HARVARD GAZETTE ARCHIVES

Charles Serhan and his colleagues have discovered that white blood cells, left over from defending the body against invading bacteria and viruses, scavenge harmful compounds from the body as they themselves commit suicide. He holds a model of molecules involved in the process. (Staff photo Jon Chase/Harvard News Office)

When you're fighting flu or any other infection, your body mobilizes battalions of cells to defend against the invading viruses or bacteria. But once the invaders have been defeated and you've recovered from aches, fever, headaches, and a sore throat, your body has to get rid of the now-unneeded fighting cells. If left alone, they can attack healthy tissues.

One way to muster them out is signaling them to commit suicide. Sounds cruel, but it's a natural protective process called "apoptosis." It is the same strategy that the human immune system uses to get rid of tumor cells.

But the old soldiers don't go peacefully. Researchers at the Harvard Medical School have discovered that, on their way out, they grab onto and remove chemicals that would otherwise promote inflammation. Said another way, they keep the body from attacking itself.

"Failure to clear the apoptotic white blood cells can result in a lupus-like syndrome and accelerated atherosclerosis," notes Charles Serhan, Simon Gelman Professor of Anaesthesia and leader of the research. In lupus, the immune system attacks the body's connective tissues; atherosclerosis leads to clogged or narrowed blood vessels.

Serhan, working with Amiram Ariel, a research fellow, and other collaborators at Brigham and Women's Hospital, Boston University, and Massachusetts General Hospital, found that the dying cells carry a protein on their surface that permits them to bind to and remove harmful chemical leftovers. The team demonstrated this previously unknown function in rabbits, mice, and cells from humans.

The suicide process increases the amount of scavenger protein that is carried by dying soldier cells. The scavengers in turn are engulfed and cleared out of the body by bigger cells known as macrophages.

Active not passive

When Serhan and his colleagues started researching how inflammation ends and the body gets back to normal, textbooks were writing it off as a passive process. But the researchers looked more closely at what actually happens, they found more and more evidence that ridding the body of spent soldier cells is a very active event. That realization led the team to work on which cells and receptors are actually involved in the clean-up operation and how they go about their work.

"We learned about the existence of then-unknown compounds - agonists - that grab onto and remove inflammatory chemicals that otherwise would attack healthy cells," Serhan explains. "We called them 'resolvins' and 'protectins,' because they resolve inflammation and protect healthy tissues. Then we investigated how these resolvins and protectins stimulated the mopping up of dying immune cells so they could be cleared out by macrophages."

By the beginning of October, the team had learned enough to publish in the journal Nature Immunology how the beginning steps of inflammation dictate, in many respects, the program that is activated to help bring inflammation to its end and tissues back to normal.

"So far, we've only done this work on isolated cells and fluids from humans with inflammatory disorders such as diseases of the gums and erosion of the bones holding teeth," Serhan notes. "What we found is a new approach that will allow us to create new drugs that will hasten the end of inflammation by using this natural clean-up system. Based on these findings, I think that pharmaceutical companies will be investigating ways to stimulate the resolution of inflammation as a new means to control many chronic inflammatory diseases in humans, such as rheumatoid arthritis.