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Caught in a tight corner

München, 04/07/2015

Unrestrained immune reactions promote atherosclerosis. Clinical researcher Christian Weber is studying the web of molecular decisions that lead to this misdirected and potentially fatal response.

Photo: Hörhager/dpa

It’s almost 25 years ago now, but Christian Weber well remembers how he sprinted from the basement to the fifth floor of the Institute of Immunology in Munich, with blood dripping from the crook of his arm. Colleagues had taken a blood sample before he set off, and were waiting at the top to take another. “We wanted to measure the concentrations of different monocyte subtypes before and after stress, and find out where they came from,” he recalls. “At the time we had no idea how important these immune cells are in the development of atherosclerosis.” The pathogenesis of this serious disease remains a complex puzzle, but it is now clear that the recruitment and functions of various monocyte subtypes play a key role in the process. By the time this recognition dawned, Weber was already an established investigator in the field.

This flashback underlines how far atherosclerosis research has come in a quarter of a century, and how far biomedical science has penetrated into the underlying mechanisms in its attempts not only to understand the condition, but also how best to treat it. At one time, those interested in vascular biology regarded immune cells, including monocytes, as bystanders, as markers for the disease state. Now, like Christian Weber, they are engaged on teasing out the details of all the processes in which these cells are involved. Weber can now describe in detail how fatty “plaques” form in the walls of major arteries, how they provoke chronic inflammation, and why the lipid-rich deposits sometimes rupture, releasing waste products and cell debris into the circulation. This material can in turn obstruct blood flow so severely that a stroke or a heart attack ensues. Indeed, this sequence of events accounts for a large fraction of premature deaths in industrialized countries. “An unrestrained immune response causes pathological deposits to form in the inner wall of the blood vessels, and the inflammatory reactions smolder on for years, stimulating further growth of the plaques”, Weber explains.

Chain reaction that leads to atherosclerosis
We owe the term “atherosclerosis” to the German pathologist Felix Jacob Marchand, who in 1904 derived it from the Greek words for “porridge” and “hardening”, to refer to the texture of the fatty plaques and the loss of elasticity of the arteries. Christian Weber, now Director of the Institute for Prophylaxis and Epidemiology of Cardiovascular Diseases at LMU, analyzes the molecular mechanisms that give rise to these plaques. Using innovative methods and a range of high-tech instrumentation, he focuses on the chronic changes that occur in the endothelium, the thin sheet of cells that lines the arteries. The integrity and function of this boundary layer between the bloodstream and the internal tissues is indispensable for normal physiology. It is also the gateway through which immune cells gain access to the underlying smooth muscle fibers and other tissues. In healthy subjects, the permeability of the endothelium is low, its surface is smooth, and blood flows in a largely undisturbed stream.

The endothelium’s gateway function for immune cells in case of emergency is controlled by a battery of signal molecules that act as alarm bells to summon an armada of helpers – in particular white blood cells such as monocytes and neutrophils, whose role is to combat the perceived threat. “Several risk factors for atherosclerosis are known to activate the endothelium in this way. Among them are high levels of circulating fat molecules especially LDL-bound cholesterol – and reactive oxygen species (ROS), found in smokers,” says Weber. Oxidation of LDL cholesterol by ROS is thought to initiate the degradation of endothelial function.

Weber is a mine of information on the intricate interactions that link these factors and others to their long-term effects, from mechanisms known to promote atherosclerosis to the metabolism of fats in diverse tissues, from the many genes involved to how mutations hasten or slow down the whole complex process. “The interaction of all these factors determines how the drama plays out in each individual,” he explains. “There are predisposing factors, as well as protective mechanisms, that operate in the body, and both are important.” He produces micrographs showing how genetically labeled immune cells migrate between the cells of the artery wall, and diagrams that schematically depict the interactions of the different cell types, signal molecules and proteins. “The pathological changes primarily occur in segments of the vasculature where flow profiles undergo sudden change, for instance due to branching,” he adds.

Weber’s team employs sophisticated technology to monitor what happens to the endothelium at these critical branch-points and sharp bends in the arterial tree, such as the super-resolution microscopy techniques that won their inventors this year’s Nobel Prize in Medicine, and multiphoton microscopy, which uses pulsed infrared laser light to visualize labeled molecules in living tissues. With these methods, researchers can follow monocytes or neutrophils as they migrate between endothelial cells, in real time. Weber focuses on what happens on the endothelial surface. The receptors CCR1 and CCR5 play a key role in the recruitment of monocytes, because they bind to the chemokine CCL5 on the endothelial surface. Indeed chemokines not only mediate monocyte recruitment, they make the arterial wall more permeable to other cells and activators of inflammation. “Agents that repress CCR1 and CCR5 or block the binding of their partner ligands may offer a new approach to the treatment of atherosclerosis,” Weber remarks.

Damage to the boundary layer caused by exposure to noxious stimuli is what starts the chain reaction that leads to atherosclerosis. This attracts circulating immune cells that recognize damaged and necrotic cells. “These cells act as watchdogs in the bloodstream,” says Weber, “they are a kind of early warning system. They express chemokines that attract other specialized immune cells to the site of damage, such as monocytes or neutrophils, whose job is to eliminate the harmful substances.”

Continued on page 2: Provoking chronic inflammation