Inflammatory Environment in MS Impairs Myelin Debris-clearing by Immune Cells

The pro-inflammatory environment characteristic of multiple sclerosis (MS) reduces the levels of PPAR-gamma — a receptor protein whose activation dampens inflammation — and impairs myelin processing in immune cells that clear myelin debris, a study suggests.

These findings may help to better understand how PPAR-gamma regulates the function of these immune cells and contributes to MS progression, the researchers noted. They also may identify potential therapeutic targets for the disease.

The study, “Altered PPARγ Expression Promotes Myelin-Induced Foam Cell Formation in Macrophages in Multiple Sclerosis,” was published in the International Journal of Molecular Sciences.

In MS, the immune system mistakenly attacks myelin, the fatty protective sheath that covers nerve fibers. Previous studies have shown that while macrophages, a type of immune cell, contribute to myelin degradation, they also can promote its repair by clearing related debris from the brain and spinal cord.

The uptake of myelin debris by macrophages leads to the transport of cholesterol, its main fatty component, out of the cell, to keep a healthy fat balance within the cell. However, many macrophages containing abundant vesicles of myelin fragments — and presenting a so-called foamy appearance — are found near sites of myelin loss. Of note, vesicles are tiny sacs that transport material within or outside the cell.

Such findings suggest that macrophages’ myelin processing and fat metabolism may be impaired in MS patients. Notably, a previous study showed that sustained accumulation of myelin debris inside macrophages promotes a pro-inflammatory state.

However, the causes of this fat metabolism dysregulation remain largely unclear.

Now, a team of researchers in Belgium, along with colleagues in France and the Netherlands, have shed light on the mechanisms behind fat metabolism deficits in macrophages.

Their focus was on PPARs, a group of cell surface receptors known to suppress inflammatory pathways and regulate fat metabolism and balance within cells.

The scientists first analyzed PPAR levels in monocytes (macrophage-precursor cells) from people with relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and healthy individuals.

The results showed that one type of PPAR, PPAR-gamma, was significantly reduced in monocytes of RRMS patients, compared with those of SPMS patients and healthy people.

These findings suggest that disease-related factors present in RRMS patients — who display a great extent of inflammation — but not in SPMS patients, promote a drop in PPAR-gamma levels in monocytes.

In agreement, growing macrophages from healthy donors in the presence of inflammatory molecules known to contribute to MS reduced their levels of PPAR-gamma. Notably, these molecules also impaired the natural ability of internalized myelin to promote the production of PPAR-gamma.

Further analysis showed that lower levels of PPAR-gamma in macrophages do not impair myelin uptake, but likely affect their ability to process it and to restore fat balance.

Specifically, suppressing PPAR-gamma production in macrophages after myelin uptake led to the buildup of fat-filled vesicles and a foamy appearance, suggesting defects in myelin processing and cholesterol elimination.

Taken together, the findings suggested that the pro-inflammatory environment that is typically associated with MS lowers PPAR-gamma levels in macrophages. In turn, that “promotes myelin-induced foam cell formation … which may negatively impact MS lesion progression,” the researchers wrote.

“This study brings us closer to understanding the mechanisms by which [PPAR-gamma] can modulate macrophage function and MS lesion progression, and may help in the development of therapeutic strategies to target MS,” the team added.

The researchers also noted that further research is needed to clarify the molecular mechanisms underlying the link between PPAR-gamma and the accumulation of fat-filled vesicles in macrophages actively clearing myelin debris in MS.