Sci. Aging Knowl. Environ., 4 August 2004
The Thing That Wouldn't Leave
Immune cells that flock to fat-laden blood vessels stay when they should go
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2004/31/nf72
Like party guests who drink too much and crash on the couch, immune cells overstay their welcome in fat-laden blood vessels, new work reveals. The cells loiter in cholesterol-laden arterial plaques and cause the lesions to grow. Researchers have known that the cells flock there, but the study reveals that once they arrive, they don't leave.
Atherosclerosis develops when damaged lipids accumulate in blood-vessel walls. These molecules attract white blood cells called monocytes, which help form plaques and spur inflammation. As a result, the lesions grow. A heart attack strikes if a plaque ruptures, triggering clot formation. Researchers have focused on understanding why immune cells congregate in blood vessels, but immunologist Gwendalyn Randolph of Mount Sinai School of Medicine in New York City and colleagues wondered whether plaques also worsen because immune cells linger.
To investigate, the researchers devised an artificial blood-vessel system. In a culture dish, they reared human blood vessel cells on a layer of the connective-tissue protein collagen. The cells would have to cross a similar layer to infiltrate a vein or artery. The scientists put human monocytes atop and gave the cells time to slither through. Then they counted the number of monocytes on the underside. Forty-eight hours later, half of these monocytes had migrated back to the top. In a separate experiment, the researchers waited until the monocytes had crossed the collagen layer, and then they added chemicals that mimic damaged lipids and that provoke atherosclerosis in animals. Half as many immune cells reemerged, compared with untreated samples. The finding suggests that atherosclerosis progresses because monocytes don't vacate plaques.
To test the idea in animals, the team raised genetically altered mice that amass plaques. These rodents' monocytes carry a particular version of a cell-surface protein. The researchers then transplanted sections of fat-laden aorta from those animals into mice whose cells display a different version of the protein. By looking in various tissues for monocytes with the donor's flavor of the marker, the scientists could track the meanderings of plaque monocytes. After normal animals received the transplant, the fatty deposits receded and monocytes from the donor animal appeared in the recipient's lymph nodes, which collect white blood cells returning from tissues. But after plaque-prone mice underwent the surgery, far fewer donor monocytes piled up in lymph nodes, and the plaques grew. Together, the results link atherosclerosis with trapped monocytes. Drugs that prod monocytes to leave blood vessels might help alleviate atherosclerosis, says Randolph, but first researchers need to identify the signals that keep cells there and the exit paths that cells take.
Scientists have kicked around the idea that monocytes get stuck in blood vessels, but "it's the first time that's been shown in a whole animal," says cell biologist Thomas McIntyre of the Cleveland Clinic Foundation in Ohio. Marred lipids tickle a cell's insides through two molecular routes, says molecular biologist Gabor Tigyi of the University of Tennessee, Memphis. Future work should address which of these avenues influences monocyte emigration. Further understanding of what makes monocytes wear out their welcome might help researchers devise therapies that encourage them to call it a night.
August 4, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150