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Uncovering the Role of Interleukin-36 Receptor Agonists in Healing Skin Ischemia-Reperfusion Injuries

A deficiency of this protein slows down wound healing in cutaneous ischemia-reperfusion injuries by promoting inflammation and apoptosis.

Ischemia is a condition in which blood flow, and consequently oxygen, is reduced or restricted in specific parts of the body. While bed-ridden patients are most vulnerable to ischemia, which can manifest as pressure ulcers, ischemia could also afflict people under severe stress or exposed to cold weather as in the case of Raynaud’s phenomenon wherein blood flow decreases to the fingers. To rescue ischemia, clinicians may perform blood reperfusion to the affected areas, but this form of treatment could lead to ischemia-reperfusion injuries. For some patients, skin-based ischemia-reperfusion injuries may not heal properly due to slow or impaired would healing processes.

To gain a better understanding of the underlying immunological mechanisms behind ischemia, researchers at Fujita Health University in Japan examined a protein with a crucial immunomodulatory role in wound healing called interleukin-36 receptor agonist (IL-36Ra). Building upon their previous studies, Yoshihito Tanaka from the School of Medicine led his team to analyse the effects of IL-36Ra deficiency on wound healing in cutaneous ischemia-reperfusion injuries.

“We wanted to understand the immunological mechanisms involved in the healing of wounds from cutaneous ischemia-reperfusion injuries, such as pressure ulcers and Raynaud’s phenomenon, to narrow down possible therapeutic targets. Drawing from experience, IL-36Ra appeared to be a promising candidate for kickstarting our investigation,” explained Tanaka.

In their research, the scientists knocked out IL-36Ra in mice and induced cutaneous ischemia-reperfusion injuries in both the knockout and wildtype control mice for comparison. The team then examined the corresponding immunological responses in both groups of mice, measuring several parameters such as the time required for wound healing, the infiltration of neutrophils and macrophages to the site of the wounds, the formation of neutrophil extracellular traps, apoptotic skin cells, as well as the activation of unwanted immunological defence mechanisms.

Their experiments revealed that the absence of IL-36Ra significantly slowed the time needed for wound healing in cutaneous ischemia-reperfusion injuries by triggering increased apoptosis of useful skin cells. Apoptosis was detected in keratinocytes through a TUNEL assay. In addition, IL-36Ra deficiency also resulted in excessive recruitment of inflammatory cells and the activation of unnecessary pro-inflammatory mechanisms that contributed to delayed wound healing.

Seeking prospective treatment options, the researchers analysed the role of a protein-arginine deaminase inhibitor, known as Cl-amidine, and found that it could normalise exacerbated ischemia-reperfusion injury in the knockout group.

As the first conclusive report demonstrating the role of IL-36Ra in cutaneous ischemia-reperfusion injuries, the scientists are optimistic that they have pinned down a highly promising therapeutic target in IL-36Ra. Their findings are expected to empower future research in skin wound healing therapeutics and bring hopes of alleviating the painful burden of these injuries.

“Our research may lead to the development of therapeutic agents for wound healing of various other refractory skin diseases too,” added Tanaka positively. [APBN]

Source: Tanaka et al. (2021). Cutaneous ischemia-reperfusion injury is exacerbated by IL-36 receptor antagonist deficiency. Journal of the European Academy of Dermatology and Venereology.