A novel CMKLR1 small molecule antagonist suppresses CNS autoimmune inflammatory disease

• Published in: PloS one Vol. 9; no. 12; p. e112925
• Main Authors: Graham, Kareem L, Zhang, Jian V, Lewén, Susanna, Burke, Thomas M, Dang, Ton, Zoudilova, Maria, Sobel, Raymond A, Butcher, Eugene C, Zabel, Brian A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.12.2014; Public Library of Science (PLoS)
• Subjects: Adoptive transfer; Animals; Arrestins - metabolism; beta-Arrestins; Biology and Life Sciences; Blood-brain barrier; Brain - drug effects; Brain - metabolism; Brain research; Cell Movement - drug effects; Central nervous system; Chemokines; Chemokines - metabolism; Dendritic cells; Drug Evaluation, Preclinical; Drug Stability; Effector cells; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - metabolism; Encephalomyelitis, Autoimmune, Experimental - pathology; Experimental allergic encephalomyelitis; Female; Glycoproteins; Humans; Immunization; Immunology; Inflammation; Intercellular Signaling Peptides and Proteins - metabolism; Iodides; Laboratories; Leukocyte migration; Leukocytes; Leukocytes - drug effects; Libraries; Lymphocytes; Lymphocytes T; Macrophages; Medicine; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Microglia; Multiple sclerosis; Myelin; Naphthalenes - adverse effects; Naphthalenes - chemistry; Naphthalenes - pharmacology; Naphthalenes - therapeutic use; Natural killer cells; Oligodendrocyte-myelin glycoprotein; Pathology; Phenotypes; Physiology; Proteins; Quaternary Ammonium Compounds - adverse effects; Quaternary Ammonium Compounds - chemistry; Quaternary Ammonium Compounds - pharmacology; Quaternary Ammonium Compounds - therapeutic use; R&D; Receptors, Chemokine; Receptors, G-Protein-Coupled - antagonists & inhibitors; Research & development; Research and Analysis Methods; Rodents; Safety; Spinal Cord - drug effects; Spinal Cord - metabolism; Structure-Activity Relationship; Veterans; Palo Alto California; United States > US; California
• ISSN: 1932-6203; 1932-6203
• 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-(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.