TOKYO, Sept. 7, 2022 /PRNewswire/ --
In a study recently published in The Journal of Clinical Investigation, researchers at Juntendo University unravel a biomolecule that mitigates eczema in mice
Dysfunctional autophagy plays a crucial role in generating epidermal barrier defects that sustain chronic inflammation in AD. hBD-3 could be an autophagy activator and a new approach to the treatment of AD through improvement of disrupted skin barrier via AhR-related autophagy activation.
Atopic dermatitis (AD), more colloquially known as eczema, is an inflammatory condition that manifests as itchy rashes on the skin. The disease flares up periodically over a patient's lifetime causing mild-to-severe discomfort. What's more, the treatment for refractory AD remains unsatisfactory. Now, a team of researchers from Juntendo University, led by François Niyonsaba, has revealed a candidate called human-β-defensin-3 (hBD-3) with potential in this regard.
One of the characteristics of AD is the disruption of the outermost layer of the skin: the epidermal barrier. Inside the cells that line this barrier, a mechanism called autophagy is involved in their differentiation and antimicrobial activity. Autophagy is a process by which damaged cells are degraded. Linking these two phenomena, the team started off by scrutinizing the association between autophagy and skin barrier function in AD and then proceeded to investigate hBD-3, a regulator of autophagy, in combating the condition.
Using the skin of human patients and mice with AD, the state of autophagy in affected cells was first analyzed. Molecules that typically drive autophagy and autophagic structures were reduced, suggesting that autophagy was indeed inhibited in these cells. When skin cells were examined closely to understand why autophagy was diminished, a class of molecules known as interleukins (which are typically released by our immune system) emerged as the culprits. Next, the role of autophagy in maintaining a healthy skin barrier was assessed by mutating mice to remove all programming for autophagy in the skin. These mice produced less proteins that are essential for developing a skin barrier. They were more susceptible to developing inflammation and lesions on their skin, similar to AD.
hBDs are biomolecules that have shown promise in restoring epidermal barrier function. Thus, the next focus was on understanding whether they play a role in restoring barrier function by regulating autophagy. Of the four types of hBDs found in human skin, one subtype, hBD-3, successfully increased autophagy in skin cells, which subsequently resulted in the development of skin barrier proteins. hBD-3 did so by activating the aryl hydrocarbon receptor (AhR) signaling—a cellular pathway responsible for proper barrier function. The researchers also confirmed this hypothesis in mice. When mice with AD were administered mBD-14 (the mouse analogue of hBD-3) they showed marked improvement in inflammation. However, this inflammation improvement was not observed in mice with a deficiency in skin autophagy or inhibition of AhR, highlighting the importance of autophagy and AhR as the mechanism of mBD-14/hBD-3 action.
"Thus, autophagy contributes to the pathogenesis of AD, and hBD-3 could be used for therapeutic purposes," concludes Niyonsaba's research group. This study gives dermatologists deeper insights into autophagy as a driving force behind AD and a possible solution to overcome it.
Background
Atopic dermatitis (AD): AD is a long-term skin condition that can affect people of any age, impact the quality of life and cause financial burden to the patients and their families. The dry, itchy rashes and scabs that accompany AD are typically managed by the use of soothing ointments and staying away from irritants.
Skin barrier: The skin barrier is essential in preventing exogenous chemicals and allergens from interacting with the sensitive immune cells in our skin. However, when this barrier is ruptured, as in AD, the skin ends up inflamed and prone to allergic reactions. Therefore, therapeutic options that restore a healthy skin barrier might be a long-term solution for treating AD.
Autophagy: Autophagy, which is Greek for 'self-devouring', is a process whereby cells engulf damaged internal components. The mechanism is a way for cells to either get rid of nonfunctional elements or eradicate toxins. Autophagy is typically triggered in stressful conditions like inflammation as a means of self-preservation. However, when autophagy is not functioning properly in such situations, conditions like AD arise.
Reference
Ge Peng, Saya Tsukamoto, Risa Ikutama, Hai Le Thanh Nguyen, Yoshie Umehara, Juan V. Trujillo-Paez, Hainan Yue, Miho Takahashi, Takasuke Ogawa, Ryoma Kishi, Mitsutoshi Tominaga, Kenji Takamori, Jiro Kitaura, Shun Kageyama, Masaaki Komatsu, Ko Okumura, Hideoki Ogawa, Shigaku Ikeda, François Niyonsaba. Human-β-defensin-3 attenuates atopic dermatitis-like inflammation through autophagy activation and the aryl hydrocarbon receptor signaling pathway. The Journal of Clinical Investigation, 2022 Sep 1;132(17):e156501.
DOI: 10.1172/JCI156501
Further information
Juntendo University
2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421 JAPAN
E-mail: [email protected]
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Mission Statement
The mission of Juntendo University is to strive for advances in society through education, research, and healthcare, guided by the motto "Jin – I exist as you exist" and the principle of "Fudan Zenshin - Continuously Moving Forward". The spirit of "Jin", which is the ideal of all those who gather at Juntendo University, entails being kind and considerate of others. The principle of "Fudan Zenshin" conveys the belief of the founders that education and research activities will only flourish in an environment of free competition. Our academic environment enables us to educate outstanding students to become healthcare professionals patients can believe in, scientists capable of innovative discoveries and inventions, and global citizens ready to serve society.
History of Juntendo University
Juntendo was originally founded in 1838 as a Dutch School of Medicine at a time when Western medical education was not yet embedded as a normal part of Japanese society. With the creation of Juntendo, the founders hoped to create a place where people could come together with the shared goal of helping society through the powers of medical education and practices. Their aspirations led to the establishment of Juntendo Hospital, the first private hospital in Japan. Through the years the institution's experience and perspective as an institution of higher education and a place of clinical practice has enabled Juntendo University to play an integral role in the shaping of Japanese medical education and practices. Along the way the focus of the institution has also expanded, now consisting of six undergraduate programs and three graduate programs, the university specializes in the fields of health science, health and sports science, nursing health care and sciences, and international liberal arts, as well as medicine. Today, Juntendo University continues to pursue innovative approaches to international level education and research with the goal of applying the results to society.
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