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.