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. 1. Introduction Chemokines are small, secreted proteins originally shown to promote the migration of leukocytes both during immune surveillance and in response to inflammation. Chemokine have been classified into CXC, CC, C, or CX3C subfamilies, according to the positions of conserved cysteine residues at their N-termini, and promiscuously bind receptor members of the G protein-coupled receptor superfamily [1]. Each chemokine or its receptor is named based on their subfamily designation with “L” indicating ligand and “R” indicating receptor plus a number, which corresponds to the same numbers used in the corresponding gene nomenclature. Binding of chemokines to their receptors generally results in calcium mobilization and cytoskeletal rearrangements required for cell motility in response to a signal of increasing chemokine concentration [2, 3]. Their initial discovery by immunologists led to an explosion of studies demonstrating their far-reaching roles in all aspects of immune function from immune surveillance and leukocyte interactions within lymph nodes to orchestration of innate and adaptive immune responses against invading pathogens. The identification of two chemokine receptors, CCR5 and CXCR4, as critical coreceptors for the entry of HIV-1 into CD4+ T cells [4–6] heralded an intense period of chemokine research leading to the detection of these molecules on multiple cell types within the CNS in both homeostatic and inflammatory
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