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PLoS One. 2014 Dec 1;9(12):e112925. doi: 10.1371/journal.pone.0112925. eCollection 2014.

A novel CMKLR1 small molecule antagonist suppresses CNS autoimmune inflammatory disease.

Author information

1
Palo Alto Veterans Institute for Research and Veterans Affairs Palo Alto Health Care System, Palo Alto, California, United States of America.
2
ChemoCentryx, Inc., Mountain View, California, United States of America.
3
Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.

Abstract

Therapies that target leukocyte trafficking pathways can reduce disease activity and improve clinical outcomes in multiple sclerosis (MS). Experimental autoimmune encephalomyelitis (EAE) is a widely studied animal model that shares many clinical and histological features with MS. Chemokine-like receptor-1 (CMKLR1) is a chemoattractant receptor that is expressed by key effector cells in EAE and MS, including macrophages, subsets of dendritic cells, natural killer cells and microglia. We previously showed that CMKLR1-deficient (CMKLR1 KO) mice develop less severe clinical and histological EAE than wild-type mice. In this study, we sought to identify CMKLR1 inhibitors that would pharmaceutically recapitulate the CMKLR1 KO phenotype in EAE. We identified 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA) as a CMKLR1 small molecule antagonist that inhibits chemerin-stimulated β-arrestin2 association with CMKLR1, as well as chemerin-triggered CMKLR1+ cell migration. α-NETA significantly delayed the onset of EAE induced in C57BL/6 mice by both active immunization with myelin oligodendrocyte glycoprotein peptide 35-55 and by adoptive transfer of encephalitogenic T cells. In addition, α-NETA treatment significantly reduced mononuclear cell infiltrates within the CNS. This study provides additional proof-of-concept data that targeting CMKLR1:chemerin interactions may be beneficial in preventing or treating MS.

PMID:
25437209
PMCID:
PMC4249827
DOI:
10.1371/journal.pone.0112925
[Indexed for MEDLINE]
Free PMC Article

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