TY - JOUR
T1 - Cuprizone-induced demyelination triggers a CD8-pronounced T cell recruitment
AU - Kaddatz, Hannes
AU - Joost, Sarah
AU - Nedelcu, Julia
AU - Chrzanowski, Uta
AU - Schmitz, Christoph
AU - Gingele, Stefan
AU - Gudi, Viktoria
AU - Stangel, Martin
AU - Zhan, Jiangshan
AU - Santrau, Emily
AU - Greiner, Theresa
AU - Frenz, Julia
AU - Müller-Hilke, Brigitte
AU - Müller, Michael
AU - Amor, Sandra
AU - van der Valk, Paul
AU - Kipp, Markus
N1 - Funding Information: This work was supported by the Deutsche Forschungsgemeinschaft (KI 1469/8‐1; MK). We thank Astrid Baltruschat, Beate Aschauer, Sarah Wübbel, Sabine Tost, Barbara Mosler, Wendy Bergmann, Frauke Winzer, and Susann Lehmann for their excellent technical assistance and Michael Frank for his valuable support in designing the ImageJ macro. Open access funding enabled and organized by Projekt DEAL. Open access funding enabled and organized by Projekt DEAL. Publisher Copyright: © 2020 The Authors. GLIA published by Wiley Periodicals LLC. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/4
Y1 - 2021/4
N2 - The loss of myelinating oligodendrocytes is a key characteristic of many neurological diseases, including Multiple Sclerosis (MS). In progressive MS, where effective treatment options are limited, peripheral immune cells can be found at the site of demyelination and are suggested to play a functional role during disease progression. In this study, we hypothesize that metabolic oligodendrocyte injury, caused by feeding the copper chelator cuprizone, is a potent trigger for peripheral immune cell recruitment into the central nervous system (CNS). We used immunohistochemistry and flow cytometry to evaluate the composition, density, and activation status of infiltrating T lymphocytes in cuprizone-intoxicated mice and post-mortem progressive MS tissues. Our results demonstrate a predominance of CD8+ T cells along with high proliferation rates and cytotoxic granule expression, indicating an antigenic and pro-inflammatory milieu in the CNS of cuprizone-intoxicated mice. Numbers of recruited T cells and the composition of lymphocytic infiltrates in cuprizone-intoxicated mice were found to be comparable to those found in progressive MS lesions. Finally, amelioration of the cuprizone-induced pathology by treating mice with laquinimod significantly reduces the number of recruited T cells. Overall, this study provides strong evidence that toxic demyelination is a sufficient trigger for T cells to infiltrate the demyelinated CNS. Further investigation of the mode of action and functional consequence of T cell recruitment might offer promising new therapeutic approaches for progressive MS.
AB - The loss of myelinating oligodendrocytes is a key characteristic of many neurological diseases, including Multiple Sclerosis (MS). In progressive MS, where effective treatment options are limited, peripheral immune cells can be found at the site of demyelination and are suggested to play a functional role during disease progression. In this study, we hypothesize that metabolic oligodendrocyte injury, caused by feeding the copper chelator cuprizone, is a potent trigger for peripheral immune cell recruitment into the central nervous system (CNS). We used immunohistochemistry and flow cytometry to evaluate the composition, density, and activation status of infiltrating T lymphocytes in cuprizone-intoxicated mice and post-mortem progressive MS tissues. Our results demonstrate a predominance of CD8+ T cells along with high proliferation rates and cytotoxic granule expression, indicating an antigenic and pro-inflammatory milieu in the CNS of cuprizone-intoxicated mice. Numbers of recruited T cells and the composition of lymphocytic infiltrates in cuprizone-intoxicated mice were found to be comparable to those found in progressive MS lesions. Finally, amelioration of the cuprizone-induced pathology by treating mice with laquinimod significantly reduces the number of recruited T cells. Overall, this study provides strong evidence that toxic demyelination is a sufficient trigger for T cells to infiltrate the demyelinated CNS. Further investigation of the mode of action and functional consequence of T cell recruitment might offer promising new therapeutic approaches for progressive MS.
KW - cuprizone
KW - multiple sclerosis
KW - neuroinflammation
KW - oligodendrocyte injury
KW - peripheral immune cell recruitment
UR - http://www.scopus.com/inward/record.url?scp=85096753017&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/glia.23937
DO - https://doi.org/10.1002/glia.23937
M3 - Article
C2 - 33245604
SN - 0894-1491
VL - 69
SP - 925
EP - 942
JO - GLIA
JF - GLIA
IS - 4
ER -