CXCR7 antagonism prevents leukocyte trafficking into the central nervous system and treats ongoing disease during experimental autoimmune encephalomyelitis. (96.5)

Abstract

Abstract Multiple Sclerosis (MS) is a neurological disorder characterized by the pathological trafficking of autoreactive leukocytes into the central nervous system (CNS). We previously showed that removal of CXCL12 from abluminal surfaces of the CNS microvasculature facilitates the entry of CXCR4-expressing leukocytes within MS tissues and in mice with experimental autoimmune encephalomyelitis (EAE), a model for MS. Recently, the orphan receptor CXCR7 was determined to bind CXCL12/11. Evidence suggests that CXCR7 mainly regulates CXCR4 signaling by sequestering CXCL12 from extracellular milieu. Using MS and EAE specimens, we tested the hypothesis that inhibition of CXCR7 would prevent leukocyte migration into the CNS and induction of autoimmunity. CXCR7 is expressed by both human and murine CNS endothelium and CXCR7 antagonism completely blocks CXCL12 internalization in brain microvascular cells in vitro. In vivo antagonism of CXCR7 led to dose-dependent inhibition of EAE and ameliorated clinical symptoms in mice with ongoing disease. Immunohistochemical analysis revealed increased leukocytes within meningeal vessels, decreased perivascular infiltrates and parenchymal entry of leukocytes compared with controls. Abluminal CXCL12 expression persisted only in mice treated with high doses of CXCR7 antagonist. The benefits of persistent abluminal CXCL12 location during EAE suggest that pharmacologic targeting of CXCR7 may have therapeutic utility for the treatment of MS.