No effective therapy exists today for sepsis, an inflammatory storm that afflicts about 3 million Americans a year - killing up to half. But now, investigators at Mayo Clinic's campus in Florida have identified a key molecule that, in mice, helps protect the body's central nervous system against the runaway inflammation.
Based on that discovery, published in Molecular Psychiatry, Mayo scientists are now on the hunt for an agent that pumps up that protective response against sepsis in humans and determine downstream pathways that can be augmented to prevent further central nervous system damage.
"Sepsis most often develops in the youngest and the oldest of us, when the immune system can respond abnormally," says the study's senior investigator, John Fryer, Ph.D., associate professor, Department of Neuroscience, at Mayo Clinic's Florida campus. "By discovering a protein that keeps the central nervous system inflammatory response from sepsis in check, we now have a path to finding or developing a targeted agent that may substantially lower the high toll experienced every year from sepsis."
A bacterial infection that sets off an overactive immune response is often the reason that sepsis develops, Dr. Fryer says. And while up to half of affected patients survive, many experience acute delirium and have substantially increased risk of long-lasting cognitive and behavioral impairments, he says.
"Few people realize how prevalent sepsis is and what a devastating immune reaction it causes. Our goal is to help the immune system react properly, and our discovery offers us an exciting prospective avenue for therapy," says Dr. Fryer, who is also assistant dean of the Mayo Clinic Graduate School of Biomedical Sciences.
Scientists who have studied the protein identified in the study — lipocalin-2 — may be surprised to learn that it is not the villain some investigators believe it to be, he adds. "There has been the suggestion that lipocalin-2 is a neurotoxic molecule. We find it, in the right context, not to be not toxic at all, but highly protective."
To conduct the study, Mayo Clinic investigators used a mouse model of sepsis to look at cytokines present in the central nervous system during sepsis. Cytokines are small proteins important for cell signaling.
Of more than 100 different cytokines, they found that lipocalin-2 was the most substantially elevated in the central nervous system as sepsis developed. To test the role of this molecule in the disease, researchers used a mouse without lipocalin-2 (a mouse in which the gene that produces lipocalin-2 is deleted) and found significantly higher levels of pro-inflammatory proteins and significantly worsening behavioral side effects. Investigators then validated their finding that lipocalin-2 was key to mediating inflammation in sepsis through a genetic analysis that revealed a number of anti-inflammatory pathways that were being controlled by this molecule.
There are two potential clinical uses of this discovery, according to Dr. Fryer. One is that lipocalin-2 could be a marker for sepsis — meaning that it may be possible to test for lipocalin-2 in patients to see whether sepsis is developing. The other use is as an agent that boosts lipocalin-2 levels or augments its function in the brain may prevent central nervous system damage and cognitive impairments that occur after sepsis-like conditions, he says.
"We are combing the National Institutes of Health's (NIH) clinical collection of currently approved drugs to see if any work like lipocalin-2, and we are also screening drug libraries of novel compounds," Dr. Fryer says. "We are also trying to understand the detailed molecular mechanism underlying the protective effect of lipocalin-2 in this context."
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