Study on the interaction between immune cells and intestinal metabolites through GPCRs in the pathogenesis of inflammatory bowel disease

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02747
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Osaka University
• Principal Investigator: Kayama Hisako 大阪大学, 高等共創研究院, 准教授 (40548814)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 自然免疫 / 獲得免疫 / 腸内細菌 / 代謝産物

Outline of Final Research Achievements

Although the incidence and prevalence of ulcerative colitis (UC) and Crohn's disease (CD) are increasing globally, their etiology remains poorly understood. To define the impacts of interactions between intestinal metabolites and immune cells through GPCRs on the pathogenesis of UC and CD, we have conducted the following studies: (1) The influence of LysoPS in progression of CD: We identified that LysoPS derived from dysbiotic microbiota enhances Th1 responses through P2Y10 receptor and exaggerate colitis. (2) The influence of UDP-glucose-P2Y10 receptor signaling in UC aggravation: We identified that P2RY14 mRNA is highly expressed in colonic mucosa from UC patients and its ligand UDP-glucose is increased in inflamed sites of colonic mucosa. We demonstrated that activation of UDP-glucose-P2Y10 receptor signaling leads to prolonged survival of colonic eosinophils by inducing phosphorylation of ERK1/2 and thereby aggravates dextran sodium sulfate-induced colitis.

Free Research Field

粘膜免疫

Academic Significance and Societal Importance of the Research Achievements

IBD患者の腸管組織において増加する代謝産物および発現が上昇するGPCRsに焦点をあてた本研究課題では、細菌由来LysoPS-P2Y10受容体シグナルがTh1細胞の解糖系活性化を介してクローン病の増悪に関与すること、UDP-glucose-P2Y14受容体シグナルが好酸球を活性化することで潰瘍性大腸炎の重症化に関与することを明らかにした。これらの成果から、P2Y10受容体アンタゴニスト・LysoPS産生酵素(ホスホリパーゼA)阻害剤・E. coliなどがクローン病の創薬標的となる可能性、P2Y14受容体アンタゴニスト・ERK1/2阻害剤などが潰瘍性大腸炎の創薬標的となる可能性を示した。