Mechanistic insights into contact hypersensitivity could pave the way for drug discovery
Contact hypersensitivity (CHS), commonly known as contact dermatitis, is an itchy rash that develops when certain substances come into direct contact with the skin. Usually it is the result of an allergic reaction and can make patients feel uncomfortable. Common substances such as perfumes, household chemicals, and accessories can trigger contact dermatitis itching. Although common, the underlying physiological mechanisms that trigger CHS remain elusive.
Recently, a research team from Fujita Health University School of Medicine, Japan, was able to shed light on the precise molecular mechanisms that trigger CHS. The group had previously shown that genetic mutations in the interleukin (IL)36RN gene, which is responsible for the synthesis of the interleukin-36 receptor antagonist protein (or IL-36Ra), can lead to improved CHS. They also observed that the mutations lead to increased formation of neutrophil extracellular traps (NETs), which are mesh-like structures of DNA and proteins released by neutrophils to capture pathogens. However, the immunological pathophysiology of NETs in CHS remained unclear.
Twice, the research team has successfully established links between IL-36Ra and psoriatic lesions as well as between IL-36Ra and wound healing. The same team has now been able to dive deep to further explore the underlying mechanisms. Their study has just been published in Scientific reports (published August 4, 2022) and shows that NETs could be a potential therapeutic target for CHS. Lead author Dr. Yurie Hasegawa, a graduate student at Fujita Health University School of Medicine, along with co-authors Dr. Yohei Iwata and Professor Kazumitsu Sugiura, together demonstrated that NETs play a leading role in the CHS response in the presence of a high number of inflammatory cells such as CD4+ and CD8+ T cells. “NETs can also exacerbate immune responses in CHS. Therefore, inhibition of NET formation may be a new therapeutic strategy in contact dermatitis,” says Dr. Hasegawa about the rationale for their study.
To test their hypothesis, the team evaluated the NET formation in Il36rn-/- mutant mice as well as wild-type mice under the influence of CHS-sensitive CD4+ and CD8+ T cells. They first tested the effects of Cl-amidine on the CHS response in mutant and wild-type mice and found that the number of infiltrating inflammatory cells and the area of NETs decreased in both types of mice.
Histopathology and cellular assays confirmed that mutant mice had significantly more macrophages and CD4+ and CD8+ T cells than wild-type mice. Additionally, they demonstrated elevated levels of inflammatory cytokines such as IL-1, CXCL1, CXCL2, IL-17A, tumor necrosis factor-α, and IL-36. Interestingly, there were striking differences in IFN-γ and CXCL1 levels between Cl-amidine-treated mutant mice and untreated wild-type mice, but not in inflammatory cytokine levels.
They then used immunofluorescence staining to show that mutant mice had more NET in their auditory tissues than wild-type mice. However, treatment of mice with Cl-amidine – an inhibitor that suppresses NET formation – resulted in a decrease in the CHS response, suggesting that NETs could be a potential therapeutic target for CHS.
Excited by their findings, the team looks forward to further exploring the links between NET formation and the treatment of CHS. Dr. Hasegawa explains: “Our study is the first to suggest the involvement of NETs in CHS immune responses. All of our results collectively indicate that blocking NET formation by Cl-amidine may be a potential therapeutic approach for allergic contact dermatitis. “
Hopefully their discovery will facilitate the development of new therapeutics for the safe and effective treatment of contact dermatitis.