Nerve Healing: Neighbor Cells Become Police Force – And May Make Tumors Benign

Drug side effects at all stages of pediatric development identified

Schwann cells are known to protect and repair nerve cells. Until now, however, it was not known that they themselves take over the functions of certain immune cells during nerve healing. For example, they produce signaling molecules that can activate other immune cells. In particular, however, they are able to stop inflammatory reactions to prevent excessive tissue damage and allow the nerve to regenerate.

“This is essential, because inflammation releases free radicals that nerve fibers cannot protect themselves against. Therefore, inflammation must be eliminated quickly, which is exactly what Schwann cells do,” explains Dr. Sabine Taschner-Mandl, who designed the study and directs a research group in St. Anna CCRI. The new results, in which the Medical University of Vienna is also significantly involved, were published in the journal glia.

Do Schwann cells protect against malignancy?

How are these results related to tumor growth? After nerve damage, Schwann cells adopt a “repair” mode that is also found in benign tumors of children’s nerves. There, it causes the tumor cells to mature and thus reach a stage where they lose their aggressive properties and no longer divide unchecked (Weiss T., Taschner-Mandl S., et al., Nat Common 2021).

“Based on the current results, we now suspect that Schwann cell immune cell functions also become effective in childhood nerve tumors. This is because in cancer, there is always a kind of inflammation bubbling up that never stops. Nerve tumors, ganglioneuromas, the chronic inflammation that accompanies them can be stopped by Schwann cells similar to nerve scarring because, unlike malignancies, benign nerve tumors have a lot of Schwann cells in their microenvironment. We also see that many immune cells migrate into these tumors, for which Schwann cells may also be responsible,” says Sabine Taschner-Mandl.

Healthy Inflammation: First On, Then Off

In particular, the current study shows that Schwann cells can influence certain immune cells, so-called T cells, which play an important role in defending against cancer. Schwann cells – both from nerve regeneration and benign tumors – carry MHC-I and MHC-II molecules on their surface that are important for the regulation of T cells. Through these molecules, Schwann cells have characteristics of recognition of material they have previously taken from their environment.

We mimic an inflammatory response in the laboratory and detect a whole range of additional stimulatory and inhibitory surface molecules that are also required for T cell activation,” explains Jakob Berner, MSc, study co-author and interim doctoral student at Kaan Boztug’s group at St. Anna CCRI “Our experiments show that Schwann cells are able to take up large amounts of material via phagocytosis.”

As the first immune response to a nerve cut, Schwann cells secrete substances that attract T cells, macrophages and other immune cells. It has now been discovered that not only does a reaction occur between classical immune cells, but also between Schwann cells and T cells.

While Schwann cells initially fuel the inflammatory response by releasing interferon-gamma, they can later turn it off by up-regulating the T-cell inhibitory molecule PD-L1.

“On first, then off – this is the normal process of an inflammatory response. If this were also the case for cancer, then it could stop the cancer from growing,” comments Sabine Taschner-Mandl. Whether and how these findings could be used for potential cancer therapies is now being researched.

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