CCR1+/CCR5+mononuclear phagocytes accumulate in the central nervous systemof patients with multiple sclerosis

Mononuclear phagocytes (monocytes, macrophages, and microglia) are consider ed central to multiple sclerosis (MS) pathogenesis. Molecular cues that med iate mononuclear phagocyte accumulation and activation in the central nervo us system (CNS) of MS patients may include chemokines RANTES/CCL5 and macro phage inflammatory protein-1 alpha /CCL3. We analyzed expression of CCR1 an d CCR5, the monocyte receptors for these chemokines, on circulating and cer ebrospinal fluid CD14+ cells, and in MS brain lesions. Approximately 70% of cerebrospinal fluid monocytes were CCR1+/CCR5+, regardless of the presence of CNS pathology, compared to less than 20% of circulating monocytes. In a ctive MS lesions CCR1+/CCR5+ monocytes were found in perivascular cell cuff s and at the demyelinating edges of evolving lesions. Mononuclear phagocyte s in early demyelinating stages comprised CCR1+/CCR5+ hematogenous monocyte s, and CCR1-/CCR5- resident microglial cells. In later stages, phagocytic m acrophages were uniformly CCR1-/CCR5+. Cultured in vitro, adherent monocyte s/macrophages up-regulated CCR5 and down-regulated CCR1 expression, compare d to freshly-isolated monocytes. Taken together, these findings suggest tha t monocytes, competent to enter the CNS compartment derive from a minority CCR1+/CCR5+ population in the circulating pool. in the presence of ligand, these cells will be retained in the CNS. During further activation in lesio ns, infiltrating monocytes downregulate CCR1 but not CCR5, whereas microgli a up-regulate CCR5.