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Antimicrobial immunity impedes CNS vascular repair following brain injury

Abstract

Traumatic brain injury (TBI) and cerebrovascular injury are leading causes of disability and mortality worldwide. Systemic infections often accompany these disorders and can worsen outcomes. Recovery after brain injury depends on innate immunity, but the effect of infections on this process is not well understood. Here, we demonstrate that systemically introduced microorganisms and microbial products interfered with meningeal vascular repair after TBI in a type I interferon (IFN-I)-dependent manner, with sequential infections promoting chronic disrepair. Mechanistically, we discovered that MDA5-dependent detection of an arenavirus encountered after TBI disrupted pro-angiogenic myeloid cell programming via induction of IFN-I signaling. Systemic viral infection similarly blocked restorative angiogenesis in the brain parenchyma after intracranial hemorrhage, leading to chronic IFN-I signaling, blood–brain barrier leakage and a failure to restore cognitive–motor function. Our findings reveal a common immunological mechanism by which systemic infections deviate reparative programming after central nervous system injury and offer a new therapeutic target to improve recovery.

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Fig. 1: Systemic infections and PAMPs impede meningeal vascular repair following mild traumatic brain injury.
Fig. 2: LCMV infection alters the distribution of myeloid cells in lesion core and perimeter.
Fig. 3: Infections induce a prolonged state of disrepair and interferon signaling in the meninges following mTBI.
Fig. 4: Deletion of pathogen sensing or interferon signaling reconstitutes meningeal repair after mTBI.
Fig. 5: Transcranial application of IFN-β1 impedes meningeal vascular repair after mTBI.
Fig. 6: Viral infection and subsequent interferon signaling blocks angiogenesis after cerebrovascular injury.
Fig. 7: Viral infection and subsequent interferon signaling blocks blood–brain barrier repair after CVI.
Fig. 8: Viral infection after CVI leads to chronic interferon signaling and a failure to recover cognitive–motor function.

Data availability

The data that support the findings of this study are available from the corresponding author upon request. There are no restrictions on data availability. Bulk RNA-seq data are available in the NCBI Gene Expression Omnibus under accession code GSE172102. The mouse genome database used in our RNA-seq analysis was GRCm38 (https://www.ncbi.nlm.nih.gov/assembly/GCF_000001635.20/). Source data are provided with this paper.

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Acknowledgements

This research was supported by the intramural program at the NINDS, NIH. We thank A. Elkahloun and W. Wu in the National Human Genome Research Institute Microarray core for their assistance with the RNA-seq experiment.

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Contributions

P.M., M.V.R. and T.Z. performed the design, data acquisition and analysis. K.J. conducted computation analyses of RNA-seq data. P.M. and D.B.M. wrote and edited the manuscript. D.B.M. supervised and directed the project and participated in experimental design, data acquisition and analysis.

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Correspondence to Dorian B. McGavern.

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The authors declare no competing interests.

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Peer review information Nature Immunology thanks Dennis Simon and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Editor recognition statement: L. A. Dempsey was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Inhibition of interferon signaling improves meningeal repair after mTBI.

The dot plot depicts the percent of meningeal lesion repair 7 days after mTBI in uninfected mice (Ctrl) as well as mice challenged with LCMV, LPS, or Candida albicans (C. Alb) on day 4 post-injury, with or without αIFNAR antibody treatment. Cumulative data from two independent experiments. Each symbol represents an individual mouse, and asterisks denote statistical significance. Data are represented as mean ± SD. (Ctrl n=6, LCMV n=8, LPS n=15, C. Alb n=15; ****P<0.0001; Two-way ANOVA/ Holm-Sidak test). Representative confocal images from meningeal wholemounts show laminin staining in red, and functional vessels visualized with i.v. fluorescent tomato lectin in green. White dotted lines denote areas of injury and vascular repair. Scale bar, 200 μm. Source data in Source Data Extended Data Fig. 1.

Source data

Extended Data Fig. 2 Viral infection after CVI reduces tight junction protein expression.

a. Axial confocal images show i.v. injected tomato lectin (green), claudin-5 (red) and ZO-1 (white) in the superficial neocortex of uninfected (Ctrl) and d4 LCMV-infected B6 mice at day 20 post-CVI. Scale bar, 50 μm. b, c. Dot plots show image-based quantification of claudin-5 (b) and ZO-1 (c) sum intensity per vascular volume. Data represent a compilation of two independent experiments. Each symbol represents an individual mouse and asterisks denote statistical significance. Data are represented as mean ± SD. (Ctrl n=6, LCMV n=8; **P<0.01, ***P<0.0001; Two-tailed Student’s t-test). Source data for b,c in Source Data Extended Data Fig. 2.

Source data

Supplementary information

Reporting Summary

Supplementary Tables 1–5

Supplementary Video 1

A representative time lapse captured through the thinned skull of a Cx3cr1GFP/WTCcr2RFP/WT mouse at day 5 after mTBI. The mouse was imaged before (left) and after (right) transcranial IFN-β1 administration. Before IFN-β1 administration, CCR2+ monocytes were observed within the lesion core (denoted with a white dashed line) and perilesional area. One hour of IFN-β1 treatment triggered increased recruitment of CCR2+ cells into the perilesional area and a decrease of these cells within the lesion core. The video is representative of three independent experiments. Quantification of these time lapses is shown in Fig. 5f.

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Mastorakos, P., Russo, M.V., Zhou, T. et al. Antimicrobial immunity impedes CNS vascular repair following brain injury. Nat Immunol 22, 1280–1293 (2021). https://doi.org/10.1038/s41590-021-01012-1

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