammation 11: 26 59. Lee, S., N.H. Varvel, M.E. Konerth, et al. 2010. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease mouse models. Am. J. Pathol. 177: 2549–2562. 60. Fuhrmann, M., T. Bittner, C.K. Jung, et al. 2010. Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease. Nat. Neurosci. 13: 411–413. 61. Liu, Z., C. Condello, A. Schain, et al. 2010. CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillaramyloid- phagocytosis. J. Neurosci. 30: 17091–17101. 62. Shan, S., T. Hong-Min, F. Yi, et al. 2011. New evidences for fractalkine/CX3CL1 involved in substantia nigral microglial activation and behavioral changes in a rat model of Parkinson’s disease. Neurobiol. Aging 32: 443–458. 63. Yeo, S.I., J.E. Kim, H.J. Ryu, et al. 2011. The roles of fractalkine/CX3CR1 system in neuronal death following pilocarpine-induced status epilepticus. J. Neuroimmunol. 234: 93–102. 64. Xu, Y., Y. Zhang, Z. Guo, et al. 2012. Increased placental growth factor in cerebrospinal fluid of patients with epilepsy. Neurochem. Res. 37: 665–670. 65. Ali, I., D. Chugh, C.T. Ekdahl. 2015. Role of fractalkineCX3CR1 pathway in seizure-induced microglial activation, neurodegeneration, and neuroblast production in the adult rat brain. Neurobiol. Dis. 74: 194–203. 66. Rancan, M., N. Bye, V.I. Otto, et al. 2004. The chemokine fractalkine in patients with severe traumatic brain injury and a mouse model of closed head injury. J. Cereb. Blood Flow Metab. 24: 1110–1118. 67. Yajima, N., T. Kasama, T. Isozaki, et al. 2005. Elevated levels of soluble fractalkine in active systemic lupus erythematosus: potential involvement in neuropsychiatric manifestations. Arthritis Rheum. 52: 1670–1675. 68. Kasama, T., T. Odai, K. Wakabayashi, et al. 2008. Chemokines in systemic lupus erythematosus involving the central nervous system. Front. Biosci. 13: 2527–2536.
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69. Kastenbauer, S., U. Koedel, M. Wick, et al. 2003. CSF and serum levels of soluble fractalkine (CX3CL1) in inflammatory diseases of the nervous system, J. Neuroimmunol. 137: 210–217. 70. Donohue, M.M., K. Cain, D. Zierath, et al. 2012. Higher plasma fractalkine is associated with better 6-month outcome from ischemic stroke. Stroke 43: 2300–2306. 71. Grosse, G.M., A.B. Tryc, M. Dirks, et al. 2014. The temporal dynamics of plasma fractalkine levels in ischemic stroke: association with clinical severity and outcome. J. Neuroinflammation 11: 74. 72. Kim, T.S., H.K. Lim, J.Y. Lee, et al. 2008. Changes in the levels of plasma soluble fractalkine in patients with mild cognitive impairment and Alzheimer’s disease. Neurosci. Lett. 436: 196–200.
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73. Cherry, J.D., J.A. Olschowka & M.K. O’Banion 2014. Neuroinflammation and M2 microglia: the god, the bad and the inflamed. J. Neuroinflammation 11: 98. 74. Varnum, M.M. & T. Ikezu. 2012. The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer’s disease brain. Arch. Immunol. Ther. Exp. 60: 251–266. 75. Wang, G., J. Zhang, X. Hu, et al. 2013. Microglia/macrophage polarization dynamics in white matter after traumatic brain injury. Neural Regen. Res. 8: 1157–1168. 76. Suenaga, J., X. Hu, H. Pu, et al. 2015. White matter injury and microglia/macrophage polarization are strongly linked with age-related long-term deficits in neurological function after stroke. Exp. Neurol. DOI: 10.1016/j.expneurol.2015. 03.021
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A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Neuroimmunomodulation in Health and Disease
Fractalkine in the nervous system: neuroprotective or neurotoxic molecule? Clotilde Lauro,1 Myriam Catalano,1,2 Flavia Trettel,1 and Cristina Limatola1,2 1
Department of Physiology and Pharmacology, Istituto Pasteur Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy. 2 IRCCS NeuroMed, Pozzilli, Italy Address for correspondence: Clotilde Lauro, Department of Physiology and Pharmacology, Istituto Pasteur Fondazione Cenci Bolognetti, Sapienza University of Rome, Piazzale Aldo Moro 5, Rome 00185, Italy. [email protected]
Fractalkine (CX3CL1) is an intriguing chemokine that plays a central role in the nervous system. The expression of CX3CL1 on neurons and of its receptor CX3CR1 on microglia facilitates a privileged interaction, playing important roles in regulating the function and maturation of these cells. CX3CL1 is reported to have neuroprotective and antiinflammatory activities in several experimental systems and animal models of disease, and its expression correlates with positive outcomes in human neuropathologies. However, a comparable amount of evidence shows that CX3CL1 sustains neuroinflammatory conditions and contributes to neurotoxicity. This review discusses the evidence in favor of the CX3CL1/CX3CR1 pair being neuroprotective and other evidence that it is neurotoxic. Our aim is to stimulate future research examining the molecular and cellular determinants responsible for this unique functional switch, which could be important for several neuropathologies. Keywords: fractalkine; neuroprotection; inflammation; brain disease; microglia
Introduction: the CX3CL1/CX3CR1 system Many aspects of brain functioning are the result of complex and concerted interactions between neurons and neighboring glial cells, and in recent years, numerous studies have aimed to understand how the cells of the central nervous system (CNS) communicate in order to maintain brain homeostasis. In this view, the fractalkine (CX3CL1)/CX3CR1 pair represents an interesting path of signaling between neurons, microglia, and astrocytes in different aspects of CNS function. CX3CL1 is the sole member of the CX3C chemokine family; in the CNS, it is constitutively and abundantly expressed on neurons,1 while in astrocytes it can be induced by tumor necrosis factor (TNF)-␣ and interferon (IFN)-␥ treatment.2 CX3CL1 is expressed as a transmembrane protein that can be cleaved in a soluble form, consisting of the extracellular N-terminal chemokine domain, by the activity of the lysosomal cysteine protease cathepsin S (CatS) or by members of the disintegrin and metalloproteinase (ADAM) family, ADAM-10 and ADAM-17.3–5 Both
membrane-bound and soluble CX3CL1 bind a unique G protein–coupled receptor, CX3CR1, that in the brain is restricted to microglial cells.1 The discovery that CX3CL1 can be expressed on the cell surface as a membrane-bound protein and in a soluble form prompted the identification of possible distinct functions, such as adhesion and chemotaxis, for the two forms, at least in circulating cells.6–8 In the nervous system, clear indications of distinctive functions for the two molecular forms were lacking until there was evidence that, in the APP/PS1 mouse model of Alzheimer’s disease (AD), different effects of the soluble and membrane-bound forms of CX3CL1 were obtained for amyloid beta (A) deposition and phagocytosis and for microtubule-associated protein tau (MAPT) phosphorylation.9 Distinctive functions have also been reported recently in the MPTP mouse model of Parkinson’s disease (PD) where, with adenovirus-mediated gene expression, Morganti described selective neuroprotective effects of the soluble CX3CL1, able to reduce motor coordination impairment, decrease dopaminergic neuron
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loss, and modify microglial activation and release of proinflammatory cytokines.10 In physiological conditions, CX3CL1/CX3CR1 signaling is involved in different brain functions both in development and adulthood. During development, the CX3CL1/CX3CR1 pair participates in functional maturation of neuronal circuits driving cell positioning. In particular, the pair plays a role in (1) determining a correct neuronal network, as reported for the survival of layer V cortical neurons during the first postnatal week;11 (2) driving correct functional maturation of synapsis in the somatosensory cortex where CX3CL1 signaling controls microglial entry in the barrel centers and the proper functional maturation of thalamocortical synapses;12 and (3) controlling the recruitment of microglia for the correct recognition of synaptic boutons during pruning, since a lack of CX3CR1 in mice has been shown to result in transiently reduced microglial cell number and delayed synaptic pruning in the developing brain, with a consequent excess of dendritic spines, immature synapses, and a persistence of electrophysiological and pharmacological hallmarks of immature brain circuitry.13 In the adult brain, CX3CL1/CX3CR1 signaling regulates synaptic plasticity and cognitive functions. In particular, in the hippocampus, CX3CL1 is a potent modulator of glutamatergic synaptic transmission by (1) operating a reversible depression of the field excitatory postsynaptic potential (fEPSP) in acute slices;14 (2) regulating AMPA receptor–mediated currents through phosphatasedependent GluR1 dephosphorylation;15 and (3) inhibiting long-term potentiation (LTP) induction at CA3–CA1 synapses.16 Moreover, CX3CL1 upregulation, observed in experiments of postspatial learning,17 supports a direct role for CX3CL1 in memory-associated synaptic plasticity; in fact, genetic disruption of CX3CR1 impairs motor learning and associative and spatial memory. More importantly, these deficits appear to be gene dose dependent and related to increased levels of interleukin (IL)-1.18,19 An interesting observation is that CX3CL1 expression is abundant in the brains of young, but decreased in those of aged, rodents; reduced hippocampal neurogenesis is also reported, likely due to age-dependent neuronal loss. The genetic deletion or pharmacological block of CX3CR1 leads to reduced neurogenesis in the dentate gyrus of 142
mouse hippocampus,18–20 and the disruption of microglia-driven CX3CR1 signaling decreases both the survival and proliferation rate of neuronal progenitors, with a mechanism requiring IL-1.20 In aged mice, together with a reduced expression of CX3CL1, there is a reduction of microglia ramification, an increase of neuroinflammatory markers,20 and an amplified microglia response to peripheral lipopolysaccharide (LPS) injection,20–22 suggesting an anti-inflammatory role of CX3CL1. Several studies have demonstrated that CX3CL1 suppresses LPS-induced microglia activation by reducing the production of nitric oxide (NO), IL-6, and TNF-␣21,23 and inhibits neuronal cell death due to LPS-activated microglia in vitro, limiting the release of inflammatory factors.23,24 These data suggest that the high level of endogenous CX3CL1 expressed on neurons in the adult CNS leads to a tonic activation of CX3CR1 on microglia, and acts as a neuronal off signal maintaining microglia in a quiescent state,25,26 thus mediating a neuroprotective role for CX3CL1/CX3CR1 signaling. However, recently, Mattison demonstrated that in mixed neuron–glia cultures derived from CX3CR1 knockout (KO) mice, as well as in BV-2 cells silenced for CX3CR1 by small interfering RNA (siRNA) technology, LPS-induced release of TNF-␣, NO, and superoxide is reduced compared to wild-type (WT) cells,27 proposing instead that CX3CL1 is involved in the release of proinflammatory substances by activated microglia. The situation is even more confounding when studies on the effects of CX3CL1 in pathological conditions are taken into account. While there is a consensus with respect to a neuroprotective role of CX3CL1 in in vitro studies, in vivo studies of CX3CR1-KO mice have produced conflicting results. A neuroprotective role of CX3CL1/CX3CR1 signaling was demonstrated in CX3CR1-KO models of amyotrophic lateral sclerosis (ALS), PD,28 and multiple sclerosis (MS),29 while a neurotoxic role emerged in CX3CR1-KO models for AD30 and stroke.31 Accordingly, CX3CL1 may have dual functions, being neuroprotective and anti-inflammatory in some contexts, while proinflammatory and contributing to neuronal damage in others. Neuroprotective profile of CX3CL1 Neurons respond to potentially toxic insults by releasing soluble factors that can be sensed by
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surrounding cells to induce a broad range of cellular responses directed at protecting, and eventually repairing, tissue damage. Among the protective factors released by injured neurons is CX3CL1, which is upregulated,32,33 cleaved, and released upon ischemia or excitotoxic insult.34–36 CX3CL1 is neuroprotective in a variety of hypoxic and excitotoxic in vitro and in vivo models; a key mechanism underlying CX3CL1 neuroprotection is its ability to trigger the release of soluble factors that orchestrate a neuroprotective response, acting on surrounding microglia, astrocytes, and neurons. One of these soluble factors is adenosine. Stimulation of microglia with CX3CL1 induces an increase in extracellular adenosine, most likely derived from ATP,37,38 whose action on specific receptors counteracts the excitotoxic cell damage triggered by the activation of different glutamate (Glu) receptors. Specifically, activation of the adenosine receptors A1 R and A3 R modulates CX3CL1 neuroprotection against Glu excitoxicity,38,39 while A2A R is involved in neuroprotection against N-methyl-d-aspartate receptor (NMDAR) overactivation.40 CX3CL1 neuroprotection against Glu challenge requires the activity of A1 R expressed on astrocytes, which is necessary for increased expression and upregulation of the excitatory amino acid transporter GLT-1 and thereby leads to a more efficient removal of glutamate from the synaptic cleft.41 Moreover, CX3CL1 acts synergistically with other chemokines to promote neuroprotection. Recent data have shown that CX3CL1 elicits from glia the release of CXCL1639 that, in turn, contributes to neuronal survival via a mechanism that involves the activation of astrocytic A3 R and the release of CCL2.42 CX3CL1 also induces the release of d-serine from glia, via an A2A Rmediated mechanism,43 that, besides modulating the NMDAR response, contributes to the neuroprotective effect by mediating the phosphorylation of cyclic AMP response element–binding protein (CREB).40 Among the factors released upon CX3CL1 stimulation is brain-derived neurotrophic factor (BDNF); hippocampal cultures treated with CX3CL1 showed increased BDNF expression and TrkB phosphorylation levels,40 both of which are correlated to phosphorylation of CREB and neuroprotection. These data corroborate the idea that, together with a direct action on microglia, the neuroprotective effect of CX3CL1 requires an intense dialogue
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among different cells of brain parenchyma that cooperate to limit brain damage by modulating the activity of neurotrophic factors and glutamate receptors, as well as the phagocytic capacity of microglia cells. In this regard, the phagocytic activity of microglia could be beneficial for tissue repair, since the clearing of cellular debris after brain injury represents an important mechanism in regaining tissue homeostasis and promoting functional recovery.44 One molecule that regulates microglia phagocytosis is milk fat globule–EGF factor 8 (MFG-E8), which recognizes the phosphatidylserine (PS) receptor on injured neurons and mediates phagocytosis of damaged cells, thereby dampening neuroinflammatory responses.45 CX3CL1 secreted from damaged neurons promotes microglia phagocytosis of neuronal debris through increased expression of MFG-E8,46 and activates anti-inflammatory and neuroprotective signals by inducing activation of c-Jun N-terminal kinases (JNK) and, consequently, nuclear translocation of the erythroidrelated transcription factor 2 (Nrf2); the latter occurs together with the expression of the antioxidant enzyme heme oxygenase-1 (HO-1) that, in turn, reduces Glu neurotoxicity.36 Another key event in CX3CL1 neuroprotection following stroke is the acute recruitment into a damaged area of Iba1+ /NG2+ progenitor cells (BINCs) and bone marrow–derived mesenchymal stem cells (BMSCs), which participate in tissue protection.33,47 BINCs contribute to neuroprotection by producing neuroprotective factors, such as insulin-like growth factor-1 (IGF-1) and hepatocyte growth factor (HGF), and by removing debris of damaged tissue.48 BMSCs exert neuroprotective action through their ability to display multilineage differentiation and to improve functional outcomes via a mechanism dependent on the stromal cell–derived factor-1␣ (SDF-1␣)–CXCR4 axis.49 CX3CL1 is neuroprotective against brain ischemia in animals with a normal CX3CR1/CX3CL1 axis. Intracerebroventricular injections of CX3CL1 result in a smaller infarct size and milder neurological deficits compared to untreated animals, both in in vivo murine models of permanent middle cerebral artery occlusion (pMCAO)50 and transient MCAO.51 Similar results have been reported in a model of transient global cerebral ischemia in rats, in which CX3CR1 inhibition by siRNA increased the activation of microglia and the release
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of proinflammatory cytokines, resulting in a general worsening of neurological deficits.52 Evidence for neuroprotective activity of CX3CL1 has also been reported in different mouse models of chronic neurodegenerative diseases, such as AD; for example, in hAPP-J20 transgenic mice, the deletion of CX3CR1 enhanced tau pathology and increased microglia activation.53 In line with these results, in a mouse model of tauopathy CX3CL1 limited the overactivation of microglia and attenuated tau-induced microgliosis by activating Nrf2 signaling.54 CX3CL1 also reduced neuronal loss in a rat model of PD produced by intrastriatal injection of 6-hydroxydopamine (6-OHDA).55 In epileptic human tissues, CX3CL1 reduced the usedependent impairment of gamma-aminobutyric acid (GABA) currents, suggesting a protective effect in this pathology, with a possible reduction of excitatory neurotransmission.56 CX3CL1/CX3CR1 axis activity has also been shown to be neuroprotective in CX3CR1-deficient mice, at least in some disease models, such as ALS,28 experimental autoimmune encephalomyelitis (EAE),29 and MPTP-induced PD.10,28 Neurotoxic profile of CX3CL1 An early event in brain inflammatory responses, the release of soluble factors from damaged neurons in response to neurotoxic insults can lead to the recruitment of reactive immune cells. Among these soluble factors, CX3CL1, acting on CX3CR1, selectively modulates microglia activity1 and regulates recruitment of circulating leucocytes to sites of injury.7,8 CX3CR1-deficient mice have reduced damage upon cerebral ischemia, showing less inflammatory infiltrate and proinflammatory cytokines, together with reduced ischemic volume, leukocyte infiltration, and blood–brain barrier (BBB) damage.31,50 MCAO ischemic Cx3cr1–/– mice have smaller infarcts than WT mice, together with reduced microglia activation (defined by a lower expression of CD11b and CD68), and mainly express M2-specific anti-inflammatory markers, such as Ym1.57 These findings suggest that in Cx3cr1–/– mice the reduced damage observed upon cerebral ischemia can be explained by a lower recruitment of peripheral macrophages along with an increased anti-inflammatory state of microglia,58 thus indicating a toxic role for CX3CL1 signaling. 144
A neurotoxic role for CX3CL1 has also been hypothesized for AD pathology. Data obtained in CX3CR1-deficient mice crossed with different mouse models of AD, such as APP/PS1 and R1.40 mice, showed reduced A deposition, and fewer dystrophic neurons and plaque-associated microglia,59 not dissimilar from what was reported in 3xTg-AD-thy1-YFP-CX3CR1GFP/GFP mice.60 In CRND8/CX3CR1GFP/GFP mice, the authors reported increased microglia phagocytic activity and reduced A deposition,61 further suggesting that CX3CL1 can exert a toxic effect, acting as a repressor of microglia phagocytic activity. In another model of a chronic neurodegenerative disorder, namely PD, a toxic effect for CX3CL1 has been shown: in rats, 1-methyl-4-phenylpyridinium (MPP) treatment increased the expression of CX3CL1/CX3CR1 in the substantia nigra (SN), and CX3CL1 injection in the SN of MPP-treated rats induced microglia activation, dopaminergic cell depletion, and motor dysfunction.62 All these effects were abolished by intracerebroventricular administration of a neutralizing antibody against CX3CR1, indicating that CX3CL1-induced microglia activation plays an important role in the development of PD, at least in this experimental model. Recent evidence suggests that CX3CL1/CX3CR1 signaling also plays a role in cell death associated with epilepsy;63,64 in particular, the expression of CX3CR1 was shown to be increased in the hippocampus of adult rats one week following status epilepticus (SE); and intracerebroventricular injection of an anti-CX3CR1 antibody diminished SE-induced microglial activation and neurodegeneration.65 Translation to human brain diseases In this complex view, it is clear that CX3CL1/ CX3CR1 signaling is crucial for neuron–microglia communication, but whether CX3CL1 can be considered a bona fide neuroprotective or neurotoxic molecule remains controversial. Although most of the studies have been performed on animal models, recent data on patients suggested that CX3CL1 could play an active role in traumatic and inflammatory neurological diseases. In patients affected by viral or bacterial meningitis or traumatic brain injury, a significant increase in CX3CL1 was reported in the cerebrospinal fluid (CSF);66–68 in MS and systemic lupus erythematosus (SLE), CX3CL1
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levels were elevated in both CSF and serum.67,69 Furthermore, a positive correlation was reported between CX3CL1 plasma levels and a better outcome in ischemic patients; high CX3CL1 levels were also associated with low percentages of white blood cells, polymorphonuclear cells, monocytes, and reduced levels of the high-sensitivity C-reactive protein at several time points after stroke.70 Similar results were recently shown in an association study between the temporal pattern of CX3CL1 expression, stroke severity, and outcome in humans.71 These data would indicate that, in humans as well, CX3CL1 limits the inflammatory response and tissue damage upon stroke, improving long-term outcomes. In accordance with the evidence of a protective function of CX3CL1, patients with mild cognitive impairment (MCI), a clinical condition that often precedes AD, have higher circulating levels of CX3CL1 in comparison with AD patients; and the level of CX3CL1 is inversely correlated to AD severity.72 CX3CL1 could also play an important protective role in human epilepsy, as shown by studies that reported increased levels of CX3CL1 in the CSF of patients with mesial temporal lobe epilepsy (MTLE)64 and increased CX3CL1 and CX3CR1 expression in brain tissue from MTLE patients.56 Electrophysiological recordings in freshly resected human brain slices from MTLE patients evidenced the ability of CX3CL1 to reduce the use-dependent decrease of GABA-evoked currents, possibly limiting the deregulation of excitatory neurotransmission that underlies SE-induced neuronal damage.56
activation state of microglia in the different phases of acute and chronic brain diseases. The message that emerges from the experimental evidence over the past 15 years is that the effects of the activation of CX3CL1/CX3CR1 signaling are context dependent: CX3CL1 might promote the brain recruitment of different innate immune cells expressing CX3CR1, but the combination of CX3CL1 expression with particular sets of cytokines, growth factors, and other soluble factors (i.e., the local microenvironment where CX3CL1 operates) may promote an imbalance between neuroprotective or neurotoxic signals, depending on the strength, duration, and nature of the toxic stimulus. This is especially true when using genetically modified mice, where the activation state of microglia might be modified by the absence of constitutive CX3CL1/CX3CR1 signaling. In this view it is clear that, to better approach the study of CX3CL1 in the nervous system, the use of conditional transgenic or viral-mediated knockdown models should be considered, since it would allow a reduced alteration of the activation state of microglia and artificial modification of the brain microenvironment. In light of the many and multifaceted potential roles of CX3CL1 in the nervous system, results obtained with these approaches might be informative for developing new therapeutic strategies for different brain diseases.
Conclusions
References
CX3CL1 is a molecule that may have dual activities, with either beneficial or destructive potential in the CNS, likely depending on the activation state of its main target, the microglia cell population. Microglia have different intermediate activation states between a pro- (M1) and anti-inflammatory phenotype (M2), the former characterized by the release of NO, reactive oxygen products, and proinflammatory cytokines, and the latter characterized by the release of anti-inflammatory cytokines and growth factors.73 Evidence suggests that microglia phenotype changes from M2 to M1 with the progression of brain diseases such as AD, traumatic brain injury, and ischemia.74–76 In this context, the ability of CX3CL1 to be either neuroprotective or neurotoxic might depend on the M1 or M2
Conflicts of interest The authors declare no conflicts of interest.
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