Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510655, China.
Int Immunopharmacol. 2024 Oct 25;140:112729. doi: 10.1016/j.intimp.2024.112729. Epub 2024 Aug 3.
ADORA3 is mainly expressed in intestinal tract, and has the potential to promote the expression of mucin 2 (MUC2), the function-related factor of goblet cells, under asthma conditions. This study aims to confirm the induction and mechanisms of ADORA3 activation on goblet cells in ulcerative colitis (UC). A significant decrease in ADORA3 expression was found in mucosal biopsies from UC patients and in the colons of colitis mice. This reduction correlated negatively with disease severity and positively with goblet cell number. ADORA3 activation mitigated dextran sulfate sodium (DSS)-induced colitis and facilitated ATOH1-mediated goblet cell differentiation in both in vivo and in vitro. Metabolomics analysis unveiled that ADORA3 activation bolstered ketogenesis, leading to elevated levels of the metabolite BHB. Subsequently, BHB heightened the activity of HDAC1/2, augmenting histone acetylation at the H3K9ac site within the promoter region of the ATOH1 gene. Furthermore, the reason for ADORA3 activation to enhance ketogenesis was attributed to controlling the competitive binding among β-arrestin2, SHP1 and PPARγ. This results in the non-ligand-dependent activation of PPARγ, thereby promoting the transcription of HMGCS2. The exact mechanisms by which ADORA3 promoted goblet cell differentiation and alleviated UC were elucidated using MRS1191 and shHMGCS2 plasmid. Collectively, ADORA3 activation promoted goblet cell differentiation and alleviated UC by enhancing ketogenesis via the "BHB-HDAC1/2-H3K9ac" pathway.
ADORA3 主要在肠道中表达，有潜力在哮喘条件下促进粘蛋白 2（MUC2）的表达，MUC2 是杯状细胞的功能相关因子。本研究旨在确认 ADORA3 在溃疡性结肠炎（UC）中对杯状细胞的激活作用及其机制。在 UC 患者的黏膜活检和结肠炎小鼠的结肠中发现 ADORA3 表达显著降低。这种减少与疾病严重程度呈负相关，与杯状细胞数量呈正相关。ADORA3 的激活减轻了葡聚糖硫酸钠（DSS）诱导的结肠炎，并促进了 ATOH1 介导的杯状细胞分化，无论是在体内还是体外。代谢组学分析显示，ADORA3 的激活增强了酮体生成，导致代谢物 BHB 水平升高。随后，BHB 增强了 HDAC1/2 的活性，增加了 ATOH1 基因启动子区域 H3K9ac 位点的组蛋白乙酰化。此外，ADORA3 激活增强酮体生成的原因归因于控制β-arrestin2、SHP1 和 PPARγ 之间的竞争结合。这导致 PPARγ 的非配体依赖性激活，从而促进 HMGCS2 的转录。使用 MRS1191 和 shHMGCS2 质粒阐明了 ADORA3 促进杯状细胞分化和缓解 UC 的确切机制。总之，ADORA3 的激活通过“BHB-HDAC1/2-H3K9ac”途径增强酮体生成，促进杯状细胞分化并缓解 UC。
