Mechanism Behind Increased Risk of Heart Disease in Autoimmune Patients Discovered
Patients with autoimmune diseases — such as psoriasis, lupus, and arthritis — tend to accumulate collagen, a connective tissue protein, in their blood vessels, which traps cholesterol in arteries and heart tissue, a mouse study has found.
These findings begin to explain why these patients have a significantly higher risk for heart disease, and suggests that blocking the interleukin 17 (IL-17) molecule — the main driver of this mechanism — could reduce the likelihood of heart problems in these patients.
The study, “Interleukin-17 Drives Interstitial Entrapment of Tissue Lipoproteins in Experimental Psoriasis,” was published in Cell Metabolism.
Autoimmune patients have a higher risk of heart disease even when their condition does not target the heart directly. This suggests there is an underlying mechanism that links autoimmunity with heart conditions, but little was known about it until now.
Using a mouse model for psoriasis — an autoimmune disease characterized by skin inflammation, rash, and skin thickening — researchers in this study have now gained some understanding of this mechanism.
One of the principal causes of heart disease is atherosclerosis, the accumulation of cholesterol in the arteries. Cholesterol is transported out of the organs and into the bloodstream by special fat molecules called high-density lipoproteins (HDL). Impaired transport of HDL leads to cholesterol accumulation.
Using a new tool capable of tracking HDL traffic in different tissues, the researchers studied the relationship between psoriasis and cholesterol accumulation.
They found that diseased mice accumulated HDL in their tissues instead of sending it to the bloodstream. This was related to an increased production of collagen, a fibrous molecule that forms a web-like structure and helps support the cells under normal conditions. When produced in higher amounts, the web trapped smaller molecules, such as HDL.
“In psoriasis mice, most of the HDL particles were trapped in the skin and collagen was accumulated. The increase of collagen was also observed in the heart and arteries leading to vascular stiffness,” senior author Gwendalyn Randolph, PhD, a professor at the Washington University School of Medicine in St. Louis, said in a press release.
Increased collagen production was mediated by IL-17, an inflammatory molecule elevated in psoriasis and lupus.
“The skin-driven immune response can drive systemic changes,” Randolph said. “Once immune cells are programmed by reactions to the inflamed skin, they move around the body to other skin sites and arteries to be ready for the next insult, enhancing the collagen density wherever they go.”
Feeding the mice with the psoriasis-like condition a high-cholesterol diet led to the formation of higher cholesterol deposits than in non-affected mice. However, inhibiting IL-17 restored HDL transport and reduced cholesterol accumulation, collagen production, and cell stiffness.
“For decades it’s been known that the trapping of cholesterol drives disease, and now we have a mechanism for how certain immune responses typical of autoimmune diseases might make that worse,” Randolph said. “In the mouse, the signs of cardiovascular disease scarcely arose when we neutralized these immune components. In people, it’s hard to be sure, but we would predict it would be preventable, too.”
These results suggest that therapies targeting IL-17 might help reduce the risk of heart disease in autoimmune patients. These treatments already exist and are used to treat psoriasis — Cosentyx (secukinumab) and Taltz (ixekizumab).
“It’ll take a few years before we know for sure, but we predict that the anti-IL-17 antibodies that already are being used to treat autoimmune diseases will be effective at reducing the risk of cardiovascular disease,” Randolph said. “This would be important because some other drugs on the market seem to improve the skin disease but not reduce cardiovascular risk.”