A team led by LMU researchers Christian Weber and Yvonne Döring has demonstrated new mechanisms involved in the development of inflammatory cardiovascular diseases.
A chronic inflammatory disease of the inner walls of blood vessels, atherosclerosis is responsible for many cardiovascular diseases. Dendritic cells, which act to recognize foreign substances in the body and mount an immune response, play an important role in the disease. They produce the signaling protein CCL17, a chemokine, which affects the activity and motility of T cells, which locate infected cells in the body and attack pathogens. However, CCL17 may also promote cardiovascular pathologies. People who suffer from cardiovascular diseases or are particularly susceptible to such diseases, have increased levels of the signaling protein. In humans and mice, elevated serum levels of CCL17 are associated with an increased risk of atherosclerosis and inflammatory diseases of the cardiovascular and digestive systems. However, scientists have yet to figure out exactly how CCL17 produced by dendritic cells regulates T cells.
A study just published in the journal Nature Cardiovascular Research has elucidated important mechanisms in the signaling pathways involved. “We know from our previous work that a genetic deficiency or an antibody blockade of CCL17 prevents the progression of atherosclerosis,” says Professor Christian Weber, Director of the Institute for Cardiovascular Prevention at the University Hospital of Munich and one of the lead authors of the new paper. Until now, only one signaling receptor was known to contribute to T cell recruitment and functions. But if this receptor is missing, the body is not protected from the negative effects of CCL17, as Weber’s group was able to demonstrate in a study in mice. Mice lacking the receptor continued to have the same extent of CCL17-induced disease. If the signaling protein acted directly and exclusively on this receptor, then its silencing should have the same effects as the absence of CCL17.
Consequently, there must be another signaling pathway in which CCL17 is involved, and the researchers demonstrated and described just such a pathway during the new study. “We provide clear evidence that CCL17 acts through an alternative high-affinity receptor, thereby activating a signaling pathway that results in the suppression of anti-inflammatory, so-called regulatory T cells,” explains Weber’s colleague and first author Professor Yvonne Döring. These T cells will no longer be able to deal with vascular inflammation. By targeting and inhibiting individual receptors of the research signaling pathway during their experiments, the authors were able to show that this mechanism plays a key role in the negative effects of CCL17. Weber is convinced that this achieves an important step forward in the understanding of inflammatory diseases: “The reaction pathway we identified represents a highly relevant mechanism in chronic inflammatory diseases and could be an important starting point for a wide variety of therapeutic interventions” .