CX3CR1 in multiple sclerosis

In a recent paper published in J. Ex. Med, we provided evidence that the knockout of CX3CR1 blocked the clearance of myelin debris by microglia, which greatly affected the integrity of axons and myelin sheaths, preventing proper remyelination. These results highlight the crucial role played by CX3CR1 in myelin removal and show that there can be no efficient remyelination following a primary demyelinating insult if myelin clearance by microglia is impaired. We also demonstrated a marked CCR2-dependent infiltration of bone marrow-derived cells in demyelinating areas but these cells do not impact demyelination and remyelination. Multiple Sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS) associated with prominent demyelination, which impairs the conduction of signals along axons. While the therapeutic control of immune processes has proven efficient to limit the relapsing-remitting form of MS, the current immunomodulatory treatments have failed to prevent patients from entering a progressive course of the disease or to limit disease progression in this phase. Remyelination is the natural regenerative mechanism to counter demyelination, but the reasons why remyelination fails or is incomplete during MS are not completely understood. Myelin removal is a critical step in the remyelination process (Kotter et al., 2006). Cells of the mononuclear phagocytic system, including monocyte-derived macrophages (MDM) and microglia, are actively implicated in the clearance of myelin debris. Microglia are resident macrophages of the CNS that originate from progenitors in the embryonic yolk sac populating the brain during early embryogenesis. Monocytes are macrophage precursors in the circulation and derive from bone marrow progenitors. While monocytes do not migrate into the CNS under normal conditions, we and others have shown the specific infiltration of MDMs under pathological conditions (Lampron et al., 2013, 2012). Microglia and macrophages are regarded as detrimental in MS and experimental autoimmune encephalomyelitis (EAE), through their roles in autoimmunity such as antigen presentation and pro-inflammatory cytokine production. However, these noxious roles might mask other beneficial properties. During demyelination, microglia exert a phenotype associated with phagocytosis and the recruitment of oligodendrocyte precursor cells (OPC). While recent work unraveled differences between the roles played by blood-borne macrophages and microglia during autoimmune-mediated demyelination (Yamasaki et al., 2014), their respective functions in the process of primary de-and remyelination of the brain were not completely understood until recently. In a recent study published in J. Ex. Med (Lampron et al., 2015), we used the cuprizone model to study the differential …