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Astrocytes decrease adult neurogenesis during virus-induced memory dysfunction via IL-1

Abstract

Memory impairment following West Nile virus neuroinvasive disease (WNND) is associated with loss of hippocampal synapses with lack of recovery. Adult neurogenesis and synaptogenesis are fundamental features of hippocampal repair, which suggests that viruses affect these processes. Here, in an established model of WNND-induced cognitive dysfunction, transcriptional profiling revealed alterations in the expression of genes encoding molecules that limit adult neurogenesis, including interleukin 1 (IL-1). Mice that had recovered from WNND exhibited fewer neuroblasts and increased astrogenesis without recovery of hippocampal neurogenesis at 30 d. Analysis of cytokine production in microglia and astrocytes isolated ex vivo revealed that the latter were the predominant source of IL-1. Mice deficient in the IL-1 receptor IL-1R1 and that had recovered from WNND exhibited normal neurogenesis, recovery of presynaptic termini and resistance to spatial learning defects, the last of which likewise occurred after treatment with an IL-1R1 antagonist. Thus, ‘preferential’ generation of proinflammatory astrocytes impaired the homeostasis of neuronal progenitor cells via expression of IL-1; this might underlie the long-term cognitive consequences of WNND but also provides a therapeutic target.

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Fig. 1: Transcripts of genes encoding molecules that affect neurogenesis and markers of proinflammatory astrocytes are altered in mice that had recovered from WNV infection.
Fig. 2: Fewer new neurons are born within the DG during recovery from infection with WNV-NS5-E218A.
Fig. 3: Deficits in adult neurogenesis during WNV infection.
Fig. 4: More astrocytes are born within the hippocampus during acute WNV encephalitis, and they adopt a proinflammatory phenotype and express IL-1β.
Fig. 5: Il1r1 −/− mice resist WNV-mediated alterations in neuroblast proliferation and recover synapses earlier than do wild-type mice.
Fig. 6: WNV-NS5-E218A-infected Il1r1 –/– mice are protected from virus-induced spatial learning deficits in the Barnes maze behavior task.
Fig. 7: WNV-NS5-E218A-infected mice treated with anakinra are protected from virus-induced spatial learning deficits on the Barnes maze behavior task.

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Acknowledgements

We thank G. Enikolopov (Cold Spring Harbor Laboratories) for Nestin-GFP mice; and M. Diamond (Washington University) for WNV-NS5-E218A. Supported by the National Institutes of Health (U19 AI083019, R01 NS052632 and HDTRA11510032 to R.S.K.), the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the US National Institutes of Health (P30AR048335) and the Speed Congenics Facility of the Rheumatic Diseases Core Center (experimental support). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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C.G., M.J.V. and R.S.K. designed the experiments; C.G. and M.J.V. did most of the experiments, compiled and analyzed the data; C.G., M.J.V. and R.S.K. prepared the figures; L.L.V., T.S. and X.J. were involved in specific experiments; and C.G., M.J.V. and R.S.K. analyzed the data and wrote the manuscript.

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Correspondence to Robyn S. Klein.

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Supplementary information

Supplementary Figure 1 Flow cytometry gating strategy.

a Following isolation and staining with Dapi and antibodies to CD45, Doublecortin, and BrdU, doublets were excluded, and the CD45-negative population was utilized for further gates. b Percentage of BrdU+ neuroblasts, through expression of the marker, DCX, was calculated and example plots shown from Hippocampus (HPC), Hippocampus from an animal which did not receive BrdU injection (HPC no BrdU), Cortex (CTX), and Subventricular Zone (SVZ).

Supplementary Figure 2 WNV permissivity of DCX+ neuroblasts in vivo.

a 5 week old mice were infected via the footpad with 100 pfu of wild type WNV(NY99) and harvested for tissue collection on day 8 post infection. Immunohistochemistry is shown for West Nile antigen and the neuroblast marker, doublecortin (DCX) within the Dentate gyrus (DG) and Subventricular Zones (SVZ). Many WNV+ neurons can be seen within the granule cell layer (GCL) of the DG and the striatum neighboring the SVZ, however only 1 out of 4 animals showed any WNV and DCX-double positive cells (shown by white arrowhead, Left), resulting in a mean % of infection of less than 1% of total DCX+ cells. Within the DG, infected DCX+ cells were always located within the GCL—indicating that they are more mature neuroblasts or immature neurons. b Immunostaining for GFP and GFAP in mock and WNV-NS5-E218A nestin-GFP reporter animals. Representative images of the dentate gyrus are shown on the left and quantification of Nestin+ transit amplifying (TA) and Nestin+GFAP+ neural stem cells (NSC) on the right. Nestin-GFP (green), GFAP (red) and DAPI (blue). ns = not significant (P > 0.05).

Supplementary Figure 3 Determination of astrocyte and microglia purity.

qRT-PCR analysis of expression of cell type specific astrocyte (GFAP), microglia (Cx3CR1, Trem2), and neuronal (RBFox3) transcripts in ex vivo isolated astrocytes (ASC2+ cells) and microglia (CD11b+ cells). *, P < 0.05 using two-way ANOVA followed by Bonferonni post test.

Supplementary Figure 4 Lack of IL-1 signaling does not affect viral control or immune cell infiltrates to the CNS.

a-c Plaque assay of CNS tissue from WNV-NS5-E218A infected wildtype (WT) and Il1r1 −/− animals at 6 d.p.i. d qPCR analysis of WNV envelope protein at 25 d.p.i. in hippocampus from WNV-NS5-E218A WT and Il1r1 −/− mice. e-l Flow cytometric analysis of stained single cell populations isolated from hippocampus of WT and Il1r1 −/− mice at 6 d.p.i. ns = not significant (P > 0.05 using two tailed student’s t test).

Supplementary Figure 5 Blood–brain barrier opening peaks at 6 d.p.i. and closes by 12 d.p.i.

a-c Relative blood brain barrier permeability of the frontal cortex, hippocampus, and cerebellum at 3, 6, 9, and 12 d.p.i. was assessed by an in vivo sodium fluorescein assay to determine optimal time for drug administration. d.p.i.: Days Post Infection.

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Garber, C., Vasek, M.J., Vollmer, L.L. et al. Astrocytes decrease adult neurogenesis during virus-induced memory dysfunction via IL-1. Nat Immunol 19, 151–161 (2018). https://doi.org/10.1038/s41590-017-0021-y

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