Delayed wound healing: TLR4 reverses IL-36Ra deficiency

A gene mutation delays wound healing and causes various inflammatory skin diseases. A research team at Fujita University in Japan has now discovered how this process can be normalized with the help of a protein.

Gene mutation and inflammatory skin diseases

A gene mutation delays wound healing and causes various inflammatory skin diseases. A research team at Fujita University in Japan has now discovered how this process can be normalized with the help of a protein.

Bleeding stoppage, the removal of pathogens and deposits, reproducing and strengthening of tissue - several biological activities trigger wound healing. A critical step is the infiltration of inflammatory cells at a wound during the "cleansing" phase. But both excessive and insufficient infiltration delays wound healing.

According to Prof. Kazumitsu Sugiura and Dr. Kenta Saito (Fujita Health University, Japan), the anti-inflammatory mediator IL-36Ra plays an important role in wound healing. IL-36Ra is encoded by the IL36RN gene. Mutations in this gene cause various inflammatory skin diseases such as psoriasis. In Japan, for example, about 2% of the population have two mutations of the IL36RN gene. Experts suspect that it is responsible for several other skin diseases.

Delayed wound healing in mice with IL-36Ra-Re

Previous studies on mice with these mutations have shown impaired wound healing. However, the exact role of IL-36Ra in wound healing is still unknown. Therefore, the team of Sugiura and Saito studied the healing of excisional wounds in 8-14 week old IL36RN mice and their wild-type siblings.
3 and 7 days after the injury, the open wound areas were larger in the IL36RN mice than in the wild type controls. The epithelial tissue also recovered poorly and a lot of granulation and connective tissue and blood vessels were formed to fill the wounds. Examinations of the IL36RN mice 3 days after injury showed a stronger infiltration of pro-inflammatory neutrophils and macrophages (another type of immune cells involved in the identification and gobbling up of pathogens and dead cells) into the wound areas and a stronger gene expression for pro-inflammatory cytokines (proteins that regulate inflammation, among other things).

TLR4 inhibitor could prevent adverse effects

While this shows the harmful effects of IL-36Ra deficiencies on wound healing, it does not show how they can be prevented. This is where the Toll-like receptor-4 (TLR4) comes in, a protein responsible for signaling cytokine production. An earlier study shows that it plays a key role in early wound healing. Sugiura and Saito are certain: treatment with the TLR4 inhibitor TAK-242 would normalize wound healing in IL36RN mice. Intraperitoneal TAK-242 injections administered to the mice shortly after injury eliminated the delays in wound healing.

TLR4 inhibitors could therefore also support wound healing in people with IL-36Ra deficiency. Although the research on mice cannot be transferred 1:1 to humans and the physiology of inflammation during wound healing would also need to be clarified, the findings could then change future clinical research. "Our observations on TAK-242 highlight TLR4 as a new therapeutic target for clinical research on neutrophilic skin diseases such as Pyoderma gangrenosum," Sugiura and Saito explain. Although they had not directly experimented with the compensatory administration of IL-36Ra itself, they speculated that IL-36Ra could be used as a treatment for various inflammatory skin diseases such as psoriasis and atopic dermatitis.

Esanum is an online network for approved doctors

Esanum is the medical platform on the Internet. Here, doctors have the opportunity to get in touch with a multitude of colleagues and to share interdisciplinary experiences. Discussions include both cases and observations from practice, as well as news and developments from everyday medical practice.

Esanum ist ein Online-Netzwerk für approbierte Ärzte

Esanum ist die Ärzteplattform im Internet. Hier haben Ärzte die Möglichkeit, mit einer Vielzahl von Kollegen in Kontakt zu treten und interdisziplinär Erfahrungen auszutauschen. Diskussionen umfassen sowohl Fälle und Beobachtungen aus der Praxis, als auch Neuigkeiten und Entwicklungen aus dem medizinischen Alltag.

Esanum est un réseau en ligne pour les médecins agréés

Esanum est un réseau social pour les médecins. Rejoignez la communauté et partagez votre expérience avec vos confrères. Actualités santé, comptes-rendus d'études scientifiques et congrès médicaux : retrouvez toute l'actualité de votre spécialité médicale sur esanum.