Inflammatory monocytes recruited from the bone marrow in West Nile virus or dengue encephalitis have distinctive differentiative fates in the CNS — Australasian Cytometry Society

Inflammatory monocytes recruited from the bone marrow in West Nile virus or dengue encephalitis have distinctive differentiative fates in the CNS (24068)

Luan D Vu 1 , Nicholas JC King 1
  1. University of Sydney, Camperdown, NSW, Australia

West Nile (WNV) and Dengue viruses (DENV) are both flaviviruses associated with significant neurological disease. In WNV encephalitis we have shown that infiltrating Ly6Chi monocytes directly correlate with disease development and mortality, but the differentiation and function of these cells remain contentious. Comparing lethal WNV and non-lethal DENV encephalitis in mice, we found two distinct differentiation patterns of bone marrow–derived monocytes (BMM) infiltrating the brain. During WNV encephalitis, BMM differentiated into Ly6ChiCD11clowMHCIIint inflammatory macrophages in an inoculation route-independent manner, while in DENV encephalitis, BMM gave rise to Ly6ChiCD11chiMHCIIhi dendritic cells (DC). Intravenous adoptively transferred BMM from WNV-infected mice into DENV-infected mice and vice versa, differentiated in the brain into DC and inflammatory macrophages, respectively, indicating that the brain, not the bone-marrow milieu, drives the fate of infiltrating BMM. Intriguingly, however, in the DENV model, differentiation of BMM into DC was abrogated when WNV donor cells were injected intracranially, suggesting a requirement for ‘priming’ during leukocyte extravasation for subsequent downstream differentiation in the brain. Pathway analysis of gene transcription between DENV- and WNV-infected brains showed greater activation of the transforming growth factor-beta (TGF-β) -signalling pathway, including TGF-β, vasoactive intestinal peptide and IL-16, in DENV- than WNV-infected brains. This pathway may modulate differentiation to favour generation of tolerogenic DC. We hypothesise that the local balance between pro- and anti-inflammatory responses, beginning at the endothelium, governs the subsequent differentiation of inflammatory monocytes infiltrating into the CNS. Understanding mechanisms underlying this differentiation may suggest potential therapeutic opportunities to control CNS inflammation.

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