How the brain’s ‘choreographers’ respond to inflammation

A New Way to Study the Human Brain

By growing cells in a lab, Steven Sloan, new group leader at the Netherlands Institute for Neuroscience, has uncovered a new function in the brain’s support cells (astrocytes). “These findings give us hope”.

Steven Sloan is a new group leader at the Netherlands Institute for Neuroscience. He will be working with a relatively new scientific approach known as ‘Brain Organoids’. These are tiny clusters of cells that resemble a simple version of the human brain.

The cell that is most commonly studied in the brain is the neuron, but Sloan is more captivated by star-shaped ‘sister cells’ known as astrocytes. “You can imagine astrocytes as the choreographers of the developing brain. If you take them out for a while, the neurons have no idea what to do”.

The inflamed reactive astrocyte

Aside from their choreographic role, astrocytes also respond strongly to inflammation. “We call this a reactive state”, Sloan explains, but he can’t say much more than that. “There are probably different types of reactive states depending on the disorder and duration, but we don’t have the words to describe each of these scenarios yet”.

Sloan has published results from his last research group, thereby showing that astrocytes become reactive during really early stages of development as well. “It’s pretty profound. We think this has implications for why infections during pregnancy can be dangerous and impact the developing brain”.

“We’ve known for a while that, if mothers have serious infections in the first trimester, the risk of autism in that child is quite a bit higher. And it could very well be related to this phenomenon”.

Chronic reactivity

But what happens when that inflammation becomes chronic? Sloan’s group was among the first to show a surprising difference between astrocyte reactivity that lasts one day, as opposed to three months. That difference had everything to do with their ability to make a special molecule: MHC2.

“If you have an infection, or something foreign in your body, there are special immune cells whose job it is to eat little pieces of that foreign entity. These specialized cells then use MHC2 as a little flag to show off that invading component so that other immune cells can recognise the threat and start an attack.”

But why would astrocytes need to be able to make MHC2 if the body already has immune cells for this? “You can think of all kinds of ideas. Maybe it’s how the immune system helps organise the nervous system during development”, Sloan explains.

The reason why chronically reactive astrocytes do this requires another idea: “maybe the astrocytes do this as a decoy”, Sloan says. “If you have chronic inflammation, you don’t want more and more immune activation. That’s what can lead to disease condition like multiple sclerosis. So what’s one way to stop all of this inflammation? The astrocytes could start to put up these pretend flags that don’t actually trigger further inflammation, and distract from it.”

When removing inflammatory cues, Sloan found that the astrocytes reverted almost completely back to normal, even if that inflammation had previously lasted months. “It was thought that, once astrocytes become reactive, that’s it. We may have to fight that reactivity to get rid of it. The fact that this isn’t true brings a lot of hope”.

Aborted human fetal tissue

A lot of Sloan’s findings about human neuroinflammation were confirmed using human fetal tissue, but he is hesitant to talk about it. “In the United States, this is a challenging topic to navigate. The political environment can lean towards the idea that abortion is bad, and therefore anything related to it is bad. But our use of the tissue had nothing to do with someone’s decision to undergo an abortion”.

Having human fetal tissue, and having access to it, has become a critical aspect of his research. “Without it, someone could roll their eyes and say that the organoids are just a ball of cells in the dish. And you have no idea if what you observe is really true in the human setting”.

From a clearer map to viable solutions

Following these findings, Sloan is keen to investigate what the exact impact of astrocyte MHC2 activation. “Is astrocyte MHCII presentation pro-inflammatory, anti-inflammatory or something in between?”. He also wants to know more about what they are actually expressing on their MHC2, or ‘little flags’.

But on the grander scheme, Sloan hopes to explore the bigger questions: “what is the impact of reactive astrocytes on the developing circuit? The link to autism and schizophrenia is high because there are more human studies showing that mothers with lots of inflammation have a risk of having kids with these disorders. But that doesn’t mean that other conditions can’t also be connected. Maybe they just haven’t been looked at”.

Source: Neuron