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Caught in a tight corner

München, 04/07/2015

Page 2/2: Provoking chronic inflammation

The monocytes differentiate into macrophages under the influence of cytokines like interleukin or interferon. Macrophages are “phagocytic” cells – they eat and digest dead cells, cell debris and excess fats. However, uptake of too much fat impairs their digestive function and can even kill them. As a result, distressed and deadcells, macrophages bloated with fat, accumulate, forming the plaque. The inflammation reaction eventually becomes chronic, as the growing plaque continues to send out distress calls in the form of biochemical signals, and the immune response goes into overdrive.

“The endothelium then summons the next wave,” says Weber, and here new signals attract a different class of immune cells, so-called dendritic cells, to the plaques. These cells have more specific targets in view. Dendritic cells instruct another set of immune effectors – so-called T-cells – to attack cells that express certain proteins in their surface membranes. They do so by themselves displaying fragments on their surfaces to which specific subsets of T cells bind. T-cell activation can also initiate antibody formation by so-called B cells. “Their function in the development of atherosclerosis is so far unclear“, Weber says. His own research on this phase focuses on the chemokine CCL17, which is secreted by certain dendritic cells. CCL17 is essential for the activation and maintenance of T-cells, but in doing so it can inhibit regression and resolution of the inflammatory reaction. “As a consequence, the inflamed cells and cell debris can never be fully disposed of,” says Weber. The plaques emulsify and cholesterol crystallizes, provoking a renewed burst of signaling.

However, there are some hopeful signs that this vicious circle can be broken. Weber and his colleagues have shown that the CCL17 produced by dendritic cells interferes with a self-regulating circuit that limits the local immune reaction – and thus enables the inflammation to persist. Weber believes that this mechanism offers a promising target for a therapeutic agent. “Using an antibody against CCL17, we have been able to arrest the progression of atherosclerosis in an animal model,” he says.

Without such interventions, the maladaptive inflammatory response ultimately runs out of control completely. Around the core of each plaque – made up of cell debris – macrophages and T-cells, both recent immigrants and the products of local cell division, continue to accumulate. And a physiological response which normally protects the organism by rapidly eliminating noxious substances that manage to penetrate the body’s natural barrier tissues, such as the skin or the mucous membranes of the gastrointestinal tract, threatens to destroy its host.

The primary goal of clinical researchers like Christian Weber is therefore to find ways to arrest this pathological cycle of reactions and restructuring processes – as early as possible – by, for instance, blocking the action of the relevant receptors or their chemokine ligands, thus preventing transmission and amplification of the potentially fatal signals. Weber has meanwhile identified another possible point of attack for such an approach. His team has shown for the first time that different chemokines can interact to form complexes. Moreover, one such complex produced by platelets is responsible for allowing immune cells to squeeze between endothelial cells into inflamed tissue, and thus furthers the development of atherosclerosis.

In his “Atheroprotect” project, which has received 2.5 million euros in funding from the European Research Council (ERC), Weber is investigating the biological significance of such interactions between chemokines further, hoping to uncover their possible roles in the fine-tuning of inflammation processes. “In my group, chemokines are our house-pets,” he says. “They mediate the relevant intercellular communication and recruit the various cell types involved in the whole process. The interaction between chemokines is actually my favorite topic. It is like a language; a sentence is made up of different words, but it only makes sense when taken as a whole.” Or one can think of it as a long phone number, consisting of a country code, an area code and the extension number. By interrupting the dialing sequence, as it were, it should be possible to stop the whole inflammation process. So Weber’s aim is to discover strategies and substances that allow the different signal molecules to be selectively inhibited or reactivated as required.

But that is not all he has in mind. Together with his coworker Andreas Schober, Weber demonstrated some years ago that so-called microRNAs in endothelial cells play an important role in the earliest phase of atherosclerosis. “MicroRNAs have a significant function in the regulation of gene activity“, Weber says. As the name implies, miRNAs are short fragments of single-stranded RNA. They are related to the longer messenger RNAs transcribed from the genomic DNA that direct protein synthesis, but they serve to inhibit the synthesis of proteins in a targeted fashion. Weber has shown that two of these RNA fragments, referred to as miR-126-3p and miR-126-5p, activate the repair of the endothelium following initial damage. In other words, they form part of a protective mechanism. In the absence of miR-126-5p, fatty deposits build up particularly in segments of the arterial tree where normal laminar flow is perturbed. As Weber and his colleagues recently reported in the journal “Nature Medicine”, a population of self-renewing endothelial cellss normally resides at these sites, which acts as a reserve supply to replace damaged and dysfunctional ones. Lack of miR-126-5p leads to loss of these precursors, and this exacerbates the impact of known risk factors, such as high fat levels. In a mouse model, the researchers demonstrated that miR-126-5p, encapsulated in nanoparticles, could be successfully delivered to the endothelial cells at these endangered points in the arteries – and slowed the progression of atherosclerosis.

Of course, there are also relatively simple behavioral ways to reduce risk. Give up smoking, be careful what and how much you eat, and don’t sit around all day. Although the effects of sporting activities have yet to be confirmed at the molecular level, numerous epidemiological studies support the beneficial impact of physical exercise. One of the latest shows that even periods of exercise lasting only for a few minutes can measurably reduce the risk of cardiovascular disease. “Short bursts of strenuous exercise seem to be more effective than half an hour of jogging,” Weber says, “though we don’t yet fully understand the underlying mechanism.” Seen in this light, sprinting up five flights of stairs 25 years ago wasn’t such a bad idea! Hubert Filser, Translation: Paul Hardy

weber_130Prof. Dr. med. Christian Weber is the Director of the Institute for Prophylaxis and Epidemiology of Cardiovascular Diseases and holds a Chair in Preventive Vascular Medicine at the Munich University Medical Center. Born in 1967, served as Professor of Cardiovascular Molecular Biology at the RWTH in Aachen, and holds a professorship at the Cardiovascular Research Institute at the Maastricht University in the Netherlands. In 2010, he was awarded an Advanced Grant by the European Research Council (ERC). In October he assumed the role of Spokesperson for the new Collaborative Research Center (SFB) 1123 funded by the DFG.

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