Role of ERK Pathway in the Pathogenesis of Atopic Dermatitis and Its Potential as a Therapeutic Target.

Abstract

Atopic dermatitis (AD) is an eczematous skin disorder characterized by type 2 inflammation, barrier disruption, and intense itch. In addition to type 2 cytokines, many other cytokines, such as interferon gamma (IFN-γ), interleukin 17 (IL-17), and interleukin 22 (IL-22), play roles in the pathogenesis of AD. It has been reported that the extracellular signal-regulated kinase (ERK) is downstream of such cytokines. However, the involvement of the ERK pathway in the pathogenesis of AD has not yet been investigated. We examined the expression of p-ERK in mouse and human AD skin. We also investigated the effects of the topical application of an ERK inhibitor on the dermatitis score, transepidermal water loss (TEWL), histological change, and expression of filaggrin, using an AD-like NC/Nga murine model. The effects of an ERK inhibitor on filaggrin expression in normal human epidermal keratinocytes (NHEKs) and on chemokine production from bone marrow-derived dendritic cells (BMDCs) were also evaluated. p-ERK was highly expressed in mouse and human AD skin. Topical application of an ERK inhibitor alleviated the clinical symptoms, histological changes, TEWL, and decrease in expression of filaggrin in the AD-like NC/Nga murine model. The ERK inhibitor also restored the IL-4 induced reduction in the expression of filaggrin in NHEK, and inhibited chemokine production from BMDC induced by IL-4. These results indicate that the ERK pathway is involved in the pathogenesis of AD, and suggest that the ERK pathway has potential as a therapeutic target for AD in the future.

• Authors: Nahoko Zeze, Makiko Kido-Nakahara, Gaku Tsuji, Eriko Maehara, Yuki Sato, Sawako Sakai, Kei Fujishima, Akiko Hashimoto-Hachiya, Masutaka Furue, Takeshi Nakahara
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 23 Issue 7 (Mar 23 2022) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 35408826 (Publication Type: Journal Article)

Chemical References

• Chemokines
• Cytokines
• Interleukin-4
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Chemokines (metabolism)
• Cytokines (metabolism)
• Dermatitis, Atopic (drug therapy, etiology, metabolism)
• Disease Models, Animal
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Interleukin-4 (metabolism)
• MAP Kinase Signaling System
• Mice
• Skin (metabolism)