A potential route to reducing brain injury in premature babies has been found, say researchers who have discovered a way to tackle overactive immune cells in the brain.

Microglia are a type of immune cell that play an important part in the building of a baby’s brain. However, if these cells go into overdrive as a result of inflammation – often because of a bacterial infection of the foetal membranes, a maternal infection or even sepsis after delivery of the baby – they can cause harm to the child’s brain. In particular, they can damage white matter, reducing the degree to which neurons are insulated and thereby affecting connectivity in the brain.

It is thought that of the 15 million infants born before 37 weeks every year, up to 9 million are left with lifelong harm to the brain, sometimes resulting in conditions such as epilepsy or cerebral palsy.

Now researchers say they have found a signalling pathway in these immune cells that is behind their transformation.

We have actually identified the immune switch that turns these immune cells in the developing brain from being helpful in building a brain and taking care of the brain to causing damage,” said Dr Bobbi Fleiss from RMIT University in Melbourne, Australia, a co-author of the study.

What is more, the researchers say, it might even be possible to intervene and turn rogue microglia back into helpful workhorses.

Writing in the journal Brain, Fleiss and colleagues reported how they took mouse pups just after birth and injected them with proteins that mimic an infection in the mother or foetus, inducing the transformation of microglia from helpful to harmful. The team said mice of this age were comparable in their development to a human pregnancy of 22 to 32 weeks.

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The team then found that if they selectively killed off these microglia, the mice ended up with less of a reduction in the insulation of their neurons. That, they said, backed up the idea that overactive microglia were involved in brain injury.

They then looked at which genes were switched on or off when the mouse was exposed to the inflammation-causing proteins, and identified a signalling pathway known as Wnt that appeared to be involved in the microglia going into “overdrive”.

The researchers carried out further experiments in a range of animals, finding drugs that specifically dampen down the signalling pathway that activates the microglia. Analysis of human tissue from premature babies also showed that when inflammation was triggered, microglia became activated and lower levels of molecules linked to the Wnt pathway were produced.

In other words, the team had found the “switch” that turned the microglia bad.

Further work combining genetical analysis of premature babies with brain imaging data backed up the idea that the Wnt pathway is important.

“We were able to show that in the human even the natural, normal level of variation in this pathway actually has an effect on brain development, so [targeting this Wnt pathway] may actually be a really novel way for us to move forward to develop a treatment to prevent brain damage in those babies,” said Fleiss.

If these genetic findings hold up, she added, they might help to predict which babies with brain injury might be at greater risk of poorer long-term outcomes.

“At the moment it is very difficult to predict from one baby to the next what will happen,” said Fleiss.

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And there could even be treatments. The team found that by injecting mice with nanoparticles carrying a substance that blocks the damping down of the Wnt pathway, they were able to reverse the activation of the microglia. This was linked to an improvement in the development of the insulating sheath around neurons and, it would seem, a reversal in memory problems triggered by the inflammation.

While premature births are often unexpected and so a drug could not necessarily be given in pregnancy, the team said it might be possible to give a drugs to premature babies after birth to limit damage from inflammation. “Even if some of the injury will have occurred, there is still injury happening [after birth] and things progressing in the brain,” said Fleiss.

However, there is still some way to go. “We think we are five to seven years away from this being a clinically applied therapy,” she said.

Neena Modi, professor of neonatal medicine at Imperial College London praised the work but was cautious. “It’s a study that has identified one potential pathway to reduce brain injury caused by inflammation,” she said. “It is important to a mechanistic understanding and a good study but it’s a very, very long step from here to achieve benefit for human babies.”



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