'What wound did ever heal but by degrees?' delayed wound healing due to gene mutations

"Wound healing is one of the most complex biological processes," write Professor Kazumitsu Sugiura and Dr Kenta Saito from Fujita Health University, Japan, in their article recently published in Nature's Scientific Reports. As countless researchers in the field have noted, several automated coordinated biological activities take place during wound healing, from stopping the bleeding to cleaning out pathogens and debris to growing back and strengthening tissue.

One critical step in wound healing is the infiltration of inflammatory cells into the vicinity of a wound in the "cleaning out" phase. But this is something of a double-edged sword: either excessive or inadequate infiltration can delay wound healing.

This reality in part led Prof Sugiura and Dr Saito to hypothesize that the anti-inflammatory mediator IL-36Ra could be playing an important role in wound healing. IL-36Ra is encoded by the IL36RN gene. Mutations in this gene have been linked to various inflammatory skin disorders such as psoriasis. In Japan, approximately 2% of the population have two mutations of the IL36RN gene and experts have conjectured that this could be behind several skin disorders.

Previous studies involving mice with these mutations (Il36rn^−/− mice) have revealed impaired wound healing. However, the exact role that IL-36Ra plays in the wound healing process remains unknown. To find out, the team led by Prof Sugiura and Dr Saito studied the healing of excisional wounds in 8-14-week-old Il36rn^−/− mice and their wild-type littermates.

When the researchers examined the animals at 3- and 7-day postinjury timepoints, they found that open wound areas were larger in the Il36rn^−/− mice than in the wild-type controls. The Il36rn^−/− mice also exhibited diminished recovery of epithelial tissue--or the outer layer of the skin--and excessive formation of granulation tissue, the connective tissue and blood vessels that grow to fill wounds. Interestingly, examinations of the Il36rn^−/− mice at the 3-day postinjury timepoint also revealed greater infiltration of proinflammatory neutrophils and macrophages (another type of immune cell involved in identifying and engulfing pathogens and dead cells) into the wound areas and greater gene expression for proinflammatory cytokines--proteins that regulate inflammation, among other things.

These results provide evidence for the deleterious effects of IL-36Ra deficiencies on wound healing, but they leave open the question of how clinicians can counter those effects.

The team led by Prof Sugiura and Dr Saito answer this question as well in their paper. Based on the findings of a recent study that toll-like receptor-4 (TLR4), a protein responsible for signaling cytokine production, plays an essential role in early wound repair, the researchers hypothesized that treatment with the TLR4 inhibitor TAK-242 would normalize wound healing in Il36rn^−/− mice. As expected, intraperitoneal TAK-242 injections administered shortly after injury eliminated the delays in wound healing observed at the 3- and 7-day postinjury timepoints.

This is preliminary evidence for the utility of TLR4 inhibitors as a way to promote wound healing in people with IL-36Ra deficiencies. Of course, these findings should be approached with some caution due to the many unanswered questions concerning the physiology of inflammation in wound healing. Further, differences between murine and human wound healing mechanisms may limit the interspecies translatability of these findings. Nonetheless, these findings point to potential directions for future clinical research. As Prof Sugiura and Dr Saito note: "Our observations concerning TAK-242 highlight TLR4 as a novel therapeutic target for clinical research related to neutrophil skin diseases such as pyoderma gangrenosum." Although they did not directly experiment with the compensatory administration of IL-36Ra itself, they also speculate that "IL-36Ra can be used as a treatment for various inflammatory skin diseases such as psoriasis and atopic dermatitis. This could be the beginning of a new direction of research on wound healing!"

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Fujita Health University is a private university situated in Toyoake, Aichi, Japan. It was founded in 1964 and houses one of the largest teaching university hospitals in Japan in terms of the number of beds. With over 900 faculty members, the university is committed to providing various academic opportunities to students internationally. Fujita Health University has been ranked eighth among all universities and second among all private universities in Japan in the 2020 Times Higher Education (THE) World University Rankings. THE University Impact Rankings 2019 visualized university initiatives for sustainable development goals (SDGs). For the "good health and well-being" SDG, Fujita Health University was ranked second among all universities and number one among private universities in Japan. The university will also be the first Japanese university to host the "THE Asia Universities Summit" in June 2021. The university's founding philosophy is "Our creativity for the people (DOKUSOU-ICHIRI)," which reflects the belief that, as with the university's alumni and alumnae, current students also unlock their future by leveraging their creativity.

Website: https://www.fujita-hu.ac.jp/en/index.html

Professor Kazumitsu Sugiura, MD, PhD, is the chairman of the Department of Dermatology at Fujita Health University. He is a graduate of the Nagoya University Graduate School of Medicine, and he has conducted research into autoimmunity at the Scripps Research Institute in addition to Nagoya University and Fujita Health University. Dr. Kenta Saito is a researcher at Fujita Health University.

This study was funded by the Japan Agency for Medical Research and Development, the Japan Society for the Promotion of Science, the Lydia O'Leary Memorial Pias Dermatological Foundation, and the Maruho Takagi Dermatology Foundation.