Chemokines Referee Inflammation within the Central Nervous System during Infection and Disease (original) (raw)
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Chemokines in the balance: maintenance of homeostasis and protection at CNS barriers
Frontiers in Cellular Neuroscience, 2014
In the adult central nervous system (CNS), chemokines and their receptors are involved in developmental, physiological and pathological processes. Although most lines of investigation focus on their ability to induce the migration of cells, recent studies indicate that chemokines also promote cellular interactions and activate signaling pathways that maintain CNS homeostatic functions. Many homeostatic chemokines are expressed on the vasculature of the blood brain barrier (BBB) including CXCL12, CCL19, CCL20, and CCL21. While endothelial cell expression of these chemokines is known to regulate the entry of leukocytes into the CNS during immunosurveillance, new data indicate that CXCL12 is also involved in diverse cellular activities including adult neurogenesis and neuronal survival, having an opposing role to the homeostatic chemokine, CXCL14, which appears to regulate synaptic inputs to neural precursors. Neuronal expression of CX 3 CL1, yet another homeostatic chemokine that promotes neuronal survival and communication with microglia, is partly regulated by CXCL12. Regulation of CXCL12 is unique in that it may regulate its own expression levels via binding to its scavenger receptor CXCR7/ACKR3. In this review, we explore the diverse roles of these and other homeostatic chemokines expressed within the CNS, including the possible implications of their dysfunction as a cause of neurologic disease.
Neuropathology and Applied Neurobiology, 2003
Haematogenous leucocytes enter the central nervous system (CNS) during diverse disorders of varied aetiologies. Understanding the trafficking cues that mediate CNS leucocyte infiltration might promote the development of flexible and selective means to modulate inflammation to achieve clinical benefit. The trafficking machinery of leucocytes has been elucidated during the past decade and consists of cell-surface adhesion molecules, chemoattractant cytokines (chemokines) and their receptors. Recent work in our laboratory characterized chemokine receptors found on T lymphocytes and monocytes in brain sections from subjects with one pathological subtype of multiple sclerosis (MS), an immune-mediated inflammatory demyelinating disease. In these tissues, the types 1 and 5 CC chemokine receptors (CCR1 and CCR5) were detected on perivascular monocytic cells whereas only CCR5 was present on parenchymal macrophages. The type 3 CXC chemokine receptor (CXCR3) was present on virtually all CD3-positive T cells. In the current study, we evaluated the expression of these receptors on the infiltrating cells present in cases of other inflammatory CNS disorders including those of dysimmune, infectious, neoplastic, and vascular aetiology. Perivascular and parenchymal monocytic cells expressed CCR1 in all cases and CXCR3 was consistently present on a substantial proportion of CD3 + T cells. The occurrence of CCR5 on parenchymal macrophages was much less uniform across the varied disorders. These data implicate CCR1 in monocyte infiltration of the CNS and are consistent with reports of studies in CCR1deficient mice. CXCR3 is also likely to play a role in accumulation of T cells in the inflamed CNS. By contrast, our findings suggest that regulation of CCR5 on phagocytic macrophages may be contingent on the lesion environment.
Chemokines in immune-mediated inflammation of the central nervous system
Cytokine & Growth Factor Reviews, 1996
Inflammatory cell recruitment to the central nervous system (CNS) is a cardinal feature of physiological and pathological processes, including multiple sclerosis (MS). Despite recent progress, the soluble signals that attract inflammatory cells from the vascular compartment into the CNS parenchyma remain obscure. We favor the hypothesis that chemoattractant cytokines termed 'chemokines' are uniquely important for mediating leukocyte entry into CNS tissues during immunemediated inflammation. Three lines of evidence supporting this hypothesis will be reviewed. The first regards expression of chemokines in animal models of immune-mediated CNS inflammation and in the human disease, multiple sclerosis. The second line of evidence involves interventional studies of chemokine blockade in such model disorders. The third line of evidence comprises function of chemokines in the CNS, as analysed in transgenic mice. Investigation of CNS chemokine function will enhance our understanding of leukocyte recruitment to the CNS and suggest therapeutic strategies for neurological disorders. Cop, r,~h, ~ I~% EJ~
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.
Brain, 2005
Understanding the mechanisms of immune cell migration to multiple sclerosis lesions offers significant therapeutic potential. This study focused on the chemokines CXCL12 (SDF-1) and CXCL13 (BCA-1), both of which regulate B cell migration in lymphoid tissues. We report that immunohistologically CXCL12 was constitutively expressed in CNS parenchyma on blood vessel walls. In both active and chronic inactive multiple sclerosis lesions CXCL12 protein was elevated and detected on astrocytes and blood vessels. Quantitative PCR demonstrated that CXCL13 was produced in actively demyelinating multiple sclerosis lesions, but not in chronic inactive lesions or in the CNS of subjects who had no neurological disease. CXCL13 protein was localized in perivascular infiltrates and scattered infiltrating cells in lesion parenchyma. In the CSF of relapsing-remitting multiple sclerosis patients, both CXCL12 and CXCL13 were elevated. CXCL13, but not CXCL12, levels correlated strongly with intrathecal immunoglobulin production as well as the presence of B cells, plasma blasts and T cells. About 20% of CSF CD4 + cells and almost all B cells expressed the CXCL13 receptor CXCR5. In vitro, CXCL13 was produced by monocytes and at much higher levels by macrophages. CXCL13 mRNA and protein expression was induced by TNFa and IL-1b but inhibited by IL-4 and IFNg. Together, CXCL12 and CXCL13 are elevated in active multiple sclerosis lesions and CXCL12 also in inactive lesions. The consequences of CXCL12 up-regulation could be manifold. CXCL12 localization on blood vessels indicates a possible role in leucocyte extravasation, and CXCL12 may contribute to plasma cell persistence since its receptor CXCR4 is retained during plasma cell differentiation. CXCL12 may contribute to axonal damage as it can become a neurotoxic mediator of cleavage by metalloproteases, which are present in multiple sclerosis lesions. The strong linkage of CXCL13 to immune cells and immunoglobulin levels in CSF suggests that this is one of the factors that attract and maintain B and T cells in inflamed CNS lesions. Therefore, both CXCL13 and CXCR5 may be promising therapeutic targets in multiple sclerosis.
Regulation and function of central nervous system chemokines
International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience
In this paper, we discuss the potential involvement of a new family of cytokines, termed chemokines, in CNS inflammatory pathology. Chemokines are a family of proinflammatory cytokines which are able to stimulate target-cell-specific directional migration of leukocytes. Because of this feature, chemokines may be potent mediators of inflammatory processes. We have previously reported observations indicating that chemokines may be involved in the process of lesion formation during autoimmune inflammation within CNS, and, in particular, are likely participants in the process of influx of inflammatory cells into the CNS parenchyma. We observed also that mechanical injury of brain and subsequent post-traumatic inflammation may in part be mediated by chemokines. Chemokines undoubtedly co-operate with cell-associated adhesion molecules during recruitment of leukocytes from blood to CNS. The sequential expression of soluble and membrane-bound signals for leukocyte migration is an intricate ...
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
Roles of Chemokines and Their Receptors in Neuroinflammation
Neuroinflammation, 2002
Chemokines are chemoattractant cytokines that stimulate directional migration of inflammatory cell in vitro and in vivo. Because of this, chemokines can be included into a large group of cytokines involved in the pathogenesis of inflammatory processes. All chemokines were identified within the last 20 yr and our knowledge about their roles in biology is rapidly growing. At present, an enormous amount of literature about chemokines and chemokine receptors is published each year. There are now more than 50 different chemokines described in the literature. They are virtually all 8-to lO-kDa proteins with 20-70% homology in amino acid sequence. Chemokines are divided according to their structure into four main subfamilies: XCL, CCL, CXCL, and CX3CL. The criterion is the presence or absence of intervening amino acids between the first two cysteines near the N-terminus. If these cysteines are adjacent, the chemokine belongs to the CCL subfamily. The presence of one or three separating amino acids assigns the chemokine to the CXCL or CX3CL subfamily. The XCL subfamily possesses only one cysteine at the N-terminus. The CX3CL subfamily comprises only one chemokine: fractalkine. The XCL subfamily includes two chemokines: XCLl (lymphotactin) and XCL2 (SCMl). The two other chemokine subfamilies, CXCL and CCL, are much larger and can be further subdivided. The CXCL family consists of at least 16 members, CCL is even larger-at least 28 members identified to date. The criterion for further division of the CXCL subfamily is the presence of the ELR motif (glutamateleucine-arginine) near the N-terminus. This subdivision also has functional significance. Chemokines with the ELR motif attract neutrophils, whereas non-ELR CXC chemokines attract predominantly mononuclear inflammatory cells: monocytes and lymphocytes. CC chemokines can also be subdivided further into monocyte chemoattractant proteins (MCP-I-5) and others (1). Originally described as chemoattractant factors, chemokines turned out to be involved also in a large diversity of other physiological and pathological processes. They can not only guide leukocytes to inflammatory sites but also activate target cells at sites of injury. ELR-positive CXC chemokines (interleukin [IL]-8, GRO possess angiogenic activity, whereas ELR-negative interferon-inducible protein [IP-lO], Mig) are angiostatic. Several chemokines may also induce smooth-muscle proliferation and induce cytokine production in lymphocytes (2).
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...
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.