Chemokines in the balance: maintenance of homeostasis and protection at CNS barriers (original) (raw)
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Frontiers in cellular neuroscience, 2014
The chemokine CXCL12/stromal cell-derived factor 1 alpha has first been described in the immune system where it functions include chemotaxis for lymphocytes and macrophages, migration of hematopoietic cells from fetal liver to bone marrow and the formation of large blood vessels. Among other chemokines, CXCL12 has recently attracted much attention in the brain as it has been shown that it can be produced not only by glial cells but also by neurons. In addition, its receptors CXCR4 and CXCR7, which are belonging to the G protein-coupled receptors family, are abundantly expressed in diverse brain area, CXCR4 being a major co-receptor for human immunodeficiency virus 1 entry. This chemokine system has been shown to play important roles in brain plasticity processes occurring during development but also in the physiology of the brain in normal and pathological conditions. For example, in neurons, CXCR4 stimulation has been shown regulate the synaptic release of glutamate and γ-aminobuty...
Chemokines Referee Inflammation within the Central Nervous System during Infection and Disease
Advances in Medicine, 2014
The discovery that chemokines and their receptors are expressed by a variety of cell types within the normal adult central nervous system (CNS) has led to an expansion of their repertoire as molecular interfaces between the immune and nervous systems. Thus, CNS chemokines are now divided into those molecules that regulate inflammatory cell migration into the CNS and those that initiate CNS repair from inflammation-mediated tissue damage. Work in our laboratory throughout the past decade has sought to elucidate how chemokines coordinate leukocyte entry and interactions at CNS endothelial barriers, under both homeostatic and inflammatory conditions, and how they promote repair within the CNS parenchyma. These studies have identified several chemokines, including CXCL12 and CXCL10, as critical regulators of leukocyte migration from perivascular locations. CXCL12 additionally plays an essential role in promoting remyelination of injured white matter. In both scenarios we have shown that...
Expression of CXCL4 in microglia in vitro and in vivo and its possible signaling through CXCR3
Journal of Neurochemistry, 2008
Signaling through chemokine receptor CXCR3 in the brain has been implicated in various brain diseases, as CXCR3 and its ligands are found under these conditions. Recently, a new chemokine ligand for CXCR3 was reported. In humans, an alternatively spliced variant of CXCR3 expressed on microvascular endothelial cells, named CXCR3b, was shown to bind CXCL4. In the periphery, the cellular expression and functions of CXCL4 are well described but in the brain its expression and function are unknown. Here, we show that brain microglia are a cellular source of CXCL4 in vitro and in vivo under neurodegenerating conditions. Microglial migration induced by CXCL4 is absent in CXCR3-deficient microglia, indicating a role of CXCR3. CXCL4 furthermore attenuates lipopolysaccharide-induced microglial phagocytosis and nitric oxide production in microglia and BV-2 cells. Based on these findings, it is proposed that locally released CXCL4 may control microglia responses.
CXCL12 in control of neuroinflammation
Immunologic Research, 2012
Inflammation within the central nervous system (CNS) is strictly controlled and if possible prevented. Such a tight control is necessary due to high sensitivity of nervous tissue to mechanical and biochemical consequences of inflammation. Still, neuroinflammation is a typical feature of a chronic, inflammatory, demyelinating disease multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). It is assumed that mechanisms that should prevent activation of immune cells at the periphery, in the lymphoid tissues, and/or inflammation within the CNS are inadequately efficient in MS patients. Here, some recent data about the importance of CXCL12 for regulation of neuroinflammation and contribution of its deviant expression within the CNS to EAE and MS pathogenesis are presented. Keywords Experimental autoimmune encephalomyelitis Á Multiple sclerosis Á Neuroinflammation Á CXCL12 Á Nitric oxide CXCL12 in brief CXCL12 or stromal cell derived factor-1 (SDF-1) is a 68-amino-acid CXC chemokine with important roles in essential biological processes such as vascular and neuronal development and hematopoiesis. The response to CXCL12 occurs at a very early stage of embryonic development and appears to be widely operative whenever cell migration is required [1]. Indeed, mice lacking CXCL12 die prenatally and exhibit defects in vascularization, neuronal development, and hematopoiesis [2-5]. CXCL12 regulates the bone marrow homing and egress of stem and endothelial progenitor cells and their migration into peripheral tissues in both steady-state conditions and injury [6, 7]. Besides these physiological functions, CXCL12 seems to be involved in pathological processes such as neoplasia, tumor progression, and chronic inflammation [8-14]. In immune system, the principal role of this chemokine is to regulate the trafficking and localization of myeloid, lymphoid, and progenitor cells between central and peripheral compartments [15, 16]. CXCL12 is constitutively expressed in a broad range of tissues [17, 18], and the major sources of CXCL12 expression are bone marrow stromal elements and endothelial cells [19, 20]. It has been shown that the effects of CXCL12, such as mobilization of leukocytes from the bone marrow and transendothelial migration of inflammatory cells, are mainly dependent on the interaction of the chemokine with CXC chemokine receptor 4-CXCR4 [19-22]. CXCR4 has been considered as the unique receptor for CXCL12 and as the only mediator of its biological effects for many years. However, recent studies have found that CXCL12 binds not only to CXCR4 but also to CXCR7 (RDC1) [23]. While CXCL12 is exclusive ligand for CXCR4, CXCR7 binds both CXCL12 and CXCL11. This recently discovered receptor for CXCL12 is phylogenetically closely related to chemokine receptors but fails to
CXCL12: Role in neuroinflammation
The International Journal of Biochemistry & Cell Biology, 2012
CXCL12, also known as SDF-1 (stromal cell derived factor-1) is a small protein that belongs to the chemokine family, whose members have a crucial role in directing cell migration. CXCL12 has an essential role in neural and vascular development, hematopoiesis and in immunity. It acts through two receptors, CXCR4 and CXCR7. While the former is a classic G protein-coupled transmembrane chemokine receptor, the latter primarily function as a scavenger of CXCL12. CXCL12 has been considered as a standard proinflammatory molecule for a long time, as it attracts leukocytes to inflammatory sites and contributes to their activation. However, recent findings indicate that this chemokine has the opposite role in neuroinflammation. In this review, basic data about molecular and functional properties of CXCL12 are presented, while its role in CNS autoimmunity is addressed in details.
Current Biology, 1998
Children are at greater risk than adults of permanent brain damage and mortality following head injury or infection [1-5]. Rodent models have demonstrated a 'window of susceptibility' in young animals during which the brain parenchyma is at greater risk of acute neutrophil-mediated breakdown of the blood-brain barrier [6,7]. The exact mechanism of this age-related susceptibility to brain inflammation has yet to be defined, but animal models have revealed that the potent pro-inflammatory cytokine interleukin-1b (IL-1b) initiates an intense acute neutrophil-mediated inflammatory response in the brains of young rats and mice that is not seen in adults [6]. Here, we demonstrate the rapid induction of CXC chemokines (which contain a Cys-X-Cys motif), in particular the cytokine-induced neutrophil chemoattractant CINC-1, following the intracerebral administration of IL-1b. The CXC chemokines produced a more intense neutrophil response in young rats than in adults. The IL-1b-induced blood-brain barrier breakdown in young rats could be attenuated by an anti-CINC-1 neutralising antibody. These results show that the immature central nervous system (CNS) is dramatically more susceptible to the chemotactic effects of CXC chemokines. Blocking the CXC chemokine activity associated with brain inflammation inhibits neutrophil-mediated blood-brain barrier damage and represents a significant therapeutic possibility.
Cxcr7 Controls Neuronal Migration by Regulating Chemokine Responsiveness
Neuron, 2011
The chemokine Cxcl12 binds Cxcr4 and Cxcr7 receptors to control cell migration in multiple biological contexts, including brain development, leukocyte trafficking, and tumorigenesis. Both receptors are expressed in the CNS, but how they cooperate during migration has not been elucidated. Here, we used the migration of cortical interneurons as a model to study this process. We found that Cxcr4 and Cxcr7 are coexpressed in migrating interneurons, and that Cxcr7 is essential for chemokine signaling. Intriguingly, this process does not exclusively involve Cxcr7, but most critically the modulation of Cxcr4 function. Thus, Cxcr7 is necessary to regulate Cxcr4 protein levels, thereby adapting chemokine responsiveness in migrating cells. This demonstrates that a chemokine receptor modulates the function of another chemokine receptor by controlling the amount of protein that is made available for signaling at the cell surface. Neuron
The Journal of Immunology, 2002
Microglial cells represent the major immunocompetent element of the CNS and are activated by any type of brain injury or disease. A candidate for signaling neuronal injury to microglial cells is the CC chemokine ligand CCL21, given that damaged neurons express CCL21. Investigating microglia in acute slices and in culture, we demonstrate that a local application of CCL21 for 30 s triggered a Cl ؊ conductance with lasted for tens of minutes. This response was sensitive to the Cl ؊ channel blockers 4,4-diisothiocyanatostilbene-2,2-disulfonic acid and 4-acetamide-4-isothiocyanatostilbene, 2,2-disulfonic acid. Moreover, CCL21 triggered a chemotaxis response, which was sensitive to Cl ؊ channel blockers. In microglial cells cultured from CCR7 knockout mice, CCL21 produced the same type of Cl ؊ current as well as a chemotaxis response. In contrast, in microglial cells from CXCR3 knockout mice, CCL21 triggered neither a Cl ؊ conductance nor a chemotaxis response after CCL21 application. We conclude that the CCL21-induced Cl ؊ current is a prerequisite for the chemotaxis response mediated by the activation of CXCR3 but not CCR7 receptors, indicating that in brain CCL21 acts via a different receptor system than in lymphoid organs.
The Journal of Immunology, 2006
Fractalkine/CX3CL1 and its specific receptor CX3CR1 are constitutively expressed in several regions of the CNS and are reported to mediate neuron-microglial interaction, synaptic transmission, and neuronal protection from toxic insults. CX3CL1 is released both by neuronal and astrocytic cells, whereas CX3CR1 is mainly expressed by microglial cells and neurons. Microglial cells efficiently migrate in response to CX3CL1, whereas no evidence is reported to date on CX3CL1-induced neuronal migration. For this reason, we have investigated in vitro the effects of CX3CL1 on basal migration of neurons and of the microglial and astrocytic populations, all these cells being obtained from the hippocampus and the cerebellum of newborn rats. We report that CX3CL1 stimulates microglial cell migration but efficiently reduces basal neuronal movement, regardless of the brain source. The effect of CX3CL1 is pertussis toxin (PTX) sensitive and PI3K dependent on hippocampal neurons, while it is PTX sensitive, PI3K dependent, and ERK dependent on cerebellar granules. Interestingly, CX3CL1 also increases neuron adhesion to the extracellular matrix component laminin, with mechanisms dependent on PTX-sensitive G proteins, and on the ERK and PI3K pathways. Both the reduction of migration and the increase of neuron adhesion require the activation of the  1 and ␣ 6 integrin subunits with the exception of cerebellar neuron migration, which is only dependent on the  1 subunit. More importantly, in neurons, CX3CL1/ CXCL12 cotreatment abolished the effect mediated by a single chemokine on chemotaxis and adhesion. In conclusion, our findings indicate that CX3CL1 reduces neuronal migration by increasing cell adhesion through integrin-dependent mechanisms in hippocampal and cerebellar neurons.