Sci. Aging Knowl. Environ., 27 October 2004
Stuck in the Skin
Blood fats waylay immune cells
Like Paul Revere on his midnight ride, immune cells that encounter intruders rush to alert other defenders. But the skewed proportions of blood fats characteristic of atherosclerosis can hobble the cells, according to new research. A particular protein releases the cells, suggesting a possible way to derail atherosclerosis.
When immune scouts called dendritic cells detect a pathogen or irritating compound, they grab a sample and hightail it to the nearest lymph node, rousing other immune cells to counterattack. However, the immune system behaves paradoxically during atherosclerosis. Mice and people with plaque buildup often develop skin inflammations, indicating a robust immune response, but they battle pathogens feebly. Other work also connects dysfunctional immunity and fat accumulation. Patients with autoimmune diseases often have unusually large amounts of LDL, the "bad" form of cholesterol, and small quantities of HDL, the "good" one. To probe the connection, cellular immunologist Gwendalyn Randolph of Mount Sinai School of Medicine in New York City and colleagues wanted to determine whether the fat-carrying conglomerations alter dendritic cell movements.
The researchers studied mice engineered to lack ApoE, a protein that helps transport and process lipids. Like atherosclerosis patients, the rodents have large quantities of LDL and small amounts of HDL, and they amass fatty plaques in their arteries. As the animals aged, their skin grew thick and spongy, a sign that their dendritic cells promoted inflammation. The team dabbed the rodents with a mixture that irritates the skin. In response, far fewer dendritic cells exited the skin in the ApoE-deficient mice than in controls. Increasing HDL concentrations eases atherosclerosis, so the researchers tested dendritic cell migration in mice that lacked ApoE but pumped out extra HDL. Almost as many dendritic cells emigrated as in genetically unaltered control animals. HDL totes a protein called PAFAH that helps sop up lipids damaged by oxidation, which accelerate atherosclerosis. Injecting ApoE-deficient rodents with PAFAH boosted the number of dendritic cells leaving the skin. Cells remained imprisoned when the researchers used an inactive form of PAFAH. Oxidized lipids might exert their effect because they mimic another inflammation-promoting compound that builds up during atherosclerosis and tells cells to stay put, the researchers conclude.
"The work suggests that the sentinels in our immune system are systemically thrown out of normal order in atherosclerotic disease," says Randolph. She and her colleagues had previously shown that immune cells called monocytes, which can become dendritic cells, tarry in plaques and worsen atherosclerosis (see "The Thing That Wouldn't Leave"). The new results might explain why the cells linger. The rise in oxidized lipid quantities might trap cells in the plaque, just as it stalls similar cells in the skin, Randolph says. Moreover, hiking PAFAH and HDL to neutralize the lipids might set these cells free and shrink plaques.
People have ignored the issue of how excess lipids affect immune system function, says immunopathologist David Katz of University College London. "This paper is a good example of why you can't." Further research should probe whether statins, which lower cholesterol quantities, influence immune cell movements, he says. Some evidence hints that the drugs increase cell mobility, so they might help dislodge cells from plaques. The key to fighting atherosclerosis might be getting immune cells moving again.
October 27, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150