• New research suggests that inflammation in the meninges, the brain’s protective barrier, may extend into the grey matter and contribute to the development of progressive multiple sclerosis (MS).
• Researchers used innovative techniques to demonstrate a gradient of immune genes and markers of inflammation extending from the meninges to the adjacent brain tissue in mice.
• While the study sheds light on the mechanisms of brain damage in MS, limitations in spatial resolution and the use of a mouse model demonstrate that further investigations using human samples are needed.

A new study — whose findings appear in eLife as a reviewed preprint — used innovative techniques to demonstrate a gradient of immune genes and markers of inflammation, extending from the meninges to the neighboring brain tissue in mice.

The meninges are a set of three layers of membranes that envelop and safeguard the brain and spinal cord.

These membranes, known as the dura mater, arachnoid mater, and pia mater, serve the purpose of shielding and securing the brain, as well as providing a structural framework for blood vessels, nerves, lymphatics, and the cerebrospinal fluid that envelops the central nervous system.

Inflammation occurring within the meninges is observed in all forms of multiple sclerosis (MS).

Increasing evidence indicates that this inflammation plays a crucial role in the advancement of the disease, including the loss of the protective covering on nerves (demyelination), the loss of newly developed nerve extensions (neurites), and a reduction in the volume of grey matter.

Damage to the grey matter is associated with debilitating symptoms of MS, such as cognitive impairment and depression. Meningeal inflammation seems to be a crucial factor contributing to the pathology of cortical grey matter.

Measuring gene activity patterns in tissue

In this study, researchers investigated the patterns of gene expression within the meninges and the neighboring grey matter, with a focus on maintaining contextual information regarding the positioning of these cells within the brain.

They utilized a technique called spatial transcriptomics, which involves measuring the gene activity pattern within a tissue and reconstructing the original gene activity pattern in its specific location.

First, they assessed the gene activity in the inflamed meninges of mice with an MS-like condition and compared it to the gene expression in the meninges of healthy mice. They then examined the gene expression in the surrounding grey matter of both groups of mice.

As expected, they observed an increased expression (upregulation) of genes associated with immune cells, immune cell infiltration, and the activation of brain-specific immune cells known as microglia.

Pro-inflammatory genes may play a role in MS

To gain insights into the proximity of this gene activity to the meningeal region, the researchers analyzed the gene expression patterns along a path from the meninges to the thalamus, finding that all groups of genes displayed decreased activity as the distance from the inflamed meningeal region increased.

However, certain genes exhibited a more gradual decline, particularly those involved in immune processes such as antigen processing and presentation.

This suggests that some pro-inflammatory genes that were upregulated had extended from the meningeal region of the brain into the grey matter.

One limitation of this study is that the spatial resolution might not be precise enough to accurately differentiate between the meninges and the adjacent grey matter.

Furthermore, although the researchers utilized a mouse model that mimics several pathological aspects of MS, it does not fully replicate the human disease.

Additionally, the analysis did not take into account different stages of MS development, or the different types of the condition that occur in humans.

However, the authors suggest that their findings could serve as a foundation for future investigations using human samples.

Expert views on inflammation and MS

Dr. Pavan Bhargava, an associate professor of neurology in the Division of Neuroimmunology and Neurological Infections at Johns Hopkins University, Baltimore, MD, and senior author of the paper, told Medical News Today that, “while inflammation in the coverings of the brain has been linked to more severe disease and more damage in the brain of people with MS, questions remain about whether the inflammation causes the damage or is simply a response to damage occurring in the brain.”

“We used a technique called spatial transcriptomics that allows us to evaluate [the] expression of genes on a slide providing critical information regarding where different genes are expressed in the brain and surrounding tissue,” Dr. Bhargava explained.

“Using a mouse model of MS we identified areas of inflammation in the coverings of the brain and noted that certain inflammatory gene signatures showed penetration into the adjacent brain tissue while others did not. This suggests that the inflammation in the coverings of the brain is impacting the brain and identifies potential targets for treatment.”

– Dr. Pavan Bhargava

Nancy Mitchell, a registered nurse and contributing writer at Assisted Living Center, not involved in the research, pointed out that “as with most autoimmune diseases, the onset of multiple sclerosis is linked to some level of inflammation in the body — in this case, in the nervous system.”

“This study highlights the relationship between inflammation at the blood-brain barrier and the progression of this disease,” Mitchell explained.

“The parenchyma is the site of the brain associated with cognitive function. It’s highly likely that inflammation — which may be caused by some immune attack or related damage — can cause impaired nervous function and promote MS,” she hypothesized.

Implications for treatment development

Dr. Bhargava pointed out that the research, should its findings be confirmed by further studies, may have some implications for the development of new MS treatments.

So far, the study “has identified potential targets to reduce the impact of meningeal inflammation on underlying brain tissue, which, if validated in human tissues, could be the basis for evaluating medications targeting these pathways in people with MS,” he told us.

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