Increasing evidence highlights the prominence of chemokines in a variety of physiologic and pathologic processes in the CNS. In particular, chemokines have been shown to be critical determinants in the positioning of cellular population in the development of CNS inflammation due to autoimmune reactions or infectious diseases (2,15). Several lines of evidence indicate that all resident cells of the CNS express functional chemokine receptors in the intact human brain and in the CNS of rodent and macaques as experimental models. Astrocytes and microglia express most of the chemokine receptors including CCR3 (16-18), CCR5 (17), CXCR3 (19-21), and CXCR4 (18,22,23). Functional expression of CCR2 by fetal human astrocytes (24) and by reactive microglia in multiple sclerosis (MS) lesions (25) has been documented. Confined exclusively to microglia in vivo is the expression of CX3CR1 (26,27). Neurons exhibit expression of CCR1 (28), CXCR1 (29), CXCR2 (29), and CXCR4. Neuronal CCR1 expression, however, is not a generalized marker during neurodegeneration but is proposed to be part of the neuroimmune response to Abeta42-positive neuritic plaques in Alzheimer disease (30). Furthermore, constitutive expression of the CXC chemokine receptors, CXCR1, CXCR2 and CXCR3, on oligodendrocytes in normal adult human CNS tissue has been demonstrated (31). In addition to chemokine receptor expression by resident brain cells, chemokine receptors are also expressed along the brain microvas-culature at the intersection of the CNS-peripheral system boundaries and include CCR1 (32), CCR2 (33,34), CCR3 (35), CCR4 (35), and CCR5 (17). It has been demonstrated that endothelial cell expression of CCR2 is involved in the passage of CCL2 from circulation to brain parenchyma across the brain microvessels (33,34); a mechanism of definitive relevance for initiation of cellular responses within the CNS.
Contrasting the large number of chemokines described in the periphery, relatively few chemokines are present in the brain under pathologic conditions. Among the most commonly found chemokines in the challenged CNS are CCL2, CCL3, CCL4, CCL5, CCL8, CCL21, CXCL8, CXCL10, and CXCL12 (36). Recent studies have shown that glial chemokines are crucial mediators of accumulation of infiltrating cells into the CNS. In order to understand the mechanisms involved in CNS infiltration of leukocytes and the contribution of systemic and local brain cells to the pathogenesis of disease, it is necessary to dissect the effects of constitutive versus inducible regulation of chemokine receptor expression.
From the large list of chemokines and chemokine receptors and their complex interactions, three chemokine/chemokine-receptor pairs constitute interesting examples due to their intrinsic CNS expression (Fig. 1; see color plate). These systems include the chemokine receptors and ligands CXCR4/CXCL12, CXCR2/CXCL1, and CX3CR1/CX3CL1, which will be further discussed below. We will also describe the inducible system CXCR3/CCL21 and its proposed role in cellular communication within the CNS.
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