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

Abstract

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.

Synaptic Loss in Multiple Sclerosis: A Systematic Review of Human Post-mortem Studies

“…In a recent study by van Olst et al ( 45 ), the overall synaptic density in the cortical layer 3 of the cingulate and insular cortex was shown to be unaltered, despite strong evidence for almost complete loss of synaptic input in colocation to microglia and presynaptic phagocytosis. Brain tissue was received from 20 patients with secondary-progressive MS and six HCs.…”

“…Six studies examined the synaptic density in different cortical areas, three of which described significant synaptic loss ( 13 , 17 , 44 ), whereas the others found no overall reduction ( 45 – 47 ) ( Table 1 ).…”

“…Demyelinated areas with a comparable density of HLA-DR-positive microglia to NAGM (which accounted for about 95% of the total area of demyelinated cortex in the coronal section) showed no alteration (47). In a recent study by van Olst et al (45), the overall synaptic density in the cortical layer 3 of the cingulate and insular cortex was shown to be unaltered, despite strong evidence for almost complete loss of synaptic input in colocation to microglia and presynaptic phagocytosis. Brain tissue was received from 20 patients with secondary-progressive MS and six HCs.…”

“…In contrast, confocal microscopy provides a higher spatial precision compared to light microscopy analysis (50), which could be a reason for higher sensitivity in detecting synaptic loss in studies relying on this technique (17)(18)(19). Nevertheless, comparable studies also provided evidence for an unaltered overall synaptic density in areas of the cortex and suggested only focal synaptic disappearance in colocation to activated microglia (45). On the other hand, stereological analysis, where the total number of synapses is estimated based on a subgroup of individually counted stained points, has been demonstrated to be both, highly sensitive and accurate in detecting local differences (27).…”

Cross Talk of Purinergic and Immune Signaling: Implication in Inflammatory and Pathogenic Diseases

“…Genetic variation in P2X4 and P2X7 receptors show susceptibility to MS. Functionally, the variants impair the expression of P2X7 on the surface resulting in the inhibition of ATP-induced pore function and phagocytic activity [149]. Cortical microglia from MS patient exhibit loss of P2Y12 receptor, which associates with the pro-inflammatory and neuronal damaging profile in MS [150]. On the other hand, P2Y12 is the markers of platelet and megakaryocyte activation.…”