Researchers at the Medical College of Georgia at Augusta University published new findings in JCI Insight that revealed there are increased levels of immune cells called innate lymphoid cells (ILCs) in the brain which promote inflammation that can worsen brain damage for up to a year following a traumatic brain injury. The researchers also report that the cell energy sensor AMPK is a brake that can stop what becomes a chronic state of destructive inflammation driven by these ILCs.
According to Dr. Krishnan Dhandapani, a neuroscientist with the Department of Neurosurgery at the Medical College of Georgia at Augusta University, “We think ILCs are kind of a master regulator of all that inflammation happening within the brain. It's like the thermostat in the room."
Dr. Babak Baban, immunologist and associate dean for research in the Dental College of Georgia at AU says “It's not just in TBI, it's in arthritis, Alzheimer's, you get this positive feedback loop of tissue damage which leads to inflammation which leads to more tissue damage and more inflammation. That is what we are trying to break."
Researchers used the common diabetes drug metformin to turn up AMPK, a crucial enzyme for maintaining sufficient energy inside cells, which restores a healthier balance between the three known subtypes of ILCs.
The scientists involved with the study say TBI is a worldwide public health issue, killing or debilitating at least three million people each year. About one-third of patients hospitalized with a TBI pass away from brain damage that occurs weeks or months after suffering the initial injury. TBI survivors also have an increased risk of dementia and cognitive decline. While ongoing inflammation in the brain parallels the ongoing damage and loss of function, standard anti-inflammatory therapies don’t help to really improve patients’ outcomes. Researchers say that therapies that target and decrease sources of increased inflammation following a TBI, such as the ILC subtypes ILC1 and ILC3 are needed.
Within a day of injury, researchers observed increases in all three ILC subtypes in the meninges of the TBI model. The meninges is the covering of the brain and spinal cord. Researchers also found that ILC2 and ILC3 levels remained higher a year after the injury, along with chronic inflammation and a 50% reduction in activation of AMPK. Researchers also observed ongoing problems with energy use.
Similar patterns of increased proinflammatory ILCs were found in the dura and the cerebral spinal fluid of patients who suffered a moderate to severe TBI. These patients needed a decompressive craniectomy to relieve pressure on their brains. Patients with hydrocephalus had lower levels of ILC cerebrospinal fluid.
When researchers completely removed the "brake" AMPK from their model, the problems grew worse. The biggest increases in the proinflammatory subtypes resulted in relentless inflammation and death. When researchers delivered metformin directly into the cerebrospinal fluid to target ILCs and instead activate AMPK, it expanded the overall pool of ILC subtypes, and inhibited the two inflammation-producing subtypes, resulting in the mice exhibiting improved movement and behavior.
According to Dr. Baban, AMPK is a switch that metformin is known to flip. “It drives everything back toward these counter-inflammatory ILC2s. It brought the seesaw back under control," said Dhandapani.
Babanaslo says a severe attack like a TBI can take the body years to get inflammation under control and restore homeostasis. The severity of the injury is a major factor in how long it takes to restore balance. "We want to bring it out of the chronic mode," said Baban. Researchers believe it’s the ILCs in the protective, three-layer meninges that respond to the 911 call a TBI triggers that can achieve this. The researchers’ findings also likely apply to other serious brain injuries like strokes.
If you or a loved one have suffered a traumatic brain injury, then please speak to a seasoned lawyer at Scarlett Law Group about what we can do to help you recover maximum compensation for your damages. Call (415) 688-2176 to request a free initial consultation.