Chemokines in the balance: maintenance of homeostasis and protection at CNS barriers

Abstract

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 CX3CL1, 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.

(Putative) sex differences in neuroimmune modulation of memory

“…Microglia, in particular, play a critical role in mediating neurogenesis (Ziv et al, 2006). CX3CL1 modulates activation of microglia in the neurogenic niche (Williams et al, 2014), increasing proliferation and contributing to survival of new cells (Bachstetter et al, 2011). In addition, microglia activated by INFɣ signaling increase survival (Butovsky et al, 2006).…”

Effect of a Broad-Specificity Chemokine-Binding Protein on Brain Leukocyte Infiltration and Infarct Development

“…3,4 Chemokines are a family of chemotactic cytokines that attract leukocytes toward a site of injury. 5,6 Thus, together with their receptors expressed on leukocytes, chemokines play a crucial role in the extravasation and migration of leukocytes under inflammatory conditions. 7 In the highly inflammatory setting of acute ischemic stroke, chemokines are generated by brain-resident microglial cells and infiltrating immune cells, resulting in further leukocyte attraction and activation.…”

Significant Role(s) of CXCL12 and the SDF-1 3′A Genetic Variant in the Pathogenesis of Multiple Sclerosis

“…CruzOrengo et al [70] claimed that, as the CXCL12 scavenger is an important factor in leukocyte infiltration via endothelial barriers into the CNS parenchyma, the CXCR7 antagonist improves EAE clinical symptoms and reduces leukocyte infiltration toward the CNS parenchyma along with parenchyma VCAM-1 expression. Moreover, recent studies by Williams et al [67,68] showed that blockade of CXCR7 improves remyelination ( Fig. 1 ).…”

“…Although the CXCL12 scavenging receptor (e.g., CXCR7) is also expressed on OPC surfaces, its role in myelin repair in the adult CNS has yet to be understood. Williams et al [67,68] showed that, during in vivo cuprizone-induced demyelination, CXCR7 antagonism augmented OPC proliferation and in turn increased the numbers of mature oligodendrocytes in demyelinated regions. Determination of the CXCR7-mediated impacts on remyelination initially required CXCR4 activation, but they have been assessed employing both phospho-S339-CXCR4-specific antibodies and administration of CXCR4 antagonists.…”