Inflammatory monocytes and the pathogenesis of viral encephalitis

Abstract

Monocytes are a heterogeneous population of bone marrow-derived cells that are recruited to sites of infection and inflammation in many models of human diseases, including those of the central nervous system (CNS). Ly6Chi/CCR2(hi) inflammatory monocytes have been identified as the circulating precursors of brain macrophages, dendritic cells and arguably microglia in experimental autoimmune encephalomyelitis; Alzheimer's disease; stroke; and more recently in CNS infection caused by Herpes simplex virus, murine hepatitis virus, Theiler's murine encephalomyelitis virus, Japanese encephalitis virus and West Nile virus. The precise differentiation pathways and functions of inflammatory monocyte-derived populations in the inflamed CNS remains a contentious issue, especially in regard to the existence of monocyte-derived microglia. Furthermore, the contributions of monocyte-derived subsets to viral clearance and immunopathology are not well-defined. Thus, understanding the pathways through which inflammatory monocytes migrate to the brain and their functional capacity within the CNS is critical to inform future therapeutic strategies. This review discusses some of the key aspects of inflammatory monocyte trafficking to the brain and addresses the role of these cells in viral encephalitis.

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).