What happens if an injury becomes inflamed? Inflammation is one way the body deals with invading germs and contamination, but oh boy, can it be unpleasant. Imagine falling off a bike and letting that scraped knee fester. Pain, pus, lots of bandage changes, and possibly a gnarly scar all ensue. In short, acute inflammation can be painful.

But inflammation can also help repair injured tissue! And it’s not just a scraped knee regrowing skin. Scientists have discovered that immune cells – key players in the inflammatory response – drive regeneration of the optic nerve, which connects each eye to the brain. 

In a mind’s eye

The optic nerve is a really important bundle of nerve fibers that connects our eyes with our brain. Like all nerves, it shoots electric impulses that code for information. Specifically, the optic nerve carries information about what we see with our eyes and sends it to regions of the brain that make sense out of it.

But what happens if an optic nerve gets injured, such as after a blunt trauma to the head? Unfortunately humans cannot regenerate their optic nerves and thus will permanently lose their eyesight. But there are creatures that can easily regenerate this nerve called zebrafish.

Zebrafish are tiny gray-ish fish, smaller than your thumb, with an amazing superpower – the ability to regenerate their organs. Zebrafish can repair their injured hearts, brains, fins, and many other organs. Because of this, scientists often study them to understand how regeneration works. 

A Belgium-based team of biologists utilized these fish and set out to understand how inflammation affects regeneration of the zebrafish optic nerve. The scientists knew that zebrafish could regenerate injured optic nerves perfectly well. But they were unsure how immune cells and inflammation raging behind the zebrafish’s eyes would affect this regeneration.

To investigate this, the researchers triggered an inflammatory response in zebrafish by injecting their eyes with zymosan – a substance that tricks the immune system into thinking there’s an infection and zaps it into action. They then crushed the optic nerves behind the zebrafish eyes and waited for the nerve connections to try and repair themselves (Figure 1).

Figure 1: Zebrafish Optic Nerves. The scientists severed an optic nerve that connected one of the zebrafish eyes to the brain, and waited for the nerve to regenerate. Image created with BioRender.com

Six days after crushing the nerves, the scientists injected a special dye behind the eyes of the fish, soaking the optic nerve endings at the injury site. If the optic nerve is repaired and intact, it will transport the dye from the eye to the brain – like a bridge that lets cars travel from one side to the other. The scientists found that the dye had fully traveled to the fish brains, confirming that the optic nerve had successfully regenerated.

Immune cells and nerve regeneration

The researchers then wanted to know how immune cells participated in this regeneration. They focused on two important types of immune cells: microglia and macrophages. Microglia are the immune cells that reside in the central nervous system (which includes eyes and the brain). After an injury, they scout nerve cells for bits of debris and clean them up. Macrophages are immune cells that travel in blood vessels throughout the body, patrolling it for signs of trouble. 

Normally, crushed optic nerves would mobilize microglia and macrophages into action. But the scientists wanted to see how injured optic nerves would recover in their absence. To do this they injected the zebrafish with drugs that curbed both microglia and macrophages and dampened the immune response.

Without macrophages or microglia hovering around, the optic nerves didn’t regenerate well. They did grow back with reluctance, but only half as well as the optic nerves in zebrafish with intact immune responses. This means that immune cells have the ability to push the optic nerves to regenerate. But is it macrophages or microglia that hold the key to regeneration?

To answer this question, the scientists crushed optic nerves in genetically engineered zebrafish without any microglia in their eyes and brains. However, circulating macrophages from the blood were still free to invade the injury site, allowing the researchers to study how macrophages alone affected regeneration of the optic nerve.

In these fish, the researchers saw something completely unexpected. This time, zebrafish lacking microglia, but not macrophages, regenerated their optic nerves much better than regular fish. Infiltrating blood macrophages got to work at the injury site, helping to fix the damaged optic nerve and reconnect it with the brain. 

Seeing the light

The scientists next strove to piece the puzzle together. They reconciled their results on the role of immune cells by suggesting that it is blood-borne macrophages – and not microglia – that help optic nerves regenerate. Without microglia, the zebrafish regenerated their optic nerves perfectly well. In fact, microglia may even hinder regeneration. But getting rid of macrophages in the zebrafish brought regeneration of the optic nerve to a screeching halt, suggesting a crucial role for these cells in the regeneration process.

Does this mean that immune cells, specifically macrophages, can help humans regenerate their own optic nerves after disease or trauma breaks them? 

Potentially! However, the immune response is a complicated affair, and damage to the optic nerve requires handling with utmost delicacy. But if scientists manage to untangle how exactly macrophages help nerves regenerate, then maybe we can see the day where a torn connection between the eye and the brain no longer means a lifelong loss of eyesight.