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Astonishing discovery: iron-overloading of macrophages is the cause of venous leg ulcers

Around three to five per cent of people in industrial nations suffer from chronic venous leg ulcers. Elderly people are particularly prone to developing these chronic wounds. A dermatologist from Ulm has now discovered the reason why chronic venous leg ulcers fail to heal even after months or years. The scientific community is astonished by the new findings.

Prof. Karin Scharffetter-Kochanek © University Hospital Ulm

Researcher and physician at the Ulm University Hospital Anca Sindrilaru and her colleagues have successfully identified the process that leads to chronic wound inflammation and have also provided detailed insights into the mechanisms. “This finding represents a real break-through in the field of dermatology, as well as for other fields,” said Karin Scharffetter-Kochanek, Medical Director of the Department of Dermatology and Allergology at the University of Ulm. “Our results suggest that the findings are also of major importance for explaining the pathogenesis of diseases such as multiple sclerosis and arteriosclerosis.

Chronic venous leg ulcers (CVUs) often occur as a result of the improper functioning of venous valves, usually in the legs. Impaired venous valve functioning is also associated with the development of varicose veins, which is another frequent condition that affects around 10 per cent of the world’s population. 

CVUs cause brownish skin

The venous valves pump the blood towards the heart. Improper functioning of the venous valves causes blood to accumulate in the lower legs. This leads to higher pressure, which in turn causes red blood cells (erythrocytes) to be pressed against the walls of the blood vessels, eventually destroying them. Early symptoms of CVU include the skin turning a brownish colour due to the erythrocytes containing large quantities of iron. The erythrocytes die and iron builds up in the tissue. In the worst cases, venous leg ulcers develop either spontaneously or as the result of minor injuries.

The healing of wounds is normally a strictly regulated process, in which macrophages play an essential role. Macrophages are vital elements in the regulation of immune responses; they protect the immune system against foreign cells such as bacteria and viruses and also against worn-out, damaged or dead body cells. The macrophages recognize such cells and engulf them; the word macrophage is derived from the Greek words for big and eating, essentially meaning that they are “big eaters”. They promote the healing of wounds by releasing substances that lead to local inflammatory reactions. This is the first of three or four phases of wound healing. In the later phases of wound healing, macrophages promote the development of scar tissue. “However, chronic venous ulcers do not follow the normal pattern of wound repair. Instead they remain in a chronic state of inflammation. We consider uncontrolled macrophage activation to be a critical event in the pathogenesis of chronic venous leg ulcers and other chronic inflammatory diseases,” said Karin Scharffetter-Kochanek.

Anca Sindrilaru discovers the important role of iron in macrophage activation

Anca Sindrilaru discovered a new type of macrophage and potentially also the cause of chronic venous leg ulcers. © University Hospital Ulm

“CVU also involves macrophages which engulf the dead iron-containing erythrocytes. We discussed the possible role that iron plays in chronic venous leg ulcers that fail to heal,” said Anca Sindrilaru. “We carried out a relatively simple experiment to find out whether we could detect iron-containing macrophages at the edge of such wounds. The results were surprising. All the macrophages contained iron.” When the researchers looked more closely at the macrophages they also found that they are not just temporarily activated, but that they remained permanently in an unrestrained proinflammatory activation state. The researcher from Ulm concluded: “The macrophages store the iron found in the wound tissue. This leads to the iron overloading of the macrophages; they become hyperactive and continue engulfing iron.”

But why does this happen? The researchers also came up with an answer to this question: “Due to the iron overloading, the macrophages release elevated quantities of TNF (tumour necrosis factor)-α, which mediates the activation of proinflammatory, TNF-α-producing macrophages. Inflammation is perpetuated and the process of wound healing impaired. The wound healing process does not progress through all phases of wound healing, but stops in the inflammatory phase. It is, in fact, a vicious circle.”

Scientific community gives the Ulm researchers’ discovery a name

Anca Sindrilaru showed that inflammatory wound environments promoted the iron overloading of macrophages and induced a previously unknown iron-induced macrophage population, which she has been able to characterize in detail. Karin Scharffetter-Kochanek: “After Anca Sindrilaru’s paper was published in the well-known “Journal of Clinical Investigation”, the renowned journal “Nature Reviews Immunology” published a ‘research highlight’ about the newly discovered macrophage population, in which the macrophages were referred to as “iron macrophages”. We now refer to these macrophages as iron-storing macrophages.”

“Huge progress” on the road towards the development of innovative therapies.

“Anca Sindrilaru’s discovery marks a major step forward in our knowledge of chronic wound healing disorders. We will now use these findings to carry out further research. We are quite confident that our research will lead to the development of new therapies for the treatment of chronic inflammatory diseases at some time in the future,” said Karin Scharffetter-Kochanek.

The researchers have already successfully re-ignited impaired wound healing processes in animal models using a TNF-α inhibitor, by removing the macrophages from the edge of wounds during a specific phase during the wound-healing process and by using iron-binding substances to remove iron.

Website address: https://www.gesundheitsindustrie-bw.de/en/article/press-release/astonishing-discovery-iron-overloading-of-macrophages-is-the-cause-of-venous-leg-ulcers