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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.

Eltayeb S, Berg AL, Lassmann H, Wallström E, Nilsson M, Olsson T, Ericsson-Dahlstrand A, Sunnemark D - J Neuroinflammation (2007)

Bottom Line: Mononuclear phagocytes are effector cells capable of phagocytosing myelin and damaging axons.Expression of all three receptors was substantially reduced during clinical remission, coinciding with diminished inflammation and demyelination in the spinal cord.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Neuroimmunology Unit, Karolinska Institute, Stockholm, Sweden. Sana.Eltayeb@ki.se <Sana.Eltayeb@ki.se>

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 with in situ hybridization 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.

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Quantification of CCR1, CCR2 and CCR5 mRNA expressing cells in defined lesional stages. Mean numbers of CCR1+ cells (A), CCR2+ cells (B) and CCR5+ cells (C) per square unit in spinal cord sections from MOG-EAE rats. Lesions were characterized as EA = early active, LA = late active and IADM = inactive demyelinated. PPWM = periplaque white matter. Bar = mean.
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Figure 5: Quantification of CCR1, CCR2 and CCR5 mRNA expressing cells in defined lesional stages. Mean numbers of CCR1+ cells (A), CCR2+ cells (B) and CCR5+ cells (C) per square unit in spinal cord sections from MOG-EAE rats. Lesions were characterized as EA = early active, LA = late active and IADM = inactive demyelinated. PPWM = periplaque white matter. Bar = mean.

Mentions: The sampling at specific time points was complemented by detailed lesion maps where each lesion area was characterized for its state of inflammatory activity and demyelination/remyelination as previously described by Brück et al [36]. A detailed analysis of CCR1, CCR2 and CCR5 in EAE rats revealed dynamic changes in their relative expression within those sub-areas in the spinal cord. Areas directly adjacent to the inflammatory lesions (the PPWM areas) contained a low but detectable number of chemokine receptor-expressing cells, with CCR5+ cells being detected at somewhat higher abundance (Table 1, Fig. 5A–C). The active border zone of the inflammatory lesions, the so called EA (early active) lesions where the inflammatory and demyelinating activity is most intensively manifested, exhibited sharply elevated numbers of cells expressing CCR1 (P < 0.001 vs PPWM), CCR2 (P < 0.05 vs PPWM) or CCR5 (P < 0.001 vs PPWM) mRNA, with the relative proportions of CCR5 > CCR1 > CCR2 (Table 1, Fig. 5A–C).


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.

Eltayeb S, Berg AL, Lassmann H, Wallström E, Nilsson M, Olsson T, Ericsson-Dahlstrand A, Sunnemark D - J Neuroinflammation (2007)

Quantification of CCR1, CCR2 and CCR5 mRNA expressing cells in defined lesional stages. Mean numbers of CCR1+ cells (A), CCR2+ cells (B) and CCR5+ cells (C) per square unit in spinal cord sections from MOG-EAE rats. Lesions were characterized as EA = early active, LA = late active and IADM = inactive demyelinated. PPWM = periplaque white matter. Bar = mean.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1884136&req=5

Figure 5: Quantification of CCR1, CCR2 and CCR5 mRNA expressing cells in defined lesional stages. Mean numbers of CCR1+ cells (A), CCR2+ cells (B) and CCR5+ cells (C) per square unit in spinal cord sections from MOG-EAE rats. Lesions were characterized as EA = early active, LA = late active and IADM = inactive demyelinated. PPWM = periplaque white matter. Bar = mean.
Mentions: The sampling at specific time points was complemented by detailed lesion maps where each lesion area was characterized for its state of inflammatory activity and demyelination/remyelination as previously described by Brück et al [36]. A detailed analysis of CCR1, CCR2 and CCR5 in EAE rats revealed dynamic changes in their relative expression within those sub-areas in the spinal cord. Areas directly adjacent to the inflammatory lesions (the PPWM areas) contained a low but detectable number of chemokine receptor-expressing cells, with CCR5+ cells being detected at somewhat higher abundance (Table 1, Fig. 5A–C). The active border zone of the inflammatory lesions, the so called EA (early active) lesions where the inflammatory and demyelinating activity is most intensively manifested, exhibited sharply elevated numbers of cells expressing CCR1 (P < 0.001 vs PPWM), CCR2 (P < 0.05 vs PPWM) or CCR5 (P < 0.001 vs PPWM) mRNA, with the relative proportions of CCR5 > CCR1 > CCR2 (Table 1, Fig. 5A–C).

Bottom Line: Mononuclear phagocytes are effector cells capable of phagocytosing myelin and damaging axons.Expression of all three receptors was substantially reduced during clinical remission, coinciding with diminished inflammation and demyelination in the spinal cord.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Neuroimmunology Unit, Karolinska Institute, Stockholm, Sweden. Sana.Eltayeb@ki.se <Sana.Eltayeb@ki.se>

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 with in situ hybridization 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.

Show MeSH
Related in: MedlinePlus