Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration
Acta Neuropathologica, vol. 141, pp. 881–899
Abstract
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.
Authors 18
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Amsterdam Neuroscience · Amsterdam University Medical Centers
Affiliation as printed
Department of Molecular Cell Biology and Immunology, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands
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Amsterdam Neuroscience · Amsterdam University Medical Centers
Affiliation as printed
Department of Molecular Cell Biology and Immunology, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands
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Hammersmith Hospital · Imperial College London
Affiliation as printed
Division of Neuroscience, Department of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building, Du Cane Road, London, W12 0NN, UK
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Amsterdam Neuroscience · Amsterdam University Medical Centers
Affiliation as printed
Department of Anatomy and Neurosciences, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands
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Hammersmith Hospital · Imperial College London
Affiliation as printed
Division of Neuroscience, Department of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building, Du Cane Road, London, W12 0NN, UK
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Amsterdam Neuroscience · Amsterdam University Medical Centers
Affiliation as printed
Department of Molecular Cell Biology and Immunology, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands
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Amsterdam Neuroscience · Amsterdam University Medical Centers
Affiliation as printed
Department of Molecular Cell Biology and Immunology, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands
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Amsterdam Neuroscience · Amsterdam University Medical Centers
Affiliation as printed
Department of Pathology, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands
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Amsterdam Neuroscience · Amsterdam University Medical Centers
Affiliation as printed
Department of Molecular Cell Biology and Immunology, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands
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Amsterdam Neuroscience · Amsterdam University Medical Centers
Affiliation as printed
Department of Molecular Cell Biology and Immunology, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands
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Amsterdam Neuroscience · Amsterdam University Medical Centers
Affiliation as printed
Department of Anatomy and Neurosciences, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands
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Amsterdam Neuroscience · Amsterdam University Medical Centers
Affiliation as printed
Department of Pathology, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands
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Hammersmith Hospital · Imperial College London
Affiliation as printed
Division of Neuroscience, Department of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building, Du Cane Road, London, W12 0NN, UK
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Amsterdam Neuroscience · Amsterdam University Medical Centers
Affiliation as printed
Department of Molecular Cell Biology and Immunology, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands
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Amsterdam Neuroscience · Amsterdam University Medical Centers · Amsterdam Cardiovascular Sciences
Affiliation as printed
Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
Department of Molecular Cell Biology and Immunology, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands
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Richard Reynolds corresponding
Nanyang Technological University · Hammersmith Hospital · Imperial College London
Affiliation as printed
Centre for Molecular Neuropathology, LKC School of Medicine, Nanyang Technological University, Singapore, Singapore. r.reynolds@imperial.ac.uk
Division of Neuroscience, Department of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building, Du Cane Road, London, W12 0NN, UK. r.reynolds@imperial.ac.uk
Centre for Molecular Neuropathology, LKC School of Medicine, Nanyang Technological University, Singapore, Singapore
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Maarten E. Witte corresponding
Amsterdam Neuroscience · Amsterdam University Medical Centers
Affiliation as printed
Department of Molecular Cell Biology and Immunology, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands. m.e.witte@amsterdamumc.nl
Department of Pathology, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands. m.e.witte@amsterdamumc.nl
Department of Molecular Cell Biology and Immunology, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands
Department of Pathology, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands
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