Involvement of beta-chemokines in the development of inflammatory demyelination

Abstract

The importance of beta-chemokines (or CC chemokine ligands - CCL) in the development of inflammatory lesions in the central nervous system of patients with multiple sclerosis and rodents with experimental allergic encephalomyelitis is strongly supported by descriptive studies and experimental models. Our recent genetic scans in families identified haplotypes in the genes of CCL2, CCL3 and CCL11-CCL8-CCL13 which showed association with multiple sclerosis. Complementing the genetic associations, we also detected a distinct regional expression regulation for CCL2, CCL7 and CCL8 in correlation with chronic inflammation in multiple sclerosis brains. These observations are in consensus with previous studies, and add new data to support the involvement of CCL2, CCL7, CCL8 and CCL3 in the development of inflammatory demyelination. Along with our own data, here we review the literature implicating CCLs and their receptors (CCRs) in multiple sclerosis and experimental allergic encephalomyelitis. The survey reflects that the field is in a rapid expansion, and highlights some of the pathways which might be suitable to pharmaceutical interventions.

Figure 1

Interaction between CCL and CCR molecules at the blood-brain barrier. This figure depicts CCL-CCR interactions at the BBB (endothelial cells and astrocytic processes) interfacing a venule and the CNS. CCL molecules (most prominently CCL2, CCL3, CCL7 and CCL8, but also CCL1, CCL4, CCL19 and CCL21) are produced by residential microglia, astrocytes and endothelial cells throughout the course of lesion development, and by infiltrating MNCs (CCL5) during late phases of plaque formation, and attract functionally different subsets of monocytes / macrophages, dendritic cells and T lymphocytes from the circulation via the BBB into the CNS. The temporal and spatial regulation of molecular events, the association of distinct CCR molecules with different histological subtypes of demyelination and the involvement of different CCL-CCR interactions in T cell polarization are detailed in the text. Here we illustrate in a simplified and cross-sectional manner the main groups of interacting receptors on various hematogenous cells and ligands released by residential immune cells of the CNS or by components of the BBB. Group A of receptors and ligands expressed by and acting on monocytes / macrophages, respectively: CCR1 / CCR2 / CCR3-CCL7, CCR2-CCL2, CCR3-CCL8, CCR4-CCL22; Group B of receptors and ligands expressed by and acting on dendritic cells, respectively: CCR4-CCL22, CCR6-CCL20, CCR7-CCL19 / CCL21; Group C of receptors and ligands expressed by and acting on T lymphocyes, respectively: CCR1-CCL3 / CCL5, CCR2-CCL2, CCR4-CCL22, CCR5-CCL3 / CCL4 / CCL5, CCR7-CCL19 / CCL21, CCR8-CCL1.