MyD88-TLR4-dependent choroid plexus activation precedes perilesional inflammation and secondary brain edema in a mouse model of intracerebral hemorrhage

Journal of Neuroinflammation

Research

Kevin Akeret¹  Luca Regli¹  Michael Hugelshofer¹  Bart R. Thomson²  Nina Schwendinger²  Nadja Schulthess-Lutz³  Dominik J. Schaer³  Florence Vallelian³  Livio Baselgia³  Kerstin Hansen³  Raphael M. Buzzi³  Jan Klohs⁴ 

[1] Department of Neurosurgery, Clinical Neuroscience Center, Universitätsspital and University of Zurich, Frauenklinikstrasse 10, 8091, Zurich, Switzerland;Department of Neurosurgery, Clinical Neuroscience Center, Universitätsspital and University of Zurich, Frauenklinikstrasse 10, 8091, Zurich, Switzerland;Division of Internal Medicine, Universitätsspital and University of Zurich, Zurich, Switzerland;Division of Internal Medicine, Universitätsspital and University of Zurich, Zurich, Switzerland;Institute for Biomedical Engineering, University of Zurich and ETH Zurich, Zurich, Switzerland;

关键词: Neuroinflammation;    Secondary brain injury;    Glymphatics;    Spatial RNA sequencing;    Quantitative histology;   

DOI  :  10.1186/s12974-022-02641-5

 received in 2022-09-21, accepted in 2022-11-10,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundThe functional neurological outcome of patients with intracerebral hemorrhage (ICH) strongly relates to the degree of secondary brain injury (ICH-SBI) evolving within days after the initial bleeding. Different mechanisms including the incitement of inflammatory pathways, dysfunction of the blood–brain barrier (BBB), activation of resident microglia, and an influx of blood-borne immune cells, have been hypothesized to contribute to ICH-SBI. Yet, the spatiotemporal interplay of specific inflammatory processes within different brain compartments has not been sufficiently characterized, limiting potential therapeutic interventions to prevent and treat ICH-SBI.MethodsWe used a whole-blood injection model in mice, to systematically characterized the spatial and temporal dynamics of inflammatory processes after ICH using 7-Tesla magnetic resonance imaging (MRI), spatial RNA sequencing (spRNAseq), functional BBB assessment, and immunofluorescence average-intensity-mapping.ResultsWe identified a pronounced early response of the choroid plexus (CP) peaking at 12–24 h that was characterized by inflammatory cytokine expression, epithelial and endothelial expression of leukocyte adhesion molecules, and the accumulation of leukocytes. In contrast, we observed a delayed secondary reaction pattern at the injection site (striatum) peaking at 96 h, defined by gene expression corresponding to perilesional leukocyte infiltration and correlating to the delayed signal alteration seen on MRI. Pathway analysis revealed a dependence of the early inflammatory reaction in the CP on toll-like receptor 4 (TLR4) signaling via myeloid differentiation factor 88 (MyD88). TLR4 and MyD88 knockout mice corroborated this observation, lacking the early upregulation of adhesion molecules and leukocyte infiltration within the CP 24 h after whole-blood injection.ConclusionsWe report a biphasic brain reaction pattern after ICH with a MyD88-TLR4-dependent early inflammatory response of the CP, preceding inflammation, edema and leukocyte infiltration at the lesion site. Pharmacological targeting of the early CP activation might harbor the potential to modulate the development of ICH-SBI.

【 授权许可】

CC BY   
© The Author(s) 2022

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