| First Author | Graham KL | Year | 2014 |
| Journal | PLoS One | Volume | 9 |
| Issue | 12 | Pages | e112925 |
| PubMed ID | 25437209 | Mgi Jnum | J:225701 |
| Mgi Id | MGI:5694039 | Doi | 10.1371/journal.pone.0112925 |
| Citation | Graham KL, et al. (2014) A novel CMKLR1 small molecule antagonist suppresses CNS autoimmune inflammatory disease. PLoS One 9(12):e112925 |
| abstractText | 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. |
