Things are not always what they seem. In multiple sclerosis (MS), immune cells are traditionally seen as the bad guys because they attack the insulating myelin sheath of wiry nerve cells and impair transmission. Cholesterol, on the other hand, which is released from the sheath, is one of the innocent bystanders.
But a recent study from Mikael Simons and colleagues at the Technical University of Munich, Germany, turns that thinking on its head.
It turns out immune cells known as phagoctyes are crucial for repairing the damaged myelin sheath – but what stops them is toxic shards of cholesterol.
The findings, published in the journal Science, show that stimulating cholesterol removal by phagocytes restores myelin repair and improves symptoms in older mice.
“It’s a new concept in terms of the damaging effect of cholesterol [in MS],” says Tobias Merson at Monash University, who was not involved in the research. It also points to a new target for developing drugs, he adds.
Globally, more than 2.3 million people have MS, but no two patients experience the disease in the same way. Symptoms include diminished cognitive function, muscle spasms, pain, and limited mobility – all a consequence of faulty transmission by neurons of the central nervous system (CNS).
Patients usually experience flare-ups followed by remission, because the myelin sheath on the neurons can be repaired. But as time goes on, the relapses grow more severe.
“People don’t recover as well,” says Simons. “There’s clearly an age-dependent component in MS.”
It was an observation that suggested a problem in myelin repair.
The repair service is provided by immature cells called oligodendrocyte progenitor cells. When they sense myelin damage, they mature into myelin-making cells called oligodendrocytes, which function to recoat the frayed sheath. But first, phagocytes – the name means “devouring cells” – must clear away the debris.
One theory for the diminishing repair holds that phagocytes become less ravenous with age. While comparing electron microscope images of damaged nerves of young and old mice, however, Simons and colleagues saw something intriguing. Phagocytes congregating around the damaged nerves of older mice looked different: they appeared foamy and contained long, needle-like crystals.
Simons had seen something like this before, in another disease entirely.
“They reminded us of atherosclerotic plaques,” he says.
Atherosclerosis is an inflammatory disease where cholesterol-laden biofilms accumulate in blood vessels. Local phagocytes break them down to a degree, but they can’t degrade cholesterol. Instead, a cholesterol export pathway is used, but eventually this becomes overwhelmed.
A hallmark of atherosclerosis is a build-up of cholesterol droplets in phagocytes, causing them to appear foamy. Excess cholesterol also forms sharp, needle-like crystals that cause internal damage to the phagocyte, triggering the release of inflammatory signals.
“It’s a call for help,” says Simons. In response, other immune cells show up and drive inflammation.
Simons wondered if cholesterol was causing problems in MS, too. After all, it’s the most abundant molecule in myelin.
To find out, he and his team used a drug to improve cholesterol export in older mice suffering from a disease similar to MS. Both the number of ‘foam cells’ and cholesterol crystals decreased, while myelin regeneration improved.
Conversely, when they turned off cholesterol export in the phagocytes of young mice, myelin regeneration was impaired.
Cholesterol transport by ageing phagocytes “is really a bottle neck in the process of repair,” he says.
It also initiates a vicious cycle where inflammation contributes to further disease.
“The exciting thing about this work,” adds Merson, “is that there could be a druggable target.”
That will require some new drug discovery, says Simons, as cholesterol-transport promoting drugs like the one used in the mouse study currently have too many side-effects to be used in humans.
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