TY - JOUR
T1 - Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration
AU - van Olst, Lynn
AU - Rodriguez Mogeda, Carla
AU - Picon, Carmen
AU - Kiljan, Svenja
AU - James, Rachel E.
AU - Kamermans, Alwin
AU - van der Pol, Susanne M.A.
AU - Knoop, Lydian
AU - Michailidou, Iliana
AU - Drost, Evelien
AU - Franssen, Marc
AU - Schenk, Geert J.
AU - Geurts, Jeroen J.G.
AU - Amor, Sandra
AU - Mazarakis, Nicholas D.
AU - van Horssen, Jack
AU - de Vries, Helga E.
AU - Reynolds, Richard
AU - Witte, Maarten E.
N1 - Funding Information: We thank the Microscopy and Cytometry Core Facility and Mike de Kok of the Amsterdam UMC for excellent technical support. We thank the Mo2Ab Core Facility for providing the HLA class II (OX6) antibody. We thank the UK MS Society Tissue Bank at Imperial College and Dr. Djordje Gveric for the supply of human post-mortem tissue samples. This work was supported by the National MS Society (Grant RG-1601-07456 to RR and JvH) and the Dutch MS Research Foundation MS18-358 to HEdV. Funding Information: We thank the Microscopy and Cytometry Core Facility and Mike de Kok of the Amsterdam UMC for excellent technical support. We thank the Mo2Ab Core Facility for providing the HLA class II (OX6) antibody. We thank the UK MS Society Tissue Bank at Imperial College and Dr. Djordje Gveric for the supply of human post-mortem tissue samples. This work was supported by the National MS Society (Grant RG-1601-07456 to RR and JvH) and the Dutch MS Research Foundation MS18-358 to HEdV. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/6
Y1 - 2021/6
N2 - Meningeal inflammation strongly associates with demyelination and neuronal loss in the underlying cortex of progressive MS patients, thereby contributing significantly to clinical disability. However, the pathological mechanisms of meningeal inflammation-induced cortical pathology are still largely elusive. By extensive analysis of cortical microglia in post-mortem progressive MS tissue, we identified cortical areas with two MS-specific microglial populations, termed MS1 and MS2 cortex. The microglial population in MS1 cortex was characterized by a higher density and increased expression of the activation markers HLA class II and CD68, whereas microglia in MS2 cortex showed increased morphological complexity and loss of P2Y12 and TMEM119 expression. Interestingly, both populations associated with inflammation of the overlying meninges and were time-dependently replicated in an in vivo rat model for progressive MS-like chronic meningeal inflammation. In this recently developed animal model, cortical microglia at 1-month post-induction of experimental meningeal inflammation resembled microglia in MS1 cortex, and microglia at 2 months post-induction acquired a MS2-like phenotype. Furthermore, we observed that MS1 microglia in both MS cortex and the animal model were found closely apposing neuronal cell bodies and to mediate pre-synaptic displacement and phagocytosis, which coincided with a relative sparing of neurons. In contrast, microglia in MS2 cortex were not involved in these synaptic alterations, but instead associated with substantial neuronal loss. Taken together, our results show that in response to meningeal inflammation, microglia acquire two distinct phenotypes that differentially associate with neurodegeneration in the progressive MS cortex. Furthermore, our in vivo data suggests that microglia initially protect neurons from meningeal inflammation-induced cell death by removing pre-synapses from the neuronal soma, but eventually lose these protective properties contributing to neuronal loss.
AB - Meningeal inflammation strongly associates with demyelination and neuronal loss in the underlying cortex of progressive MS patients, thereby contributing significantly to clinical disability. However, the pathological mechanisms of meningeal inflammation-induced cortical pathology are still largely elusive. By extensive analysis of cortical microglia in post-mortem progressive MS tissue, we identified cortical areas with two MS-specific microglial populations, termed MS1 and MS2 cortex. The microglial population in MS1 cortex was characterized by a higher density and increased expression of the activation markers HLA class II and CD68, whereas microglia in MS2 cortex showed increased morphological complexity and loss of P2Y12 and TMEM119 expression. Interestingly, both populations associated with inflammation of the overlying meninges and were time-dependently replicated in an in vivo rat model for progressive MS-like chronic meningeal inflammation. In this recently developed animal model, cortical microglia at 1-month post-induction of experimental meningeal inflammation resembled microglia in MS1 cortex, and microglia at 2 months post-induction acquired a MS2-like phenotype. Furthermore, we observed that MS1 microglia in both MS cortex and the animal model were found closely apposing neuronal cell bodies and to mediate pre-synaptic displacement and phagocytosis, which coincided with a relative sparing of neurons. In contrast, microglia in MS2 cortex were not involved in these synaptic alterations, but instead associated with substantial neuronal loss. Taken together, our results show that in response to meningeal inflammation, microglia acquire two distinct phenotypes that differentially associate with neurodegeneration in the progressive MS cortex. Furthermore, our in vivo data suggests that microglia initially protect neurons from meningeal inflammation-induced cell death by removing pre-synapses from the neuronal soma, but eventually lose these protective properties contributing to neuronal loss.
KW - Cortical pathology
KW - Meninges
KW - Microglia
KW - Multiple sclerosis
KW - Neurodegeneration
KW - Neuroinflammation
UR - http://www.scopus.com/inward/record.url?scp=85103416968&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s00401-021-02293-4
DO - https://doi.org/10.1007/s00401-021-02293-4
M3 - Article
C2 - 33779783
SN - 0001-6322
VL - 141
SP - 881
EP - 899
JO - Acta neuropathologica
JF - Acta neuropathologica
IS - 6
ER -