A putative REE-ERB agonist SR9009 inhibits IgE-mediated mast cell activation

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08904
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: University of Yamanashi
• Principal Investigator: Ishimaru Kayoko 山梨大学, 大学院総合研究部, 助教 (10710353)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: マスト細胞 / 時計遺伝子 / アレルギー

Outline of Final Research Achievements

The cell-autonomous circadian clock regulates IgE- and IL-33-mediated mast cell activation, both of which are key events in the development of allergic diseases. Accordingly, clock modifiers could be used to treat allergic diseases, as well as many other circadian-related diseases, such as sleep and metabolic disorders. The nuclear receptors REV-ERB-α and -β (REV-ERBs) are crucial components of the circadian clockwork. Efforts to pharmacologically target REV-ERBs using putatively specific synthetic agonists, particularly SR9009, have yielded beneficial effects on sleep and metabolism. Here, we found that bone marrow-derived mast cells (BMMCs) obtained from wild-type mice expressed REV-ERBs. SR9009, a REV-ERB agonist, inhibited IgE- and IL-33-mediated mast cell activation in wild-type BMMCs in association with inhibition of Gab2/PI3K and NF-κB activation. Thus, SR9009 or other synthetic REV-ERB agonists may have potential for anti-allergic agents.

Free Research Field

アレルギー

Academic Significance and Societal Importance of the Research Achievements

日本人の３人に１人が花粉症や喘息、食物アレルギー、アトピー性皮膚炎などの何らかのアレルギー疾患に罹患しており、その治療法の開発は医学だけでなく社会的課題である。しかしながら現在の抗アレルギー薬のほぼ全てが対症療法薬であり根本的かつ新しい治療法が望まれている。本研究で研究代表者らは、私たちの生理活動の日内リズムを司る体内時計の構成要素である時計遺伝子を標的とすることがアレルギー創薬に繋がることを明らかにした。