Cycle 2 project 3

Project 3: Targeting cellular migration into the CNS in early MS


PhD student: Margit Lanzinger, Austria
Home Institute:
Neuroscience Center Zürich; Principle Investigator: Burkhard Becher
Host Institute: Amsterdam Neuroscience; Principle Investigator: Elga de Vries

Executive Summary
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that leads to severe neurological deficits. During autoimmune inflammation of the CNS, which is observed in MS as well as its representative animal model experimental autoimmune encephalomyelitis (EAE), bloodderived immune cells cross the blood-brain barrier (BBB) to invade the CNS, and ultimately induce severe tissue damage.

Although most research focuses primarily on tissue-invading lymphocytes and the underlying mechanisms of their migration across the BBB, to date not much is known on the role of infiltrating neutrophils in the course of MS. Studies of the Becher group strongly indicate that in EAE the first cell type to invade the CNS is actually a neutrophil, although its underlying kinetics and time-frame is yet unknown. Activation and accumulation of granulocytes has been shown to be closely connected with the activity of TH17 cells and the prime celly type within the CNS to express the receptor for IL-17 is the BBB endothelial cell. Interestingly, life cell imaging studies from the group of de Vries demonstrate that in an in vitro system of the human BBB, that unlike monocytes, neutrophils migrate across the barrier in vitro by penetrating through the endothelial body within a relative short time frame.

Together these data illustrate that neutrophils may indeed contribute to brain inflammation and that the means by which TH17 cells influence the disease is through the recruitment of neutrophils. However, to this day, the functional impact of an innate immune cell invasion at such an early time-point remains 2 elusive. Within this joined project we aim to combine our expertise on in vivo models for MS (Becher group) and cellular migration and BBB physiology (de Vries group) to unravel the functional role of neutrophilic invasion in early phases of MS.

We plan to i) describe precise qualitative and quantitative kinetics of neutrophil invasion in the context of chronic as well as relapsing-remitting EAE, ii) determine the functional impact of neutrophils on blood-brain-barrier (BBB) integrity in an in vitro model of the BBB and iii) define underlying mechanisms and translate findings to the in vivo situation. This expansion of the research focus beyond adaptive immune cells will clearly broaden our understanding of the events related to innate immune cell participation in MS and reveal potential new targets for treatment to halt this detrimental neurological disorder.

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