A Novel CMKLR1 Small Molecule Antagonist Suppresses CNS Autoimmune Inflammatory Disease

作者：Graham Kareem L; Zhang Jian V; Lewen Susanna; Burke Thomas M; Dang Ton; Zoudilova Maria; Sobel Raymond A; Butcher Eugene C; Zabel Brian A^*

来源：PLos One, 2014, 9(12): e112925.

DOI：10.1371/journal.pone.0112925

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-(alpha-naphthoyl) ethyltrimethylammonium iodide (alpha-NETA) as a CMKLR1 small molecule antagonist that inhibits chemerin-stimulated beta-arrestin2 association with CMKLR1, as well as chemerin-triggered CMKLR1(+) cell migration. alpha-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, alpha-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.

• 出版日期2014-12-1