Biology subjects

James, R. E.

Publications and source records attributed to James, R. E..

2 recordsLinked to original sources

bioRxiv2021

Lymphotoxin-alpha expression in the meninges causes lymphoid tissue formation and neurodegeneration

Lymphotoxin alpha (LT) plays an important role in lymphoid organ development and cellular cytotoxicity in the immune system. LT expression is increased in the cerebrospinal fluid of naive and progressive multiple sclerosis (MS) patients and post-mortem meningeal tissue. Here we show that persistently increased levels of LT in the cerebral meninges can give rise to lymphoid-like structures and underlying MS-like cortical pathology. Stereotaxic injections of recombinant LT into the rat meninges leads to acute meningeal inflammation and subpial demyelination that resolves after 28 days. Injection of an LT lentiviral vector induces lymphoid-like immune cell aggregates, maintained over 3 months, including T-cell rich zones containing podoplanin+ fibroblastic reticular stromal cells and B-cell rich zones with a network of follicular dendritic cells, together with expression of lymphoid chemokines and their receptors. Extensive microglial activation, subpial demyelination and marked neuronal loss occurs in the underlying cortical parenchyma. These results show that chronic LT overexpression is sufficient to induce formation of meningeal lymphoid-like structures and subsequent neurodegeneration. SummaryIncreased release of lymphotoxin-alpha contributes to the pro-inflammatory milieu of the cerebrospinal fluid of MS patients. A persistent elevated expression of this cytokine in the meninges of rats gives rise to chronic inflammation with lymphoid tissue induction and accompanying neurodegenerative and demyelinating pathology in the underlying brain tissue.

neuroscience↗

bioRxiv2020

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

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.

neuroscience↗