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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially
Lynn van Olst1, Carla Rodriguez-Mogeda1, Carmen Picon2
1Department of Molecular Cell Biology and Immunology, Amsterdam UMC, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands.
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.
Insights
In progressive multiple sclerosis (MS), meningeal inflammation drives cortical pathology. Microglia in MS patients and a rat model develop two distinct phenotypes, with early protective roles followed by neurodegeneration.
Area of Science:
- Neuroimmunology
- Neurodegeneration
- Multiple Sclerosis Pathogenesis
Background:
- Meningeal inflammation is linked to cortical damage and disability in progressive multiple sclerosis (MS).
- The precise mechanisms by which meningeal inflammation causes cortical pathology remain unclear.
- Cortical microglia play a crucial role in the central nervous system's response to inflammation.
Purpose of the Study:
- To investigate the pathological mechanisms of meningeal inflammation-induced cortical pathology in progressive MS.
- To identify and characterize distinct microglial populations in the MS cortex associated with meningeal inflammation.
- To explore the dynamic changes in microglial phenotypes and their relationship with neurodegeneration in vivo.
Main Methods:
- Analysis of post-mortem progressive MS cortical tissue to identify microglial populations.
- Characterization of microglial phenotypes using markers (HLA class II, CD68, P2Y12, TMEM119) and morphology.
- Utilizing a rat model of chronic meningeal inflammation to replicate MS-specific microglial changes over time.
- In vivo assessment of microglial-neuronal interactions, including synaptic alterations and phagocytosis.
Main Results:
- Two distinct MS-specific microglial populations (MS1 and MS2 cortex) were identified in progressive MS cortical tissue.
- MS1 microglia exhibited increased activation markers and were associated with synaptic alterations and neuronal sparing.
- MS2 microglia showed altered morphology, reduced specific markers, and were linked to substantial neuronal loss.
- The identified microglial phenotypes were time-dependently replicated in the in vivo rat model of meningeal inflammation.
Conclusions:
- Meningeal inflammation induces two distinct microglial phenotypes in the progressive MS cortex, differentially impacting neurodegeneration.
- Early MS1 microglial activity may offer neuroprotection by managing synaptic changes.
- Later MS2 microglial phenotype is associated with neuronal loss, suggesting a loss of protective functions over time.
- These findings highlight the complex, dynamic role of microglia in MS pathogenesis and suggest potential therapeutic targets.
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