Glycolytic enzymes play important roles in innate immune memory of neuroimmune responses triggered by systemic inflammation

The brain is often imagined as a fortress, sealed off from the rest of the body to protect its delicate circuits. Yet, this barrier is not impenetrable. When the body suffers a severe infection or undergoes major surgery, the resulting inflammation can ripple across the blood-brain barrier, alerting the brain's resident immune cells. These cells, known as microglia, act as the brain's first responders. In a healthy state, they patrol quietly, but when triggered by outside threats, they spring into action to clear debris and fight infection. For decades, scientists believed that once the body's inflammation subsided, the brain would return to its calm baseline. However, a growing body of research suggests that the brain may remember these attacks long after the body has healed, a phenomenon known as innate immune memory. This memory can sometimes be a double-edged sword, leaving the brain in a state of heightened alert that might contribute to long-term cognitive issues or anxiety.

A new study from researchers at The University of Hong Kong and The Hong Kong Polytechnic University investigates exactly how this memory forms and persists. The team focused on the hippocampus, a seahorse-shaped region of the brain critical for learning and memory. They wanted to understand what happens inside this region after the body experiences systemic inflammation, and whether a second bout of inflammation changes the outcome. By observing mice, they discovered that the brain does not simply return to normal after an inflammatory event. Instead, the immune cells within the brain undergo a fundamental shift in how they produce energy. This metabolic change appears to be the engine driving a prolonged state of inflammation that can last for weeks, long after the initial trigger has vanished.

The researchers induced inflammation in mice using two different methods: a sterile surgical procedure that mimics the stress of major surgery, and an injection of a bacterial toxin that mimics a severe infection. They then tracked the mice for two weeks. They found that within days, the microglia in the hippocampus became activated, changing their shape and releasing signals that indicated a state of alarm. Crucially, this activation did not fade away. Even fourteen days after the inflammation had resolved in the body, the brain's immune cells remained in a state of dysfunction. The cells looked worn out and damaged, a condition the researchers described as senescence, where they lose their ability to function properly. When the mice were subjected to a second inflammatory challenge, the response was even more severe, with the brain showing signs of heightened anxiety and reduced movement, suggesting that the initial event had "trained" the immune system to overreact.

To understand why the brain remained in this agitated state, the team looked at the fuel the immune cells were using. Normally, cells burn sugar through a process called the tricarboxylic acid cycle to generate energy efficiently. However, the researchers found that after inflammation, the microglia switched to a different, less efficient method called glycolysis. This shift is similar to a car engine suddenly switching from a smooth highway cruise to a high-revving, fuel-guzzling mode that produces more exhaust. In the brain, this switch meant that the cells were burning sugar rapidly but failing to process it fully. This metabolic imbalance caused significant damage to the mitochondria, the tiny power plants inside the cells, and led to breaks in the cells' DNA. The damage was so severe that it triggered a cycle where the cells continued to release inflammatory signals, keeping the brain in a state of chronic alert.

The study also revealed that this internal damage attracted new immune cells from the bloodstream. The researchers observed that the damaged microglia and the broken DNA they released acted like a beacon, drawing in monocytes and macrophages from the body to enter the brain. These new arrivals joined the existing immune cells, further fueling the fire of inflammation. The team noted that this process was not just a passive reaction but an active, sustained response driven by the metabolic changes within the cells. The more the cells struggled with their energy production, the more damage they accumulated, and the more they signaled for help, creating a self-perpetuating loop of neuroinflammation.

To test if they could break this cycle, the researchers used a specialized virus to deliver a genetic tool directly into the brain. This tool was designed to lower the activity of a key enzyme that drives the glycolytic switch in the microglia. By dialing down this enzyme, they forced the cells to stop the inefficient energy production and return to a healthier metabolic state. The results were striking. When the glycolytic shift was suppressed, the damage to the mitochondria and the DNA breaks largely disappeared. The immune cells stopped looking worn out, and the influx of new inflammatory cells from the body was reduced. The brain began to resolve the inflammation, returning to a state closer to normal.

The findings suggest that the key to preventing long-term brain inflammation after a systemic illness might lie in managing how immune cells produce energy. The researchers found that simply reducing the overactive glycolysis in the microglia was enough to stop the cascade of damage. Interestingly, they also observed that while the cells were producing less of a byproduct called lactate, the remaining lactate seemed to interact with the cells' DNA in a way that might actually help repair them, though this mechanism requires further study. The study did not claim to have found a cure for all brain conditions, but it provided a clear map of the mechanism: systemic inflammation triggers a metabolic switch in brain immune cells, which causes cellular damage and recruits more immune cells, leading to a sustained inflammatory state that can be reversed by correcting the metabolic error.

This work offers a new perspective on why some people experience cognitive decline or anxiety long after recovering from a severe infection or surgery. It suggests that the problem is not just the initial attack, but the lingering metabolic state of the brain's immune cells. By identifying the specific enzymes that drive this harmful energy shift, the researchers have pointed toward a potential therapeutic target. If doctors can one day intervene to prevent or reverse this metabolic switch, they might be able to stop the brain from getting stuck in a state of inflammation, protecting memory and mood from the long shadow of systemic illness. The study confirms that the brain's immune system is capable of remembering trauma, but it also shows that this memory is written in the language of metabolism, a language that can potentially be rewritten.