RGD Reference Report - Pharmacological inhibition of the chemokine receptor CX3CR1 attenuates disease in a chronic-relapsing rat model for multiple sclerosis. - Rat Genome Database

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Pharmacological inhibition of the chemokine receptor CX3CR1 attenuates disease in a chronic-relapsing rat model for multiple sclerosis.

Authors: Ridderstad Wollberg, A  Ericsson-Dahlstrand, A  Jureus, A  Ekerot, P  Simon, S  Nilsson, M  Wiklund, SJ  Berg, AL  Ferm, M  Sunnemark, D  Johansson, R 
Citation: Ridderstad Wollberg A, etal., Proc Natl Acad Sci U S A. 2014 Apr 8;111(14):5409-14. doi: 10.1073/pnas.1316510111. Epub 2014 Mar 25.
RGD ID: 9491767
Pubmed: PMID:24706865   (View Abstract at PubMed)
PMCID: PMC3986185   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.1316510111   (Journal Full-text)

One hallmark of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is infiltration of leukocytes into the CNS, where chemokines and their receptors play a major mediatory role. CX3CR1 is a chemokine receptor involved in leukocyte adhesion and migration and hence a mediator of immune defense reactions. The role of CX3CR1 in MS and EAE pathogenesis however remains to be fully assessed. Here, we demonstrate CX3CR1 mRNA expression on inflammatory cells within active plaque areas in MS brain autopsies. To test whether blocking CNS infiltration of peripheral leukocytes expressing CX3CR1 would be a suitable treatment strategy for MS, we developed a selective, high-affinity inhibitor of CX3CR1 (AZD8797). The compound is active outside the CNS and AZD8797 treatment in Dark Agouti rats with myelin oligodendrocyte glycoprotein-induced EAE resulted in reduced paralysis, CNS pathology, and incidence of relapses. The compound is effective when starting treatment before onset, as well as after the acute phase. This treatment strategy is mechanistically similar to, but more restricted than, current very late antigen-4-directed approaches that have significant side effects. We suggest that blocking CX3CR1 on leukocytes outside the CNS could be an alternative approach to treat MS.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Objects Annotated

Genes (Rattus norvegicus)
Cx3cr1  (C-X3-C motif chemokine receptor 1)

Genes (Mus musculus)
Cx3cr1  (C-X3-C motif chemokine receptor 1)

Genes (Homo sapiens)
CX3CR1  (C-X3-C motif chemokine receptor 1)


Additional Information