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 in 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 itchy rashes from contact dermatitis. Although common, the underlying physiological mechanisms that trigger CHS remain elusive.

Recently, a research team from Fujita Health University School of Medicine, Japan, has been 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 protein interleukin-36 receptor antagonist (or IL-36Ra), may result in enhanced CHS. They also observed that the mutations led to the 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.

On two previous occasions, the research team 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 in deep to further explore the underlying mechanisms. Their study was recently published in Scientific Reports (published on Aug 4, 2022) and shows that NETs could be a potential therapeutic target for CHS. The lead author, Dr. Yurie Hasegawa, a graduate student at the Fujita Health University School of Medicine, along with co-authors Dr. Yohei Iwata and Prof. Kazumitsu Sugiura, together demonstrated that NETs play a prominent role in the CHS response in the presence of a high number of inflammatory cells like CD4+ and CD8+ T-cells. “NETs may also exacerbate immune reactions in CHS. Therefore, the inhibition of NET formation may be a new therapeutic strategy in contact dermatitis,” explains Dr. Hasegawa about the rationale of their study.

To test their hypothesis, the team evaluated NET formation in Il36rn^-/- mutant mice as well as wild-type mice under the influence of CHS-responsive CD4+ and CD8+ T cells. They first tested the effects of Cl-amidine on the CHS response in the mutant and wild-type mice and found that the number of infiltrating inflammatory cells and area of NETs decreased in both mice types.  

Histopathology and cell assays confirmed that the mutant mice had considerably more macrophages and CD4+ and CD8+ T cells than the wild-type mice. Moreover, they demonstrated elevated levels of inflammatory cytokines like 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 the levels of inflammatory cytokines.

They next used the immunofluorescence staining to show that the mutant mice had more NETs in their ear tissues than the wild-type mice. However, treating mice with Cl-amidine—an inhibitor that suppresses the formation of NETs—resulted in a decreased CHS response, suggesting that NETs could be a potential therapeutic target for CHS.

Thrilled by their findings, the team is looking forward to further exploring the connections between NET formation and CHS treatment. Dr. Hasegawa explains, “Our study is the first to suggest the involvement of NETs in the immune responses in CHS. All our findings collectively indicate that the blockade of NET formation by Cl-amidine may be a potential treatment approach for allergic contact dermatitis”.

Let’s hope that their discovery facilitates the development of novel therapeutics for the safe and effective treatment of contact dermatitis.

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Reference
DOI: https://doi.org/10.1038/s41598-022-16449-z

About Fujita Health University
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 became 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

About Dr. Yurie Hasegawa from Fujita Health University
Dr. Yurie Hasegawa is currently pursuing her graduate studies at Fujita Health University School of Medicine’s Department of Dermatology. Her research primarily focuses on interleukins—cytokine proteins that play an important role in the activation, differentiation, proliferation, maturation, migration, and adhesion of immune cells. Dr. Hasegawa has published her cutting-edge research on Interleukin-36 (IL-36) receptor antagonists in the prestigious journal Scientific Reports on at least three different occasions so far.

Funding information
This study was supported by grants from AMED (grant number 19ek0109295H0003) and JSPS KAKENHI (grant numbers 18K08281 and 21K08336) to Kazumitsu Sugiura. This project was supported by a grant from the Maruho Takagi Dermatology Foundation to Kazumitsu Sugiura.