Researchers solve stroke research mystery

New study disproves theory of destructive role of immune cells / Münster University researchers involved

Münster (upm), Di, 08 Jan 2013

A blood vessel in the brain: contrary to conventional wisdom, the neutrophil granulocytes (red) do not infiltrate the brain tissue.

photo: WWU - Lydia Sorokin

In a recently completed study, researchers from the Universities of Münster, Berne, Berlin, Freiburg, Tübingen and Frankfurt have gained new insights into the causes of strokes. These results will now require a completely new examination of the real causes of nerve cell death after a stroke, thus opening up new approaches to the treatment of strokes.

In order to assess the role of the inflammatory reaction after a stroke, the researchers concentrated on the influence of a group of immune cells, the neutrophil granulocytes, which are a part of the rapid immune response in the case of infections and traumata. The team of researchers belong to the "European Stroke Network", which is funded by the European Union (EU). Conventional wisdom has it that these immune cells are particularly harmful, as it was assumed that that they migrated into the brain after a stroke and destroyed the nerve cells there. It was now possible to demonstrate for the first time that, after a stroke, neutrophil granulocytes become trapped in the blood vessels and do not progress as far as the nerve cells.

Prof. Lydia Sorokin is one of the authors of the study and she too is convinced that, as she puts it, "stroke therapy must now be reconsidered." Sorokin, Director of the Institute of Physiological Chemistry and Pathobiochemisty at Münster University (WWU), attributes the success of the study in particular to the close cooperation between basic researchers and clinical colleagues. "Without the development of new immunohistological analytical procedures in animal models we would never have been able to establish that neutrophil granulocytes get trapped in the blood vessels," says Sorokin. And without the neuropathologists and neurologists we would never have been able to demonstrate the importance of this for strokes. Lydia Sorokin is a member of the Coordinating Team for the "Cells in Motion" (CIM) Excellence Cluster at Münster University which is working in particular on visualizing and analysing the behaviour of cells in living organisms. "This study," she says, "shows that the CIM concept is the right way to proceed and to help us arrive at new results."

Strokes are the third most frequent cause of death worldwide and the most frequent cause of disabilities in old age. In Germany around 200,000 people suffer a stroke every year. Strokes occur when the bloodflow to the brain is suddenly interrupted. The most frequent way this happens is because of a blood clot (thrombus) that gets trapped in a blood vessel in the brain, thus blocking it up. Any diminished bloodflow to that area of the brain to which this blood vessel supplies blood leads to a lack of oxygen and nutrients, and also, within hours, to the death of nerve cells in this part of the brain.

Even if speedy medical care is provided in a Stroke Unit and the blood supply is re-established in the relevant vessel, further nerve cells in the brain still die in the days following a stroke. An inflammatory reaction is held to be responsible for this. After a stroke, the cells of the immune system try to dispose of the dead brain cells and for this purpose they migrate from the blood circulation into the area of the brain affected. Hitherto it was assumed that neutrophil granulocytes also migrated into the brain, where they killed further brain cells – this group of immune cells is specialized in responding rapidly in the case of infections and traumata, killing germs and devouring dead cells. However, no therapeutic approach aimed at blocking the migration of neutrophil granulocytes into the brain, or at preventing them from functioning, had any success in clinical studies previously carried out to treat strokes.

The new study carried out by biochemists, cell biologists, neuroimmunologists and doctors (neuropathologists and neurologists) now solves this mystery. On the basis of immunohistological analytical procedures the researchers have demonstrated that after a stroke the neutrophil granulocytes do not migrate into the brain tissue. This means that these dangerous cells of the immune system do not move into the vicinity of the nerve cells.

In their study the researchers show what led in the past to the erroneous interpretation in localizing the neutrophil granulocytes after a stroke. On the one hand there were not many possibilities until recently of clearly distinguishing the neutrophil granulocytes from other phagocytes of the immune system. On the other hand, dying nerve cells look just like the neutrophil granulocytes when the usual dyeing procedures are applied. The brain is a so-called immune-privileged organ which is adept at protecting itself from the dangerous cells of the immune system. In their study, the researchers point out in particular that for this purpose the brain surrounds itself with two "walls" (basement membranes). To monitor immunity, cells of the immune system constantly migrate from the blood circulation to the surrounding vicinity. While, in other organs, they permeate the blood vessel wall and then arrive in the tissue, in the brain they only reach a space in an "antechamber" between the two walls. In the case of inflammatory diseases of the brain, such as multiple sclerosis, immune cells migrate through the second wall and cause severe damage in the brain.

In the case of a stroke the neutrophil granulocytes do not succeed in breaking through the walls. The question now is whether – and, if so, how – neutrophil granulocytes could harm the neurones by "remote action". The blood vessels in the brain are different from those in other organs as they strictly control the transport of substances into and out of the brain. They establish the blood-brain barrier. Further analyses will be necessary to see whether the neutrophil granulocytes lead to a local disturbance of the blood-brain barrier.

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