Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients

TLDR

Chemokines guide leukocyte infiltration into tissues, and in multiple sclerosis they may drive the CNS inflammatory response dominated by mononuclear phagocytes and T cells. The study aimed to determine whether specific chemokines are expressed in the CNS during acute demyelinating events and whether their corresponding receptors are present on infiltrating cells in MS lesions and cerebrospinal fluid. Researchers analyzed cerebrospinal fluid for chemokine concentrations and examined receptor expression on infiltrating cells in active MS brain lesions and CSF. They found that CSF levels of IP‑10, Mig, and RANTES were elevated during attacks, CXCR3 was expressed on virtually all perivascular lymphocytes in active lesions, CCR5 was present on lymphocytes, macrophages, and microglia, and CSF T cells were enriched for CXCR3 or CCR5, suggesting pathogenic chemokine‑receptor interactions and new therapeutic targets.

Abstract

Chemokines direct tissue invasion by specific leukocyte populations. Thus, chemokines may play a role in multiple sclerosis (MS), an idiopathic disorder in which the central nervous system (CNS) inflammatory reaction is largely restricted to mononuclear phagocytes and T cells. We asked whether specific chemokines were expressed in the CNS during acute demyelinating events by analyzing cerebrospinal fluid (CSF), whose composition reflects the CNS extracellular space. During MS attacks, we found elevated CSF levels of three chemokines that act toward T cells and mononuclear phagocytes: interferon-gamma-inducible protein of 10 kDa (IP-10); monokine induced by interferon-gamma (Mig); and regulated on activation, normal T-cell expressed and secreted (RANTES). We then investigated whether specific chemokine receptors were expressed by infiltrating cells in demyelinating MS brain lesions and in CSF. CXCR3, an IP-10/Mig receptor, was expressed on lymphocytic cells in virtually every perivascular inflammatory infiltrate in active MS lesions. CCR5, a RANTES receptor, was detected on lymphocytic cells, macrophages, and microglia in actively demyelinating MS brain lesions. Compared with circulating T cells, CSF T cells were significantly enriched for cells expressing CXCR3 or CCR5. Our results imply pathogenic roles for specific chemokine-chemokine receptor interactions in MS and suggest new molecular targets for therapeutic intervention.