How the signaling proteins of the immune system regulate the development of atherosclerosis


Mouse that does not have the CD40L-CD40 axis of the dendritic T-cell. Credit: LMU Clinic

Medical researchers at the Ludwig-Maximilians-Universitaet (LMU) in Munich have discovered how signaling proteins in the immune system regulate the development of atherosclerosis.

Atherosclerosis is one of the most common causes of death in Germany. The condition is characterized by the accumulation of cholesterol and other fatty metabolites in the arterial wall directly below the endothelial cell layer, which is in direct contact with the bloodstream. This process results in constriction of the artery, which obstructs blood flow and can cause heart attacks and strokes. Atherosclerosis is usually treated with medications that reduce the concentration of lipids in the circulation, often using compounds called statins. However, statins effectively reduce the risk of cardiovascular disease in only 35 to 40% of treated patients. The remaining 60% do not respond to medication. This has led to the pursuit of other drug targets. Because atherosclerosis is associated with chronic inflammatory processes, the immune system may offer new therapeutic options to fight the disease. A group of researchers led by Professor Esther Lutgens and Dr. Dorothee Atzler of LMU Medical Center have now explained an important component of the immune reaction involved in atherogenesis.

Immunotherapy as a treatment for atherosclerosis

Lutgens and his team at the Institute for Cardiovascular Prevention (Director: Prof. Dr. Christian Weber) and the University of Amsterdam have now shown that the interaction between proteins called CD40L and CD40 represents a promising target for the suppression of atherosclerosis. The CD40L protein is synthesized and expressed on the specialized surface of the immune system. It is recognized by the CD40 protein, a membrane-bound receptor that is expressed on antigen-presenting cells. However, CD40L also binds to receptors in other cell types that have diverse physiological functions. Using a file , LMU researchers removed the CD40L gene specifically in T cells and platelets, as well as its counterpart, CD40, in dendritic cells. They then crossed these mice with a strain that is especially prone to developing atherosclerosis.

Interferon-gamma secretion by T cells is known to stimulate immune functions, but CD40L-deficient T cells were found to secrete less interferon-gamma than those in which the gene is intact. In addition, other experiments showed that in the absence of CD40L in T cells, the which were formed were smaller and more stable. This suggests that inhibition of CD40L could improve the stability of atherosclerotic plaques and therefore reduce the incidence of heart attacks induced by rupture of blood vessels.

Similar results were obtained in a mouse strain that was unable to produce CD40 in dendritic cells. Suppression of CD40L in platelets, in contrast, had no effect on the incidence of atherosclerosis, but was associated with a reduction in clot formation associated with atherosclerosis.

“Our results provide clear evidence of cell-type differential functions of the CD40L / CD40 interaction in the context of atherosclerosis, and this has implications for therapeutic strategies that focus on this signaling pathway,” says Lutgens. His group is now expanding its studies on the effects of CD40 and CD40L to others , with the aim of developing drugs that can inhibit the functions of these proteins in a specific way in cells. In principle, this could be done using small molecule inhibitors or bifunctional antibodies with different binding sites.

Discovery of new proteins with an important role in atherosclerosis

More information:
Michael Lacy et al, Divergent and specific functions of CD40L-CD40 axis cells in atherosclerotic vascular disease, Communications on Nature (2021). DOI: 10.1038 / s41467-021-23909-z

Citation: Cardiovascular disease: how immune system signaling proteins regulate the development of atherosclerosis (2021, July 6) recovered on July 6, 2021 at -proteins-immune-atherosclerosis .html

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