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An Inflammatory Theory of Brain Disease

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Though it may be going too far to call inflammation a grand unifying theory of chronic disease, the link between the two is a focus of labs around the world. “I do think inflammation is an important element, and maybe at the heart of a variety of disorders,” Meier says, “and does account for a lot of the comorbidity that occurs between disorders. Why on earth is there comorbidity between depression and heart disease? But once you start thinking about inflammation, you realize they may be both inflammatory disorders or at least involve an inflammatory element.”

In the last decade, interest in the relationship between inflammation and brain disease in particular has exploded. Tantalizing associations abound. For example, some population-based studies of Alzheimer’s patients suggested that people who took non-steroidal anti-inflammatories—so-called NSAIDs like aspirin or ibuprofen—for long periods have a reduced risk of developing Alzheimer’s. Low-grade systemic inflammation, as measured by higher than normal levels of certain inflammatory molecules in the blood, have been found in people with depression. And in children with severe epilepsy, techniques to reduce inflammation have succeeded in stopping their seizures in cases where all other attempts had failed.

The Brain’s Immune System

The key is the brain’s unique immune system, which is slightly different from the rest of the body. For starters, it’s less heavy-handed. “The immune system, during evolution, learned that, ‘This is the brain, this is the nervous system. I cannot really live without it, so I have to be very, very, careful,’” says Bibiana Bielekova, chief of the Neuroimmunological Diseases Unit at the NIH.

The first line of defense for the central nervous system is the blood brain barrier, which lines the thousands of miles of blood vessels in your brain. It is largely impermeable, for the most part letting in only glucose, oxygen, and other nutrients that brain cells need to function. This prevents most of the toxins and infectious agents we encounter daily from coming into contact with our brain’s delicate neurons and fragile microenvironment, preserving the brain’s balance of electrolytes—such as potassium—which if disturbed can wreak havoc on the electrical signaling required for normal brain function. Normally the blood brain barrier is very selective about what it invites inside the brain, but when the barrier gets damaged, for example because of a traumatic brain injury, dangerous molecules and immune cells that aren’t supposed to be there can slip inside.

The second line of defense are microglia, the brain’s specialized macrophages, which migrate into the brain and take up permanent residence. Typically, microglia have a spindly, tree-like structure. Their branches are in constant motion, which allows them to scan the environment, but also delicate enough to do so without damaging neural circuits. However, when they’re activated by injury or infection, microglia multiply, shape-shift into blobby, amoeba-like structures, release inflammatory chemicals, and engulf damaged cells, tissue debris, or microbes.

I'm not familiar with the word comorbidity.

Inflammation correlates with chronic illness but is it a cause or a symptom?

Microglia releasing inflammatory chemicals is a sobering thought. 

Microglia (please let the G be silent!) release inflammatory chemicals for the good, too.

Nope, the G is a hard G.

Wait, there are good inflammatory chemicals?!

Well, dammit.  A silent G would have been sublime.

On the dual nature of inflammation:

The microglia were acting like immune sensors,” says Chiu. They were surveying the tissue as an immune cell would roam in the blood circulation in search of a virus or bacterium. But there was no microbe. What were these activated immune-like cells doing?

Chiu turned to a technology called microarray analysis, which measures gene activity in cells, to see if he could determine what kinds of proteins the cells were making. He expected to see the microglia in ALS mice, as they got sicker, churn out progressively more toxic, pro-inflammatory agents. This would be a sign that the immune system was attacking motor neurons, as hypothesized. Shockingly, Chiu found the opposite: the activated microglia were damping down production of pro-inflammatory agents, while boosting production of protective growth factors.

“This went against the grain,” Carroll recalls. “The newest thinking at the time was that inflammation is actually causing injury in the central nervous system. But in this case, inflammation is protective.”

So small amounts of inflammation are an immune system protection response.

It's when inflammation persists that it becomes harmful because it puts the body in always-on-alert mode?

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