Erythrocyte–Brain Endothelial Interactions Induce Microglial Responses and Cerebral Microhemorrhages in Vivo

Authors

Hai Zhang, University of California, Irvine
Rachita K. Sumbria, Chapman UniversityFollow
Rudy Chang, Chapman University
Jiahong Sun, Chapman University
David H. Cribbs, University of California, Irvine
Todd C. Holmes, University of California, Irvine
Mark J. Fisher, University of California, IrvineFollow
Xiangmin Xu, University of California, Irvine

Document Type

Article

Publication Date

11-15-2023

Abstract

Background

Cerebral microhemorrhages (CMH) are associated with stroke, cognitive decline, and normal aging. Our previous study shows that the interaction between oxidatively stressed red blood cells (RBC) and cerebral endothelium may underlie CMH development. However, the real-time examination of altered RBC–brain endothelial interactions in vivo, and their relationship with clearance of stalled RBC, microglial responses, and CMH development, has not been reported.

Methods

RBC were oxidatively stressed using tert-butylhydroperoxide (t-BHP), fluorescently labeled and injected into adult Tie2-GFP mice. In vivo two-photon imaging and ex vivo confocal microscopy were used to evaluate the temporal profile of RBC–brain endothelial interactions associated with oxidatively stressed RBC. Their relationship with microglial activation and CMH was examined with post-mortem histology.

Results

Oxidatively stressed RBC stall significantly and rapidly in cerebral vessels in mice, accompanied by decreased blood flow velocity which recovers at 5 days. Post-mortem histology confirms significantly greater RBC–cerebral endothelial interactions and microglial activation at 24 h after t-BHP-treated RBC injection, which persist at 7 days. Furthermore, significant CMH develop in the absence of blood–brain barrier leakage after t-BHP-RBC injection.

Conclusions

Our in vivo and ex vivo findings show the stalling and clearance of oxidatively stressed RBC in cerebral capillaries, highlighting the significance of microglial responses and altered RBC–brain endothelial interactions in CMH development. Our study provides novel mechanistic insight into CMH associated with pathological conditions with increased RBC–brain endothelial interactions.

Comments

This article was originally published in Journal of Neuroinflammation, volume 20, in 2023. https://doi.org/10.1186/s12974-023-02932-5

Recommended Citation

Zhang H, Sumbria RK, Chang R, et al. Erythrocyte–brain endothelial interactions induce microglial responses and cerebral microhemorrhages in vivo. J Neuroinflammation 2023;20:265. https://doi.org/10.1186/s12974-023-02932-5

Copyright

The authors

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.