In vitro studies have implicated chemokine receptors in consumption and clearance of specific ligands. We studied the role that various signaling chemokine receptors play during ligand homeostasis in vivo. We examined the levels of ligands in serum and CNS tissue in mice lacking chemokine receptors. Compared with receptor-sufficient controls, Cx3cr1 Ϫ/Ϫ mice exhibited augmented levels of CX3CL1 both in serum and brain, and circulating levels of CXCL1 and CXCL2 were increased in Cxcr2 Ϫ/Ϫ mice. CCR2-deficient mice showed significantly increased amounts of circulating CCL2 compared with wild-type mice. Cxcr3 Ϫ/Ϫ mice revealed increased levels of circulating and brain CXCL10 after experimental autoimmune encephalomyelitis ( IntroductionActions of chemokines through chemokine receptor signaling leads to an array of diverse functions in different tissue compartments. 1,2 Such functions go beyond the original assigned roles of chemokines in leukocyte chemoattraction to inflamed tissues, and involve physiological trafficking to localize surveillant populations in noninflamed tissues, cellular activation, proliferation, adhesion, phagocytosis, apoptosis, and angiogenesis. [3][4][5][6] Chemokine/ chemokine receptor interactions exhibit defined roles during inflammation, atherosclerosis, autoimmunity, viral pathogenesis, cancer, and neurodegeneration. [7][8][9][10][11] Even though the system exhibits apparent redundancy, modulation of chemokine function via chemokine receptor blockade is a challenging area of considerable interest for therapeutic purposes.Among the chemokine receptors, CCR2 and its ligand CCL2 (MCP-1) have been extensively studied, and their role in regulating monocyte and T-cell infiltrations is well established. In 2002, Tylaska et al showed that CCR2-knockout mice manifested extremely high levels of CCL2 at sites of alloinduced inflammation, and in vitro studies confirmed that clearance of ligand was mediated by CCR2. 12 Our group reported that CCL2 is consumed by CCR2 ϩ migrating cells in a human blood-brain barrier model using peripheral blood mononuclear cells from healthy donors. 13 These results suggest an important biologic role of chemokine receptors as scavenger molecules involved in clearance of specific ligands.Chemokine receptor-deficient mouse strains have been instrumental in understanding chemokine biology in health and disease states. 14 In the present study, we evaluated levels of chemokines in 4 receptor-deficient mice, including those lacking CC, CXC, and CX3C receptors. Both circulating and brain tissue levels were studied. Brain was selected for study as a distinct tissue compartment in which chemokines may be produced under physiological and pathological conditions. We found that the levels of circulating and-in some instances-tissue chemokines are dramatically increased in healthy chemokine receptor-deficient mice. Reconstitution with wild-type bone marrow cells restored chemokine homeostasis. Importantly, for chemokines that signal to more than one receptor, absence of one recep...

Demyelination and axonal degeneration are determinants of progressive neurological disability in patients with multiple sclerosis (MS). Cells resident within the central nervous system (CNS) are active participants in development, progression and subsequent control of autoimmune disease; however, their individual contributions are not well understood. Astrocytes, the most abundant CNS cell type, are highly sensitive to environmental cues and are implicated in both detrimental and protective outcomes during autoimmune demyelination. Experimental autoimmune encephalomyelitis (EAE) was induced in transgenic mice expressing signaling defective dominant-negative interferon gamma (IFN-γ) receptors on astrocytes to determine the influence of inflammation on astrocyte activity. Inhibition of IFN-γ signaling to astrocytes did not influence disease incidence, onset, initial progression of symptoms, blood brain barrier (BBB) integrity or the composition of the acute CNS inflammatory response. Nevertheless, increased demyelination at peak acute disease in the absence of IFN-γ signaling to astrocytes correlated with sustained clinical symptoms. Following peak disease, diminished clinical remission, increased mortality and sustained astrocyte activation within the gray matter demonstrate a critical role of IFN-γ signaling to astrocytes in neuroprotection. Diminished disease remission was associated with escalating demyelination, axonal degeneration and sustained inflammation. The CNS infiltrating leukocyte composition was not altered; however, decreased IL-10 and IL-27 correlated with sustained disease. These data indicate that astrocytes play a critical role in limiting CNS autoimmune disease dependent upon a neuroprotective signaling pathway mediated by engagement of IFN-γ receptors.

Leukocyte access into the central nervous system (CNS) parenchyma is tightly regulated by the bloodbrain barrier (BBB). Leukocyte migration through the endothelial cell wall into the perivascular space is well characterized; however, mechanisms regulating their penetration through the glia limitans into the parenchyma are less well studied, and the role of monocytes relative to neutrophils is poorly defined. Acute viral encephalitis was thus induced in CCL2-deficient (CCL2 ؊/؊ ) mice to specifically abrogate monocyte recruitment. Impaired monocyte recruitment prolonged T cell retention in the perivascular space, although no difference in overall CNS accumulation of CD4 or CD8 T cells was detected by flow cytometry. Delayed penetration to the CNS parenchyma was not associated with reduced or altered expression of either matrix metalloproteinases (MMP) or the T cell chemoattractants CXCL10 and CCL5. Nevertheless, decreased parenchymal leukocyte infiltration delayed T cell-mediated control of virus replication as well as clinical disease. These data are the first to demonstrate that the rapid monocyte recruitment into the CNS during viral encephalitis is dispensable for T cell migration across the blood vessel endothelium. However, monocytes facilitate penetration through the glia limitans. Thus, the rapid monocyte response to viral encephalitis constitutes an indirect antiviral pathway by aiding access of effector T cells to the site of viral infection.

Actions of chemokines and the interaction with specific receptors go beyond their original, defined role of recruiting leukocytes to inflamed tissues. Chemokine receptor expression in peripheral elements and resident cells of the central nervous system (CNS) represents a relevant communication system during neuroinflammatory conditions. The following examples are described in this review: Chemokine receptors play important homeostatic properties by regulating levels of specific ligands in blood and tissues during healthy and pathological conditions; chemokines and their receptors are clearly involved in leukocyte extravasation and recruitment to the CNS, and current studies are directed toward understanding the interaction between chemokine receptors and matrix metalloproteinases in the process of blood brain barrier breakdown. We also propose novel functions of chemokine receptors during demyelination/remyelination, and developmental processes.

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