The accumulation of macrophages (red) in arterial plaques (top) is reduced by inactivating the IL-6 receptor gp130 (bottom).

Liver-secreted inflammatory proteins and thickened arteries are two harbingers of heart disease. Luchtefeld et al. (page 1935) now find a cause-and-effect link between these risk factors. Their study shows that the pathway to inflammation amplifies plaque build-up in the arteries.

Plaques are a consequence of high dietary cholesterol, which gloms onto arterial walls. Macrophages ingest the fat, die, and further harden the area into plaque. This condition, known as atherosclerosis, is associated with high levels of inflammatory cytokines such as interleukin (IL)-6. Liver cells activated by these cytokines release “acute phase” proteins (APPs), which are markers of heart disease.

When released during an immune response, however, APPs have an immediate benefit. They trigger the complement cascade and recruit macrophages to the inflamed areas. These events help clean up infection and injury—situations that require a strong, swift response. But APPs can cause a lot of damage if they are perpetually present, as seen in patients suffering from arthritis or lupus. These chronically inflamed individuals also suffer from atherosclerosis and are at high risk for heart failure.

Luchtefeld and colleagues now reveal the mechanism that links chronic inflammation to heart disease: APPs seem to amplify plaques by attracting macrophages. The team inactivated the IL-6 receptor, gp130, in mice that are genetically predisposed to atherosclerosis. The mice thus had fewer APPs. Even on a high cholesterol diet, these animals had smaller plaques that contained fewer macrophages. Normally, cells in the plaque lure more macrophages by secreting the chemokine CCL2. But without APPs, this chemokine was not produced.

The continuous triggering of gp130 might also worsen cardiac health in humans. The authors tracked genetic variations in the human gp130 homologue IL-6ST in families with a history of heart disease. They found that individuals who had developed coronary plaques carried the same IL-6ST allele. Screening for IL-6ST polymorphisms might thus allow for the early identification of those who are predisposed to coronary artery disease.