Targeting CSF-1 ameliorates experimental autoimmune encephalomyelitis by depleting inflammatory monocytes and microglia in the central nervous system without affecting quiescent microglia

ABSTRACTMultiple sclerosis (MS) and its model, experimental autoimmune encephalomyelitis (EAE), are autoimmune diseases characterized by extensive infiltration of myeloid cells into the central nervous system (CNS). Although myeloid cells are essential to MS/EAE pathology, none of the current MS therapies specifically target them. A promising strategy for bridging this gap may be targeting the biological activity of CSF-1R, a receptor tyrosine kinase important for survival and functioning of certain myeloid cells, such as monocytes and macrophages. It has been shown that CSF-1R inhibitors suppress EAE, but it is not known whether targeting CSF-1R ligands, CSF-1 and IL-34, could be a viable therapeutic strategy. We found that neutralization of CSF-1 with Ab attenuates ongoing EAE, similar to CSF-1R inhibitor BLZ945, whereas neutralization of IL-34 had no effect. Both anti-CSF-1- and BLZ945-treated mice with EAE had greatly diminished numbers of monocyte-derived dendritic cells and microglia in the CNS. However, anti-CSF-1 antibody selectively depleted inflammatory microglia, whereas BLZ945 depleted virtually all microglia, including quiescent microglia. We also found depletion of myeloid cells in the spleen and lymph nodes of anti-CSF-1- and BLZ945-treated mice, but only a modest decrease in encephalitogenic T cell responses, suggesting that the depletion of CNS myeloid cells is more relevant to EAE suppression. Decreased myeloid cell populations in treated mice resulted in reduced production of IL-1β, a key inflammatory mediator in EAE. The treatments also reduced the frequencies of CCL2- and CCR2-expressing cells in the CNS, suggesting that CSF-1/CSF-1R inhibition may hinder recruitment of immune cells to the CNS. Our findings suggest that targeting CSF-1 may be effective in ameliorating myeloid cell-mediated MS pathology, while preserving homeostatic functions of microglia and decreasing risks that might arise from their ablation with small molecule inhibitors of CSF-1R.