Figure 1

Development of monocytes in the bone marrow and recruitment to the virus-infected brain. Monocytes are generated from hematopoietic precursors in the bone marrow (BM). Sca-1⁺ Lin^- HSC (a) give rise to CD34⁺, Sca-1^- CMP (b). These cells in turn give rise to a pool of precursors known as granulocyte/macrophage precursors (GMPs), which express CD34 and CD16/32 (c). A fraction of these progenitors also express CD115 and CX₃CR1 and are known as macrophage/dendritic cell precursor (MDP) (d). MDPs are the direct precursors of Ly6C^hi inflammatory monocytes (e). MDPs also give rise to circulating Ly6C^lo/- monocytes directly, or via a Ly6C^hi monocyte intermediate (f). During viral encephalitis, large quantities of the chemokine CCL2 is produced by infected astrocytes, macrophages/microglia and/or neurons (g). CCL2 binds the chemokine receptor CCR2, expressed at high levels by Ly6C^hi inflammatory monocytes, which promotes the egress of these cells from the BM (h) into the blood, and thus recruitment from the blood into the infected central nervous system (CNS) (i). Here, these cells can give rise to CD45^hi Ly6C^hi macrophages (j) and/or CD45^int Ly6C^int immigrant microglia (k), although it is unclear whether Ly6C^int immigrant microglia are derived from a Ly6C^hi macrophage intermediate or directly differentiate from Ly6C^hi monocytes. Furthermore, it is unclear whether recruited macrophages and immigrant microglia give rise to CD45^lo Ly6C^lo/- resident microglia (l) if/when virus is cleared from the CNS. In some models of viral encephalitis, Ly6C^hi inflammatory monocytes can also give rise to Ly6C^hi/CD11c⁺ DC in the brain (m).