The choroid plexus, a small but essential structure in the brain, is best known for producing cerebrospinal fluid and acting as a barrier between the brain and the body. The choroid plexus also acts as a hub of immune activity. In mouse studies, when brain inflammation occurs, the epithelial cells lining the choroid plexus trigger an immune response. These cells not only recruit immune cells, but also temporarily open the barrier between the blood and the cerebrospinal fluid, allowing immune cells to enter the brain. The epithelial cells then support these immune cells as they fight off the infection. Once the job is done, epithelial cells reseal the barrier, restoring the brain’s protective layer. This discovery is the first evidence that the choroid plexus plays a role in immune defense.

*******************

The brain is home to a series of interconnected, fluid-filled chambers called ventricles. Within these chambers is the choroid plexus, a small coral reef-life structure producing the cerebrospinal fluid that flows through the ventricles and around the brain and spinal cord. The choroid plexus is comprised of a dense network of blood vessels surrounded by epithelial cells that form a tight, protective barrier known as the blood-cerebrospinal fluid barrier.

The choroid plexus is also home to a number of immune cells. Scientists have known that these immune cells, which originate from outside the brain, can enter the brain through the choroid plexus, but the mechanics of this process—and whether it is harmful or beneficial—were less clear. Due to imaging limitations, scientists only had snapshots at specific points along a timeline and not the full story of the process. However, recent advances in imaging technologies reveal, in real-time, how the choroid plexus of live, awake mice respond when faced with a bacterial meningitis-like infection in the brain. The choroid plexus acts as a sophisticated immune organ, carefully coordinating a stepwise response to inflammation, with epithelial cells orchestrating the process.

“The epithelial cells are the conductor of this whole symphony,” principal investigator Dr. Maria Lehtinen explains.

When the epithelial cells sense the infection, they send out chemical signals, akin to flares at the scene of an accident, to attract immune cells. Normally, these epithelial cells are tightly bound together to form the blood-cerebrospinal fluid barrier. However, in response to the infection, they release enzymes to temporarily break apart these bonds, allowing neutrophils, the body’s frontline defenders against infection, to flood into the cerebrospinal fluid.

Following this initial surge of neutrophils, the body recruits monocytes—a special type of white blood cell. Some of these transform into macrophages, which combat infection and help to repair tissue damage. What is particularly intriguing is that the macrophages came from both sides of the choroid plexus. Some were recruited from the bloodstream on the body’s side, and others came from the brain’s side.

Once the epithelial cells call the immune cells to the choroid plexus and into the cerebrospinal fluid to help, they produce all the nutrients necessary for the immune cells to thrive. “They’re like parents,” Dr. Lehtinen describes. “They initiate the response, but then they don’t leave the cells stranded. They nurse the whole thing along.”

The epithelial cells also produce a sticky velcro-like substance that allows the macrophages to adhere to the brain side of the choroid plexus. “The choroid plexus is in constantly flowing fluid,” lead investigator Dr. Huixin Xu explains, “If the immune cells are not attached, they’re going to be washed away like a branch in a running river.” This attachment keeps macrophages near where the choroid plexus opens its barrier.

After addressing the infection, the macrophages glued to the choroid plexus reseal the blood-cerebrospinal fluid barrier, while those within the cerebrospinal fluid clear out the remaining neutrophils, bringing the immune response to a close.

Not all epithelial cells within the choroid plexus drive this complex immune response. Using single-cell transcriptomics, specific regions where these responses were most likely to occur were identified and coined inflamed epithelial cells.

This study offers the first clear evidence of the choroid plexus’s role in immune function and the potential benefits of its controlled inflammatory response in the brain. “Thinking inflammation in the brain is good is a pretty recent concept,” Dr. Xu points out. “It’s not black and white that all immune responses are bad. It’s more like the right type of immune responses are essential and important to help the brain recover from the initial insult.”

Published in Cell

Maria K. Lehtinen, Ph.D., Boston Children’s Hospital/Harvard Medical School

Huixin Xu, Ph.D., Boston Children’s Hospital/Harvard Medical School

The choroid plexus synergizes with immune cells during neuroinflammation