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Chemokines Referee Inflammation within the Central Nervous System during Infection and Disease.

Durrant DM, Williams JL, Daniels BP, Klein RS - Adv Med (2014)

Bottom Line: 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 chemokines serve as molecular links between inflammatory mediators and other effector molecules involved in neuroprotective processes.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Washington University School of Medicine, Campus Box 8051, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.

ABSTRACT
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 chemokines serve as molecular links between inflammatory mediators and other effector molecules involved in neuroprotective processes.

No MeSH data available.


Related in: MedlinePlus

Chemokines mediate repair in the adult CNS. Following demyelination, CXCL12 and its receptors, CXCR4 and CXCR7, are upregulated on astrocytes and endothelial cells. CXCL12 binding to CXCR4 on OPCs induces proliferation and maturation into myelin-producing oligodendrocytes. CXCR7 regulates CXCR4 activation by sequestering CXCL12 into lysosomal compartments for degradation.
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Related In: Results  -  Collection


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fig1: Chemokines mediate repair in the adult CNS. Following demyelination, CXCL12 and its receptors, CXCR4 and CXCR7, are upregulated on astrocytes and endothelial cells. CXCL12 binding to CXCR4 on OPCs induces proliferation and maturation into myelin-producing oligodendrocytes. CXCR7 regulates CXCR4 activation by sequestering CXCL12 into lysosomal compartments for degradation.

Mentions: While CXCL12 is indispensable for the plasticity of the demyelinated adult CNS, there are several factors that regulate CXCL12 expression during neuroinflammation (Figure 1). In addition to soluble factors, CXCR7, an alternative scavenger receptor, works to sequester and degrade CXCL12 [17, 54], regulating activation of CXCR4. CXCR7 is highly expressed during CPZ-mediated demyelination and expression subsides during remyelination, while levels of CXCR4 and CXCL12 remain elevated. This suggests that downregulation of CXCR7 is necessary for CXCL12-CXCR4 binding during repair. To determine if high levels of CXCR7 might regulate CXCL12 expression during demyelination, Williams et al. administered a small molecule inhibitor of CXCR7, CCX771, versus a vehicle control and found that antagonism of CXCR7 during late CPZ-mediated demyelination resulted in increased expression of CXCL12 and an upregulation of activated CXCR4 in OPCs [32]. In vitro experiments determined that CCX771-mediated regulation of CXCL12 was due to a decrease in CXCL12 internalization, suggesting that CCX771 works to limit CXCL12 targeting to lysosomal compartments for degradation. In vivo CXCR7 antagonism during demyelination led to an increase in OPC proliferation and in mature oligodendrocytes within demyelinated lesions. Further, CCX771 treatment during CPZ-induced demyelination enhanced remyelination, which, through the use of AMD3100, was shown to be CXCR4-dependent suggesting that the CCX771-mediate increase in CXCL12 expression during demyelination has potentially beneficial consequences [32]. These findings are significant as current treatment strategies for MS employ immunosuppressive compounds and do not promote repair. Further, while OPCs are found in MS lesions they are developmentally arrested [55, 56], remyelination gradually fails, and demyelination persists, which leads to progression of clinical disease [57]. Since CXCR7 regulates CXCL12-CXCR4-mediated CNS myelin repair, it may, therefore, serve as a therapeutic target to promote OPC differentiation and remyelination in the adult CNS.


Chemokines Referee Inflammation within the Central Nervous System during Infection and Disease.

Durrant DM, Williams JL, Daniels BP, Klein RS - Adv Med (2014)

Chemokines mediate repair in the adult CNS. Following demyelination, CXCL12 and its receptors, CXCR4 and CXCR7, are upregulated on astrocytes and endothelial cells. CXCL12 binding to CXCR4 on OPCs induces proliferation and maturation into myelin-producing oligodendrocytes. CXCR7 regulates CXCR4 activation by sequestering CXCL12 into lysosomal compartments for degradation.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4590974&req=5

fig1: Chemokines mediate repair in the adult CNS. Following demyelination, CXCL12 and its receptors, CXCR4 and CXCR7, are upregulated on astrocytes and endothelial cells. CXCL12 binding to CXCR4 on OPCs induces proliferation and maturation into myelin-producing oligodendrocytes. CXCR7 regulates CXCR4 activation by sequestering CXCL12 into lysosomal compartments for degradation.
Mentions: While CXCL12 is indispensable for the plasticity of the demyelinated adult CNS, there are several factors that regulate CXCL12 expression during neuroinflammation (Figure 1). In addition to soluble factors, CXCR7, an alternative scavenger receptor, works to sequester and degrade CXCL12 [17, 54], regulating activation of CXCR4. CXCR7 is highly expressed during CPZ-mediated demyelination and expression subsides during remyelination, while levels of CXCR4 and CXCL12 remain elevated. This suggests that downregulation of CXCR7 is necessary for CXCL12-CXCR4 binding during repair. To determine if high levels of CXCR7 might regulate CXCL12 expression during demyelination, Williams et al. administered a small molecule inhibitor of CXCR7, CCX771, versus a vehicle control and found that antagonism of CXCR7 during late CPZ-mediated demyelination resulted in increased expression of CXCL12 and an upregulation of activated CXCR4 in OPCs [32]. In vitro experiments determined that CCX771-mediated regulation of CXCL12 was due to a decrease in CXCL12 internalization, suggesting that CCX771 works to limit CXCL12 targeting to lysosomal compartments for degradation. In vivo CXCR7 antagonism during demyelination led to an increase in OPC proliferation and in mature oligodendrocytes within demyelinated lesions. Further, CCX771 treatment during CPZ-induced demyelination enhanced remyelination, which, through the use of AMD3100, was shown to be CXCR4-dependent suggesting that the CCX771-mediate increase in CXCL12 expression during demyelination has potentially beneficial consequences [32]. These findings are significant as current treatment strategies for MS employ immunosuppressive compounds and do not promote repair. Further, while OPCs are found in MS lesions they are developmentally arrested [55, 56], remyelination gradually fails, and demyelination persists, which leads to progression of clinical disease [57]. Since CXCR7 regulates CXCL12-CXCR4-mediated CNS myelin repair, it may, therefore, serve as a therapeutic target to promote OPC differentiation and remyelination in the adult CNS.

Bottom Line: 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 chemokines serve as molecular links between inflammatory mediators and other effector molecules involved in neuroprotective processes.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Washington University School of Medicine, Campus Box 8051, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.

ABSTRACT
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 chemokines serve as molecular links between inflammatory mediators and other effector molecules involved in neuroprotective processes.

No MeSH data available.


Related in: MedlinePlus