Temporal expression and cellular origin of CC chemokine receptors CCR1, CCR2 and CCR5 in the central nervous system: insight into mechanisms of MOG-induced EAE
Open Access
- 7 May 2007
- journal article
- research article
- Published by Springer Science and Business Media LLC in Journal of Neuroinflammation
- Vol. 4 (1), 14
- https://doi.org/10.1186/1742-2094-4-14
Abstract
Background: The CC chemokine receptors CCR1, CCR2 and CCR5 are critical for the recruitment of mononuclear phagocytes to the central nervous system (CNS) in multiple sclerosis (MS) and other neuroinflammatory diseases. Mononuclear phagocytes are effector cells capable of phagocytosing myelin and damaging axons. In this study, we characterize the regional, temporal and cellular expression of CCR1, CCR2 and CCR5 mRNA in the spinal cord of rats with myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE). While resembling human MS, this animal model allows unique access to CNS-tissue from various time-points of relapsing neuroinflammation and from various lesional stages: early active, late active, and inactive completely demyelinated lesions.Methods: The expression of CCR1, CCR2 and CCR5 mRNA was studied within situhybridization using radio labelled cRNA probes in combination with immunohistochemical staining for phenotypic cell markers. Spinal cord sections from healthy rats and rats with MOG-EAE (acute phase, remission phase, relapse phase) were analysed. In defined lesion stages, the number of cells expressing CCR1, CCR2 and CCR5 mRNA was determined. Data were statistically analysed by the nonparametric Mann-Whitney U test.Results: In MOG-EAE rats, extensive up-regulation of CCR1 and CCR5 mRNA, and moderate up-regulation of CCR2 mRNA, was found in the spinal cord during episodes of active inflammation and demyelination. Double staining with phenotypic cell markers identified the chemokine receptor mRNA-expressing cells as macrophages/microglia. Expression of all three receptors was substantially reduced during clinical remission, coinciding with diminished inflammation and demyelination in the spinal cord. Healthy control rats did not show any detectable expression of CCR1, CCR2 or CCR5 mRNA in the spinal cord.Conclusion: Our results demonstrate that the acute and chronic-relapsing phases of MOG-EAE are associated with distinct expression of CCR1, CCR2, and CCR5 mRNA by cells of the macrophage/microglia lineage within the CNS lesions. These data support the notion that CCR1, CCR2 and CCR5 mediate recruitment of both infiltrating macrophages and resident microglia to sites of CNS inflammation. Detailed knowledge of expression patterns is crucial for the understanding of therapeutic modulation and the validation of CCR1, CCR2 and CCR5 as feasible targets for therapeutic intervention in MS.Keywords
This publication has 84 references indexed in Scilit:
- Predictions of CCR1 Chemokine Receptor Structure and BX 471 Antagonist Binding Followed by Experimental ValidationPublished by Elsevier BV ,2006
- Immune cell migration in inflammation: present and future therapeutic targetsNature Immunology, 2005
- Modulating CCR2 and CCL2 at the blood–brain barrier: relevance for multiple sclerosis pathogenesisBrain, 2005
- CCR1 antagonists in clinical developmentExpert Opinion on Investigational Drugs, 2005
- Induction of experimental autoimmune encephalomyelitis in C57BL / 6 mice deficient in either the chemokine macrophage inflammatory protein-1α or its CCR5 receptorEuropean Journal of Immunology, 2000
- Control of TH2 polarization by the chemokine monocyte chemoattractant protein-1Nature, 2000
- Increased numbers of CCR5+ interferon-?- and tumor necrosis factor-?-secreting T lymphocytes in multiple sclerosis patientsAnnals of Neurology, 2000
- Expression of monocyte chemoattractant protein-1 and other β-chemokines by resident glia and inflammatory cells in multiple sclerosis lesionsJournal of Neuroimmunology, 1998
- Mechanisms of Immune Injury in Multiple SclerosisBrain Pathology, 1996
- Multiple SclerosisNew England Journal of Medicine, 1982