Defective inflammatory monocyte development in IRF8-deficient mice abrogates migration to the West Nile virus-infected brain

Rachael L. Terry, Celine Deffrasnes, Daniel R. Getts, Carsten Minten, Caryn Van Vreden, Thomas M. Ashhurst, Meghann T. Getts, Rui Dan Vicki Xie, Nicholas J C King

Research output: Contribution to journalArticleResearchpeer-review

11 Citations (Scopus)

Abstract

IRF8 (interferon-regulatory factor-8) plays a critical role in regulating myeloid cell differentiation. However, the role of this transcription factor in the development of Ly6C+ inflammatory monocytes and their migration to the infected brain has not been examined. We have previously shown that West Nile virus (WNV) infection of wild-type (WT) mice triggers a significant increase in numbers of Ly6C+ monocytes in the bone marrow. These cells traffic via the blood to the infected brain, where they give rise to proinflammatory macrophages. Here, we show that WNV-infected IRF8-deficient (IRF8-/-) mice had significantly reduced numbers of Ly6C+ monocytes in the periphery, with few of these cells found in the blood. Furthermore, low numbers of inflammatory monocyte-derived macrophages were observed in the brains of IRF8-/-mice throughout infection. Adoptive transfer of IRF8-/-Ly6C+ monocytes demonstrated that these cells were intrinsically unable to traffic to the inflamed brain. Low expression of the chemokine receptor CCR2 and integrin VLA-4 by IRF8-/-monocytes likely contributed to this defect, as the interactions between these proteins and their ligands are critical for monocyte egress and migration to inflammatory foci. These data highlight a critical role for IRF8 in inflammatory monocyte differentiation and migration during WNV infection.

Original languageEnglish
Pages (from-to)102-112
Number of pages11
JournalJournal of Innate Immunity
Volume7
Issue number1
DOIs
Publication statusPublished - 2015
Externally publishedYes

Keywords

  • CCR2
  • Encephalitis
  • Inflammatory monocytes
  • IRF8
  • Ly6C+ monocytes
  • VLA-4
  • West Nile virus

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