Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration

AbstractMeningeal 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.

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Surface-in pathology in multiple sclerosis: a new view on pathogenesis?

Brain ◽

10.1093/brain/awab025 ◽

2021 ◽

Author(s):

Matteo Pardini ◽

J William L Brown ◽

Roberta Magliozzi ◽

Richard Reynolds ◽

Declan T Chard

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Grey Matter ◽

Magnetization Transfer ◽

Neuronal Loss ◽

Magnetization Transfer Ratio ◽

Supporting Evidence ◽

Transfer Ratio ◽

Meningeal Inflammation

Abstract While multiple sclerosis can affect any part of the CNS, it does not do so evenly. In white matter it has long been recognized that lesions tend to occur around the ventricles, and grey matter lesions mainly accrue in the outermost (subpial) cortex. In cortical grey matter, neuronal loss is greater in the outermost layers. This cortical gradient has been replicated in vivo with magnetization transfer ratio and similar gradients in grey and white matter magnetization transfer ratio are seen around the ventricles, with the most severe abnormalities abutting the ventricular surface. The cause of these gradients remains uncertain, though soluble factors released from meningeal inflammation into the CSF has the most supporting evidence. In this Update, we review this ‘surface-in’ spatial distribution of multiple sclerosis abnormalities and consider the implications for understanding pathogenic mechanisms and treatments designed to slow or stop them.

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Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration

Acta Neuropathologica ◽

10.1007/s00401-021-02293-4 ◽

2021 ◽

Author(s):

Lynn van Olst ◽

Carla Rodriguez-Mogeda ◽

Carmen Picon ◽

Svenja Kiljan ◽

Rachel E. James ◽

...

Keyword(s):

Animal Model ◽

Neuronal Cell ◽

Neuronal Loss ◽

Activation Markers ◽

Post Induction ◽

Meningeal Inflammation ◽

Neuronal Cell Bodies ◽

Neuronal Soma ◽

Cortical Pathology

AbstractMeningeal 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.

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A “kissing lesion”: In-vivo 7T evidence of meningeal inflammation in early multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458516683267 ◽

2017 ◽

Vol 23 (8) ◽

pp. 1167-1169 ◽

Cited By ~ 7

Author(s):

Pierre Kolber ◽

Amgad Droby ◽

Alard Roebroeck ◽

Rainer Goebel ◽

Vinzenz Fleischer ◽

...

Keyword(s):

Multiple Sclerosis ◽

Early Stage ◽

Precentral Gyrus ◽

Inflammatory Infiltration ◽

Mild Disease ◽

Rapid Acquisition ◽

Meningeal Inflammation ◽

Relapsing Remitting ◽

Cortical Pathology

Background: The role of cortical lesions (CLs) in disease progression and clinical deficits is increasingly recognized in multiple sclerosis (MS); however the origin of CLs in MS still remains unclear. Objective: Here, we report a para-sulcal CL detected two years after diagnosis in a relapsing-remitting MS (RRMS) patient without manifestation of clinical deficit. Methods: Ultra-high field (7T) MR imaging using magnetization-prepared 2 rapid acquisition gradient echoes (MP2RAGE) sequence was performed. Results: A para-sulcal CL was detected which showed hypointense rim and iso- to hyperintense core. This was detected in the proximity of the leptomeninges in the left precentral gyrus extending to the adjacent postcentral gyrus. Conclusion: This finding indicates that inflammatory infiltration into the cortex through the meninges underlies cortical pathology already in the early stage of disease and in mild disease course.

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Neuron-specific activation of necroptosis signaling in multiple sclerosis cortical grey matter

Acta Neuropathologica ◽

10.1007/s00401-021-02274-7 ◽

2021 ◽

Vol 141 (4) ◽

pp. 585-604 ◽

Cited By ~ 1

Author(s):

Carmen Picon ◽

Anusha Jayaraman ◽

Rachel James ◽

Catriona Beck ◽

Patricia Gallego ◽

...

Keyword(s):

Multiple Sclerosis ◽

Signaling Pathway ◽

Cortical Neurons ◽

Grey Matter ◽

Molecular Mechanisms ◽

Fold Increase ◽

Cell Types ◽

Meningeal Inflammation ◽

Cortical Grey Matter

AbstractSustained exposure to pro-inflammatory cytokines in the leptomeninges is thought to play a major role in the pathogenetic mechanisms leading to cortical pathology in multiple sclerosis (MS). Although the molecular mechanisms underlying neurodegeneration in the grey matter remain unclear, several lines of evidence suggest a prominent role for tumour necrosis factor (TNF). Using cortical grey matter tissue blocks from post-mortem brains from 28 secondary progressive MS subjects and ten non-neurological controls, we describe an increase in expression of multiple steps in the TNF/TNF receptor 1 signaling pathway leading to necroptosis, including the key proteins TNFR1, FADD, RIPK1, RIPK3 and MLKL. Activation of this pathway was indicated by the phosphorylation of RIPK3 and MLKL and the formation of protein oligomers characteristic of necrosomes. In contrast, caspase-8 dependent apoptotic signaling was decreased. Upregulation of necroptotic signaling occurred predominantly in macroneurons in cortical layers II–III, with little expression in other cell types. The presence of activated necroptotic proteins in neurons was increased in MS cases with prominent meningeal inflammation, with a 30-fold increase in phosphoMLKL+ neurons in layers I–III. The density of phosphoMLKL+ neurons correlated inversely with age at death, age at progression and disease duration. In vivo induction of chronically elevated TNF and INFγ levels in the CSF in a rat model via lentiviral transduction in the meninges, triggered inflammation and neurodegeneration in the underlying cortical grey matter that was associated with increased neuronal expression of TNFR1 and activated necroptotic signaling proteins. Exposure of cultured primary rat cortical neurons to TNF induced necroptosis when apoptosis was inhibited. Our data suggest that neurons in the MS cortex are dying via TNF/TNFR1 stimulated necroptosis rather than apoptosis, possibly initiated in part by chronic meningeal inflammation. Neuronal necroptosis represents a pathogenetic mechanism that is amenable to therapeutic intervention at several points in the signaling pathway.

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Investigation of outer cortical magnetisation transfer ratio abnormalities in multiple sclerosis clinical subgroups

Multiple Sclerosis Journal ◽

10.1177/1352458514522537 ◽

2014 ◽

Vol 20 (10) ◽

pp. 1322-1330 ◽

Cited By ~ 36

Author(s):

Rebecca S Samson ◽

Manuel J Cardoso ◽

Nils Muhlert ◽

Varun Sethi ◽

Claudia AM Wheeler-Kingshott ◽

...

Keyword(s):

Multiple Sclerosis ◽

Three Dimensional ◽

Neuronal Loss ◽

Magnetisation Transfer ◽

Magnetisation Transfer Ratio ◽

Outer Cortex ◽

Transfer Ratio ◽

Relapsing Remitting ◽

Healthy Control

Background: Pathological abnormalities including demyelination and neuronal loss are reported in the outer cortex in multiple sclerosis (MS). Objective: We investigated for in vivo evidence of outer cortical abnormalities by measuring the magnetisation transfer ratio (MTR) in MS patients of different subgroups. Methods: Forty-four relapsing–remitting (RR) (mean age 41.9 years, median Expanded Disability Status Scale (EDSS) 2.0), 25 secondary progressive (SP) (54.1 years, EDSS 6.5) and 19 primary progressive (PP) (53.1 years, EDSS 6.0) MS patients and 35 healthy control subjects (mean age 39.2 years) were studied. Three-dimensional (3D) 1×1×1mm3 T1-weighted images and MTR data were acquired. The cortex was segmented, then subdivided into outer and inner bands, and MTR values were calculated for each band. Results: In a pairwise analysis, mean outer cortical MTR was lower than mean inner cortical MTR in all MS groups and controls ( p<0.001). Compared with controls, outer cortical MTR was decreased in SPMS ( p<0.001) and RRMS ( p<0.01), but not PPMS. Outer cortical MTR was lower in SPMS than PPMS ( p<0.01) and RRMS ( p<0.01). Conclusions: Lower outer than inner cortical MTR in healthy controls may reflect differences in myelin content. The lowest outer cortical MTR was seen in SPMS and is consistent with more extensive outer cortical (including subpial) pathology, such as demyelination and neuronal loss, as observed in post-mortem studies of SPMS patients.

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Alterations in sensorimotor and mesiotemporal cortices and diffuse white matter changes in primary progressive multiple sclerosis detected by adiabatic relaxometry

10.21203/rs.3.rs-85334/v1 ◽

2020 ◽

Author(s):

Pavel Filip ◽

Michal Dufek ◽

Silvia Mangia ◽

Shalom Michaeli ◽

Martin Bares ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Large Scale ◽

Diffusion Tensor ◽

Neuronal Loss ◽

Progressive Multiple Sclerosis ◽

Primary Progressive Multiple Sclerosis ◽

Primary Progressive ◽

T1 And T2

Abstract Background: The research of primary progressive multiple sclerosis (PPMS) has not been able to capitalize on recent progresses in advanced MRI protocols searching for disease-specific microstructural changes. Methods: Conventional free precession T1 and T2, and rotating frame adiabatic T1ρ and T2ρ maps in combination with diffusion weighted parameters were acquired in 13 PPMS patients and 13 age and sex-matched controls.Results: T1ρ, a marker of crucial relevance for PPMS due to its sensitivity to neuronal loss, revealed large-scale changes in mesiotemporal structures, sensorimotor cortex and cingulate, in combination with diffuse alterations in the white matter and cerebellum. T2ρ, particularly sensitive to local tissue background gradients and thus indicator of iron accumulation, concurred with similar topography of damage, but of lower extent. Moreover, these adiabatic protocols completely dwarfed the outcomes of both conventional T1 and T2 maps and diffusion tensor/kurtosis approaches –methods previously implicated in the MRI research of PPMS.Conclusion: This study introduces adiabatic T1ρ and T2ρ as elegant markers confirming large-scale cortical grey matter, cerebellar and white matter alterations in PPMS invisible to other in vivo biomarkers.

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A GMCSF/Interleukin-15 Fusokine Leads to the Generation of a Novel Type of CD2/MHCII Immune Regulatory Cell with Potent Immune Suppressive Properties as Demonstrated in the EAE Mouse Model of Multiple Sclerosis.

Blood ◽

10.1182/blood.v110.11.2295.2295 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2295-2295

Author(s):

Moutih Rafei ◽

Jeremy Hsieh ◽

Meng Yang Li ◽

Simone Zehntner ◽

Kathy Forner ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Autoimmune Disease ◽

Ex Vivo ◽

Regulatory Cell ◽

Autoreactive T Cell ◽

Experimental Allergic Encephalitis ◽

Over Time

Abstract Multiple sclerosis (MS) is an autoimmune disease characterised by the infiltration of autoreactive T-cell causing damages to the central nervous system. So far, interferon-β and glatiramer acetate are the only two immunomodulatory coumpounds that have been approved as non-curative disease managing strategies. Therefore, there is an urgent need for the development of novel efficient therapies that can be both safe and potent in inhibiting MS progression and promote reversal of disease state. We have recently published a report describing a novel synthetic GMCSF and IL15 Fusion Transgene (GIFT15) and have described its paradoxical and potent immune suppressive properties in vivo [Rafei et al., Blood (March 2007)]. Its mechanism of action relies on STAT3 hyperactivation arising from aberrant signalling taking place downstream of the IL15 receptor. We have now further studied the effect of GIFT15 on mouse spleen cells in vitro and here demonstrate that it leads to the conversion of murine T-cells to a novel suppressive regulatory cell type. Indeed, GIFT15-treated splenocytes (hereafter GIFT15 regs) shed their TCR and loose expression of CD3, CD4 and CD8, retain CD2 expression and acquire expression of MHC II. Distinct to classic T-regulatory cells, GIFT15 regs do not express CD25 or FOXP3. GIFT15 regs were able to suppress an in vitro two-way MLR by a contact-dependent mechanism as well as by the contemporaneous production of interleukin (IL)-10. Furthermore, GIFT15 regs were able to block antigen-specific activation of CD4-T-cells in response to autologous macrophage stimulation. As a proof-of-principle in vivo study, GIFT15 regs were injected intravenously in mice with pre-established experimental allergic encephalitis (EAE) and disease score was monitored over time. Interestingly, mice recovered significantly faster than controls following administration GIFT15 regs and a blockade in EAE progression was also noticed over time. In conclusion, our data suggests that GIFT15 can be used as a method to ex vivo generate suppressor cells of a new type which are distinct from classic Tregs or Tr1 cells. We propose that GIFT15 regs derived from autologous lymphocytes may be exploited for the treatment of autoimmune disease such as MS and may also be of use for other autoimmune ailments as well.

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In-vivo imaging of meningeal inflammation in multiple sclerosis: Presence of evidence or evidence of presence?

Multiple Sclerosis Journal ◽

10.1177/1352458517704924 ◽

2017 ◽

Vol 23 (8) ◽

pp. 1169-1171 ◽

Cited By ~ 2

Author(s):

Iris D Kilsdonk ◽

Menno Schoonheim ◽

Mike P Wattjes

Keyword(s):

Multiple Sclerosis ◽

In Vivo Imaging ◽

Meningeal Inflammation

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High-resolution myelin water imaging in post-mortem multiple sclerosis spinal cord: A case report

Multiple Sclerosis Journal ◽

10.1177/1352458515624559 ◽

2016 ◽

Vol 22 (11) ◽

pp. 1485-1489 ◽

Cited By ~ 19

Author(s):

Cornelia Laule ◽

Andrew Yung ◽

Vlady Pavolva ◽

Barry Bohnet ◽

Piotr Kozlowski ◽

...

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

Cross Sections ◽

Anatomical Variation ◽

Conus Medullaris ◽

Entire Length ◽

Post Mortem ◽

Water Fraction ◽

Formalin Fixed

Background: Loss of myelin in the spinal cord in multiple sclerosis (MS) is likely an important, and early, contributor to atrophy and associated disability. In vivo measurement of myelin is possible using myelin water fraction (MWF) imaging, but MWF has never been assessed in MS along the entire length of the spinal cord in vivo or in post-mortem tissue. Objective: To assess the feasibility of measuring the distribution of MWF along the entire length of the spinal cord in post-mortem MS tissue using high-field MRI. Methods: One formalin-fixed spinal cord from a female with secondary progressive MS (age: 78 years, disease duration: 25 years) was cut into 104 5-mm-thick cross sections along the entire length of the spinal cord from the cervico-medullary junction to the conus medullaris and imaged using a 64 echo T2 relaxation experiment at 7T. Results: Myelin water maps showed cord anatomy in superb detail, white matter demonstrating a higher MWF than the grey matter. Anatomical variation in myelin distribution along cervical, thoracic and lumbar regions was observed. Lesions demonstrated myelin loss. Conclusion: Post-mortem myelin water imaging of formalin-fixed MS spinal cord is feasible.

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