Immune cell plays good cop, bad cop

Talk about a mixed blessing. A pair of new studies shows that immune cells known as macrophages can do an injured neuron good, or can impart further harm.

As the real estate axiom about location predicts, the outcome partly depends on where the neuron is injured. A neuron that controls motion or feeling starts out in the brain, runs down the spinal cord and eventually connects with muscles, skin or other organs.

If the neuron is wounded in the portion located in the brain or spinal cord (known as the central nervous system) macrophages can prevent regeneration, a new study in the Sept. 17 Journal of Neuroscience shows. But if the injury occurs in other parts of the body (the peripheral nervous system) macrophages help heal the hurt, a second study in the same issue of the journal demonstrates.

Although a single neuron traverses the central nervous system and ends up in the peripheral nervous system, conditions between the two are very different. “We’re really talking about two different biologies,” says Jerry Silver, a neuroscientist from CaseWestern ReserveUniversity in Cleveland who led one of the studies.

Injured neurons regenerate by reconnecting long projections called axons to the muscles, nerves or other organs to which the axons were originally attached. Macrophages can either help axons regrow or can attack, causing the neuron to retract the axon, the studies show.

“Those are seemingly contradictory results, but they’re really not,” says Phillip G. Popovich, a neuroimmunologist at OhioStateUniversity in Columbus. He was not involved in either study, but for many years has investigated the role immune cells play in regenerating nerve cells. “People like to think of these as black and white responses, but it’s not that simple.”

One critical measure of whether a macrophage will wear a white hat or a black hat is whether the cell has been activated by inflammation-promoting chemicals. Activated macrophages race to the scene of an injury to clean up debris and stand guard against microbes that try to infect the wound.

“These cells can do some good things when they are properly activated,” says Steve Lacroix, a neuroimmunologist at LavalUniversity in Quebec City, Canada.

When a neuron is injured, debris from the cell is scattered like shrapnel in the wound, blood and inflammatory chemicals spill in and immune cells come running. The chemicals and debris may stop axons from growing for a short time, but after about two months, neurons in the peripheral nervous system are usually healed. Lacroix and his colleagues investigated how macrophages influence the regeneration of the sciatic nerve, a peripheral neuron, in mice.

The researchers genetically engineered mice so that the animals would not make a subset of macrophages and some other types of immune cells. Then the scientists crushed part of the sciatic nerve in the mice’s legs. After about seven weeks, normal mice recovered fully, but mice lacking some macrophages didn’t get better.

Macrophages are needed to remove the molecules that inhibit axon growth, the team found. The researchers also discovered that the immune cells secrete factors that help axons grow, and that macrophages are important for the formation and stabilization of blood vessels.

“The basic biology of showing that the macrophage is a good guy in the periphery is really clear and outstanding,” says Silver, of Lacroix’s study. Silver’s group found that, in the central nervous system, macrophages are “bad guys.”

Previous work in Silver’s lab also indicated that macrophages support the regeneration of axons of peripheral nerves, so he and his colleagues were surprised to see the immune cells attacking injured axons in the spinal cord.

In the central nervous system, when an axon is crushed or cut, support cells called astrocytes immediately begin building a wall around the wound. The wall is composed of chemicals called proteoglycans. But those chemicals, in addition to protecting the wound, also stop axons in their tracks.

“They really, really struggle for days, but they can’t move forward,” Silver says. The axons also don’t retreat.

Immediately after an injury, resident macrophages in the spinal cord, known as microglia, begin clearing debris and fending off invading microbes. But after a few days, much more aggressive macrophages from the blood supply begin pouring into the wound site. Scientists used to think that substances given off by the immune cells caused injured axons to retract. But Silver’s team found that the “angry” macrophages from the blood actually latch on to struggling axons and make them retreat.

“Something (in the axon) says ‘I’m sick. I’m struggling,’ and the macrophages attack it. They do their jobs,” Silver says. “The macs really, directly, cause this phenomenon.”

Stopping this “mac attack” may be a key to regenerating spinal cords after injury, Silver says. That might be accomplished, for example, by modulating the level of macrophage activity or by giving axons chemicals that will induce them to grow. Less angry macrophages don’t attack axons and even riled-up immune cells leave growing axons alone, Silver’s team found.