Citation

4165 total record number 127 records this year

A novel CMKLR1 small molecule antagonist suppresses CNS autoimmune inflammatory disease

Graham, KL;Zhang, JV;Lewn, S;Burke, TM;Dang, T;Zoudilova, M;Sobel, RA;Butcher, EC;Zabel, BA;

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