Chemokine receptor expression and function in experimental autoimmune neuroinflammation
Author: Eltayeb, Sana
Date: 2007-06-15
Location: Seminar Room L8:00, Karolinska Hospital, Solna
Time: 09.00
Department: Institutionen för medicin / Department of Medicine
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thesis.pdf (636.8Kb)
Abstract
Neuroinflammatory lesions in the central nervous system (CNS) are
characterized by the presence of leukocytes, mainly
monocytes/macrophages, derived from the systemic compartment. We believe
CC inflammatory chemokine receptors (CkRs), CCR1, CCR2 and CCR5 are
prerequisite for controlling the migration of monocytes/macrophages into
inflammatory foci. The role of fractalkine (CX3CL1) and its receptor
CX3CR1 in the CNS is more unclear, but their expression pattern suggests
a role in neuron-microglia interaction.
Chronic rat model for Multiple Sclerosis (MS), myelin oligodendrocyte
glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE),
was employed here to determine the role of these CkRs during
neuroinflammation. In situ hybridization histochemistry combined with
immunohistochemistry (ISH/IHC) demonstrated high-level of CCR1/CCR5, and
moderate-level of CCR2 mRNA expression on mononuclear phagocytes (ED1+
GSA/B4+) correlated with active demyelination. Expression of CCR1, CCR2
and CCR5 was substantially reduced during clinical remission. CX3CR1
displayed a low constitutive expression on microglia on the basis of
their cellular morphology and positive lectin staining. There was a
notably increased density of CX3CR1 mRNA expressing cells within the
inflammatory areas, especially during the acute and relapse phase of the
perivascular and submeningeal lesions. CCR1 and CX3CR1 were also found to
be differentially expressed at the protein level on monocyte/ microglia
populations by flow cytometric analysis of leukocytes extracted from the
inflamed CNS tissue, confirming non-overlapping expression. CkR Ls
ligands, MIP-1 ¿ (CCL3) and RANTES (CCL5), were found abundantly
expressed in neuroinflammatory lesions, but not in the healthy CNS. There
was a neuronal expression of CX3CL1 throughout the CNS at all time points
examined (constitutive expression), with induced expression on astrocytes
within inflammatory lesions.
A low-molecular weight CCR1 selective antagonist was able to potently
abrogate both clinical and histopathological signs of the disease during
the effector stage of EAE without any signs of peripheral immune
compromise. The antagonist also reduced the severity of ongoing disease
when given after clinical onset of disease.
In conclusion, the thesis shed light on some of CkRs and provide new
information about mechanisms controlling their mRNA expression during
neuroinflammation. Because this research carries potential medical
implications, detailed knowledge of the roles of specific CkRs and
ligands in the CNS in health and in disease and identifying their
cellular phenotypes could be of use in the identification of disease
mechanisms, and enabling more specific future therapeutic interventions
List of papers:
I. Sunnemark D, Eltayeb S, Wallstrom E, Appelsved L, Malmberg A, Lassmann H, Ericsson-Dahlstrand A, Piehl F, Olsson T (2003). "Differential expression of the chemokine receptors CX3CR1 and CCR1 by microglia and macrophages in myelin-oligodendrocyte-glycoprotein-induced experimental autoimmune encephalomyelitis." Brain Pathol 13(4): 617-29
Pubmed
II. Sunnemark D, Eltayeb S, Nilsson M, Wallstrom E, Lassmann H, Olsson T, Berg AL, Ericsson-Dahlstrand A (2005). "CX3CL1 (fractalkine) and CX3CR1 expression in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis: kinetics and cellular origin." J Neuroinflammation 2: 17
Pubmed
III. Eltayeb S, Berg AL, Lassmann H, Wallstrom E, Nilsson M, Olsson T, Ericsson-Dahlstrand A, Sunnemark D (2007). "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." J Neuroinflammation 4(1): 14 [Epub ahead of print]
Pubmed
IV. Eltayeb S, Sunnemark D, Berg AL, Nordvall G, Malmberg A, Lassmann H, Wallstrom E, Olsson T, Ericsson-Dahlstrand A (2003). "Effector stage CC chemokine receptor-1 selective antagonism reduces multiple sclerosis-like rat disease." J Neuroimmunol 142(1-2): 75-85
Pubmed
I. Sunnemark D, Eltayeb S, Wallstrom E, Appelsved L, Malmberg A, Lassmann H, Ericsson-Dahlstrand A, Piehl F, Olsson T (2003). "Differential expression of the chemokine receptors CX3CR1 and CCR1 by microglia and macrophages in myelin-oligodendrocyte-glycoprotein-induced experimental autoimmune encephalomyelitis." Brain Pathol 13(4): 617-29
Pubmed
II. Sunnemark D, Eltayeb S, Nilsson M, Wallstrom E, Lassmann H, Olsson T, Berg AL, Ericsson-Dahlstrand A (2005). "CX3CL1 (fractalkine) and CX3CR1 expression in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis: kinetics and cellular origin." J Neuroinflammation 2: 17
Pubmed
III. Eltayeb S, Berg AL, Lassmann H, Wallstrom E, Nilsson M, Olsson T, Ericsson-Dahlstrand A, Sunnemark D (2007). "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." J Neuroinflammation 4(1): 14 [Epub ahead of print]
Pubmed
IV. Eltayeb S, Sunnemark D, Berg AL, Nordvall G, Malmberg A, Lassmann H, Wallstrom E, Olsson T, Ericsson-Dahlstrand A (2003). "Effector stage CC chemokine receptor-1 selective antagonism reduces multiple sclerosis-like rat disease." J Neuroimmunol 142(1-2): 75-85
Pubmed
Issue date: 2007-05-25
Rights:
Publication year: 2007
ISBN: 978-91-7357-197-5
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