RT Journal Article
SR Electronic
T1 Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.09.03.281543
DO 10.1101/2020.09.03.281543
A1 Lynn van Olst
A1 Carla Rodriguez-Mogeda
A1 Carmen Picon-Munoz
A1 Svenja Kiljan
A1 Rachel E. James
A1 Alwin Kamermans
A1 Susanne M.A. van der Pol
A1 Lydian Knoop
A1 Evelien Drost
A1 Marc Franssen
A1 Geert Schenk
A1 Jeroen J.G. Geurts
A1 Sandra Amor
A1 Nicholas D. Mazarakis
A1 Jack van Horssen
A1 Helga E. de Vries
A1 Richard Reynolds
A1 Maarten E. Witte
YR 2020
UL http://biorxiv.org/content/early/2020/09/04/2020.09.03.281543.abstract
AB Meningeal inflammation strongly associates with demyelination and neuronal loss in the underlying cortex of progressive MS patients, contributing to clinical disability. However, the pathological mechanisms of meningeal inflammation-induced cortical pathology are still largely elusive. Using extensive analysis of human post-mortem tissue, we identified two distinct microglial phenotypes, termed MS1 and MS2, in the cortex of progressive MS patients. These phenotypes differed in morphology and protein expression, but both associated with inflammation of the overlying meninges. We could replicate the MS-specific microglial phenotypes in a novel in vivo rat model for progressive MS-like meningeal inflammation, with microglia present at 1 month post-induction resembling MS1 microglia whereas those at 2 months acquired an MS2-like phenotype. Interestingly, MS1 microglia were involved in presynaptic displacement and phagocytosis and associated with a relative sparing of neurons in the MS and animal cortex. In contrast, the presence of MS2 microglia coincided with substantial neuronal loss. Taken together, we uncovered that in response to meningeal inflammation, microglia acquire two distinct phenotypes that differentially associate with neurodegeneration in the progressive MS cortex. Our data suggests that these phenotypes occur sequentially and that microglia may lose their protective properties over time, contributing to neuronal loss.Competing Interest StatementThe authors have declared no competing interest.