Elucidation of molecular mechanisms of monocyte activation through TLR signaling in Sjögrens syndrome.

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08919
• 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: Keio University
• Principal Investigator: Ikeda Yumi 慶應義塾大学, 医学部(信濃町), 研究員 (70826156)
• Co-Investigator(Kenkyū-buntansha): 吉本 桂子 慶應義塾大学, 医学部(信濃町), 研究員 (20383292)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: シェーグレン症候群 / 単球 / Toll様受容体

Outline of Final Research Achievements

The purpose of this study is to clarify the regulatory mechanisms of elevated expression of BAFF receptor(BR3) in monocytes and search novel therapeutic targets for Sjogren’s syndrome (SS). In our previous study, we found that BR3 expression was elevated in peripheral SS monocytes and that elevation was correlated with clinical parameters of patients. It has been reported that signaling pathways via TLRs are involved in onset and/or development of SS and that monocytes expressing TLRs play a crucial role in the pathogenesis of the disease. In this study, we focused on TLR4 and investigated possible involvement of signaling pathways of TLR4 in enhanced expression of BR3 in human monocytes. As a results, we found that TLR4 expression was elevated in SS monocytes and phosphorylation of several TLR4 signaling molecules were upregulated by LPS stimulated monocytes These findings suggest that these molecules may be involved in the pathogenesis of SS.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

研究代表者らのこれまでの研究成果より、単球におけるTLR発現亢進に起因したBR3発現異常が単球を活性化しSS患者の病変部位の組織障害を引き起こすという独自の仮説に基づく病態解明の取り組みは新規治療標的の探索を可能にし、極めて独自性、新規性、創造性が高いと考える。本研究の成果はSS病態形成機序の解明に伴う、新たな治療標的タンパク質の探索及び同定につながり、標的タンパク質の作用を制御する化合物はSS根治的治療薬のシーズとなり得る。よって本研究は学術的に有意義であるばかりでなく、根治療薬の存在しない免疫難病分野への新規治療薬の提供という点において社会的貢献度も高い。