Ly6c+ “inflammatory monocytes” are microglial precursors recruited in a pathogenic manner in West Nile virus encephalitis

Abstract

In a lethal West Nile virus (WNV) model, central nervous system infection triggered a threefold increase in CD45 int /CD11b + /CD11c ؊ microglia at days 6 -7 postinfection (p.i.). Few microglia were proliferating, suggesting that the increased numbers were derived from a migratory precursor cell. Depletion of " circulating " (Gr1 ؊ (Ly6C lo )CX3CR1 + ) and " infl ammatory " (Gr1 hi /Ly6C hi /CCR2 + ) classical monocytes during infection abrogated the increase in microglia. C57BL/6 chimeras reconstituted with cFMS -enhanced green fl uorescent protein (EGFP) bone marrow (BM) showed large numbers of peripherally derived (GFP + ) microglia expressing GR1 + (Ly6C + ) at day 7 p.i., suggesting that the infl ammatory monocyte is a microglial precursor. This was confi rmed by adoptive transfer of labeled BM (Ly6C hi /CD115 + ) or circulating infl ammatory monocytes that traffi cked to the WNV-infected brain and expressed a microglial phenotype. CCL2 is a chemokine that is highly expressed during WNV infection and important in infl ammatory monocyte traffi cking. Neutralization of CCL2 not only reduced the number of GFP + microglia in the brain during WNV infection but prolonged the life of infected animals. Therefore, CCL2-dependent infl ammatory monocyte migration is critical for increases in microglia during WNV infection and may also play a pathogenic role during WNV encephalitis.

Differential Replication of Pathogenic and Nonpathogenic Strains of West Nile Virus within Astrocytes

“…Increasing evidence suggests that WNV entry into the CNS is a multistep process that can occur through one of several routes (17,20,(31)(32)(33)(34)(35). WNV entry into the CNS has been shown to precede disruption of the BBB and leukocyte infiltration (32,33,36,37), suggesting that WNV utilizes a direct mechanism to initially invade the CNS, such as basolateral secretion of virus particles from infected brain endothelial cells or transcytosis. Thus, the brain endothelium likely constitutes a primary barrier to WNV neuroinvasion.…”

Harnessing Nanoparticles for Immune Modulation

“…Work in many areas, including infectious disease, hypoxia, autoimmunity, and cancer, shows a definable wave of inflammatory monocyte recruitment into inflamed tissues expressing CCL2 and other chemokines. Once in the target tissue, these cells may differentiate into different effector cells, including DCs, macrophages, and even cells with a microglial phenotype [4,76], depending on the prevailing soluble factor milieu. In some cases these cells have important housekeeping functions (i.e., to digest and clear tissue debris before tissue remodelling); however, in many cases they express high levels of NO via induced NOS2 expression, as well as increased levels of NADPH oxidase, cathepsins, and myeloperoxidase, all of which may demonstrably contribute to further tissue damage in numerous conditions, including experimental autoimmune encephalomyelitis, myocardial infarction, and viral encephalitis [8,77,78].…”

“…More recently, our increasing knowledge of the cellular subsets and regulatory roles of various members of immune system, combined with the emergence of safe, biocompatible nanoparticle platforms, is catalyzing the development of complex, highly adaptable, and programmable NP therapies that are predicted to revolutionize the standard of care of numerous disorders. For example, NPs may be engineered to specifically target cells of the mononuclear phagocyte system (MPS) for the purposes of restoring peripheral immune tolerance or to regulate aberrant monocyte activities during severe inflammation [2,[4][5][6][7]. Five-hundred-nanometer NPs with negative zeta potential can be harnessed to target circulating monocytes, reducing their potential for causing immune pathology in numerous experimental disease models including West Nile virus (WNV) encephalitis, myocardial infarction, and inflammatory bowel disease (IBD) [8].…”

Luminescent nanodiamonds for biomedical applications

“…These approaches are important when the aim is to gather data from large numbers of cells, and they have been successfully used with fluorescent polystyrene beads for tracking macrophage lineage (i.e. using their phagocytic function) cells in vivo (Getts et al 2008). …”

“…This approach, while obvious for cancer, could easily be adapted for various infectious diseases, particularly infections by extracellular organisms, those with extracellular phases, such as malaria, and/or those expressing pathogen-specific molecules on infected cell surfaces. Furthermore, specific cellular subsets in diseases characterised by over-exuberant pro-inflammatory immune responses could be targeted and inactivated or destroyed, for example, in autoimmune disease and even certain infectious diseases (Getts et al 2008;Getts et al 2011). Dually conjugated nanodiamonds could also be used to target cell subsets expressing a particular proinflammatory chemokine or cytokine receptor using the relevant chemokine or cytokine to deliver a behaviourmodifying signal to these cells .…”