5 | Define underlying mechanisms of specialized pro-resolving mediators in controlling blood-brain barrier function and fighting neuro-inflammation

Dysfunction of the blood-brain barrier (BBB) and inflammation thereof may lead to neuro-inflammation and neurodegeneration, as seen in Alzheimer’s disease and multiple sclerosis, both also marked by activated microglia and macrophages. Ways to counteract impaired BBB properties and microglia activation may be beneficial to fight such devastating disorders. Our recent data have shown that specialized pro-resolving lipid mediators (SPMs), key mediators of resolution of inflammation, not only control barrier function but also potently differentiate macrophages and microglia into anti-inflammatory and neuroprotective cells.

To elucidate the underlying molecular mechanisms, we here will investigate how the resolution pathway controls the function of the BBB and how it can promote neuroprotection using a combination of in vitro and in vivo models and well-characterized human post-mortem tissues. To define dynamic SPM receptor function and down-stream signaling pathways, we will use multiple quantitative high-end microscopical techniques (i.e. super resolution, life cell, intravital, 3D imaging using light sheet), combined with lipidomics, deep-sequencing, phospho-proteomics, bio-informatics, and assays for BBB, microglia and neuronal function. Ultimately, this project will identify new ways to boost this endogenous protective mechanism, thereby fighting neurodegeneration.

Publications

  • Derada Troletti C, Fontijn RD, Gowing E, Charabati M, van Het Hof B, Didouh I, van der Pol SMA, Geerts D, Prat A, van Horssen J, Kooij G, de Vries HE. Inflammation-induced endothelial to mesenchymal transition promotes brain endothelial cell dysfunction and occurs during multiple sclerosis pathophysiology. Cell Death Dis. 2019;10:45-50
  • Chakraborty A, Kamermans A, van Het Hof B, Castricum K, Aanhane E, van Horssen J, Thijssen VL, Scheltens P, Teunissen CE, Fontijn RD, van der Flier WM, de Vries HE. Angiopoietin like-4 as a novel vascular mediator in capillary cerebral amyloid angiopathy. Brain. 2018;141:3377-3388
  • Kamermans A, Planting KE, Jalink K, van Horssen J, de Vries HE. Reactive astrocytes in multiple sclerosis impair neuronal outgrowth through TRPM7-mediated chondroitin sulfate proteoglycan production. Glia. 2019;67:68-77.
  • Derada Troletti C, Lopes Pinheiro MA, Charabati M, Gowing E, van Het Hof B, van der Pol SMA, Geerts D, Prat A, Fontijn RD, Unger WW, de Vries HE. Notch signaling is impaired during inflammation in a Lunatic Fringe-dependent manner. Brain Behav Immun. 2018 Mar;69:48-56
  • Beaino W, Janssen B, Kooij G, van der Pol SMA, van Het Hof B, van Horssen J, Windhorst AD, de Vries HE. Purinergic receptors P2Y12R and P2X7R: potential targets for PET imaging of microglia phenotypes in multiple sclerosis. J Neuroinflammation. 2017;14(1):259.
  • Lopes Pinheiro MA, Kamermans A, Garcia-Vallejo JJ, van Het Hof B, Wierts L, O'Toole T, Boeve D, Verstege M, van der Pol SM1, van Kooyk Y, de Vries HE, Unger WW. Internalization and presentation of myelin antigens by the brain endothelium guides antigen-specific T cell migration. eLife 2016;5: e13149

Potential secondments

UNIBERN (Britta Engelhardt), month 15-16; UZL (Markus Schwaninger), month 22-23.

Host Organisation:
Department of Molecular and Cell Biology and Immunology, Stichting Vumc, Amsterdam, Netherlands
Supervisor:
Elga de Vries, Gijs Kooij