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MyD88 signaling in brain endothelial cells is essential for the neuronal activity and glucocorticoid release during systemic inflammation

Molecular Psychiatry volume 13, pages 480–497 (2008)Cite this article

Abstract

Activation of neuronal circuits involved in the control of autonomic responses is critical for the host survival to immune threats. The brain vascular system plays a key role in such immune-CNS communication, but the signaling pathway and exact type of cells within the blood-brain barrier (BBB) mediating these functions have yet to be uncovered. To elucidate this issue we used myeloid differentiation factor 88 (MyD88)-deficient mice, because these animals do not show any responses to the cytokine interleukin-1β (IL-1β). We created chimeric mice with competent MyD88 signaling in either the BBB endothelium or perivascular microglia of bone marrow origin and challenged them with IL-1β. Systemic treatment with the cytokine caused a robust transcriptional activation of genes involved in the prostaglandin E2 (PGE2) production by vascular cells of the brain. Upregulation of these genes is dependent on a functional MyD88 signaling in the endothelium, because MyD88-deficient mice that received bone marrow stem cells from wild-type animals (for example, functional perivascular microglia) exhibited no response to systemic IL-1β administration. MyD88 competent endothelial cells also mediate neuronal activation and plasma release of glucocorticoids, whereas chimeric mice with MyD88-competent perivascular microglia did not show a significant increase of these functions. Moreover, competent endothelial cells for the gene encoding Toll-like receptor 4 (TLR4) are essential for the release of plasma corticosterone in response to low and high doses of lipopolysaccharide. Therefore, BBB endothelial cells and not perivascular microglia are the main target of circulating inflammatory mediators to activate the brain circuits and key autonomic functions during systemic immune challenges.

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Acknowledgements

The Canadian Institutes in Health Research (CIHR) supported this research. Serge Rivest hold a Canadian Research Chair in Neuroimmunology. The authors thank Dr S Akira (Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan) for the gift of the MyD88-deficient breeding pair of mice and Martine Lessard for the help in the generation of chimeric mice and FACS analysis.

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  1. CHUL Research Center and Department of Anatomy and Physiology, Laboratory of Molecular Endocrinology, Laval University, QC, Canada

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Correspondence to S Rivest.

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Gosselin, D., Rivest, S. MyD88 signaling in brain endothelial cells is essential for the neuronal activity and glucocorticoid release during systemic inflammation. Mol Psychiatry 13, 480–497 (2008). https://doi.org/10.1038/sj.mp.4002122

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