Maarten Witte is group leader in the Department of Molecular Cell Biology & Immunology and part of the MS center Amsterdam. Throughout his career, he has been fascinated by the interplay between perhaps the two most complex systems in the human body, the immune and central nervous system (CNS), and how neuroinflammation contributes to neuronal damage in neurological diseases. Supported by grants from the US Department of Defense, Institute of Chemical Immunology (NWO) and an MS fellowship from the Dutch MS research foundation, his group aims to elucidate the immunological mechanisms that drive neurodegeneration in several neurological diseases, in particular multiple sclerosis (MS). To disentangle these neurodegenerative pathways, they study human post-mortem tissue and various in vitro and in vivo model systems using both state-of-the-art microscopy and single cell approaches.
Although the central nervous system has traditionally been defined as ‘immune-privileged’, research over the last decades has taught us that there is considerable interaction between the peripheral immune system and the brain in both health and disease. Similarly, we have come to appreciate that CNS-resident immune cells, particularly microglia, are not only involved in protecting the brain from pathogens and clearing debris, but play multiple critical roles in development, homeostasis and degeneration of the CNS.
Inflammation-driven neurodegeneration in MS
Here, we aim to identify which infiltrated peripheral immune cell subsets drive neurodegeneration in progressive MS and to elucidate the mechanisms involved. We are particularly interested in the role of meningeal immune cells and how they might affect cortical microglia and neurons. Hopefully, this will allow us to identify novel therapeutic targets to stop neurodegeneration in progressive MS, which at present cannot be treated.
Neuron-microglia crosstalk in health and disease
Recent literature suggests that direct, physical interaction between microglia and neurons is essential in maintaining neuronal function during brain homeostasis, and can be both neuroprotective and neurodegenerative under neuroinflammatory & neurodegenerative conditions. We aim to study cause and consequence of this physical interaction in health and disease by using newly developed photoactivatable ligands. These photochemical tools allow us to control the activation of individual microglia in vitro and in vivo and to subsequently assess the interaction between microglia and neurons.
1. van Olst L, Rodriguez-Mogeda C, Picon C, Kiljan S, James RE, Kamermans A, van der Pol SMA, Knoop L, Michailidou I, Drost E, Franssen M, Schenk GJ, Geurts JJG, Amor S, Mazarakis ND, van Horssen J, de Vries HE, Reynolds R, Witte ME. Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration. Acta Neuropathologica 2021 Jun;141(6):881-899.
2. Rodríguez-Lorenzo S, Konings J, Van der Pol S, Kamermans A, Amor S, Van Horssen J, Witte ME*, Kooij G*, De Vries HE*. Inflammation of the choroid plexus in progressive multiple sclerosis: accumulation of granulocytes and T cells. Acta Neuropathologica Communications 2020 Feb 26;8(1):24. * authors contributed equally
3. Witte ME, Schumacher AM, Mahler CF, Bewersdorf JP, Lehmitz J, Scheiter A, Sánchez P, Williams PR, Griesbeck O, Naumann R, Misgeld T, Kerschensteiner M. Calcium influx through plasma-membrane nanoruptures drives axon degeneration in a model of multiple sclerosis. Neuron 2019 Feb 20;101(4):615-624.
4. Witte ME, Mahad D, Lassmann H, Van Horssen J. Mitochondrial dysfunction contributes to neurodegeneration in Multiple Sclerosis. Trends in Molecular Medicine 2014 20(3):179-87.
5. Witte ME, Nijland P, Reijerkerk A, Drexhage JA, Gerritsen WH, Vent I, Van Het Hof B, De Vries HE, Van Der Valk P, Van Horssen J. Reduced expression of PGC-1α partly underlies mitochondrial changes and correlates with neuronal loss in multiple sclerosis cortex. Acta Neuropathologica 2013 125(2):231-43.
Sigrid Roks, PhD student
Carla Rodriguez-Mogeda, PhD student