Department of Gastroenterology, Shengzhou People's Hospital, Shaoxing, China.
Genet Res (Camb). 2022 Aug 8;2022:9313559. doi: 10.1155/2022/9313559. eCollection 2022.
Ulcerative colitis (UC) is characterized by chronic, recurrent intestinal inflammation and intestinal epithelial injury including a wide range of epithelial cell death, ulcers, crypt abscesses, and the formation of fibrosis. The intestinal barrier dysfunction runs through the whole process of the occurrence and development of UC. A recent study revealed that an ubiquitin binding protein ABIN1 played a role in tissue homeostasis and autoimmunity diseases which involved in the anti-inflammatory response of intestinal epithelia cells. However, the roles of ABIN1 in ulcerative colitis pathogenesis remain unclear.
The mRNA and protein expression level of ABIN1 and necroptosis-associated genes (RIPK1, RIPK3, and MLKL) were conducted to investigate the relationship between ABIN1 and necroptosis in clinical UC specimens. Subsequently, the dextran sodium sulfate (DSS)-induced mice colitis model was used to verify the ABIN1 function in vivo. Furthermore, we established ABIN1 gain and loss function assay in CACO-2 to confirm the mechanism in UC in vitro.
We found that ABIN1, RIPK1, RIPK3, and MLKL were upregulated in UC sample and DSS-induced colitis. Upon TNF- stimulation in the intestinal epithelia cell line, overexpression of ABIN1 significantly inhibits necroptosis in the intestinal inflammation model along with the reduction expression of pro-inflammatory cytokines such as IL1B, IL6, IL8, and TNF-. Blocking RIPK1 by Nec-1s and dramatically alleviated the colitis and cell death which shares the same phenotype with ABIN1 overexpression.
Hence, the dysregulation of ABIN1 may relate to the uncontrolled necroptosis and inflammation in UC, and negatively regulate the occurrence and process of ulcerative colitis. ABIN1 activation may be considered a therapeutic strategy for UC.
溃疡性结肠炎（UC）的特征是慢性、复发性肠道炎症和肠道上皮损伤，包括广泛的上皮细胞死亡、溃疡、隐窝脓肿和纤维化的形成。肠道屏障功能障碍贯穿于 UC 的发生发展全过程。最近的一项研究表明，一种泛素结合蛋白 ABIN1 在组织稳态和自身免疫性疾病中发挥作用，涉及肠道上皮细胞的抗炎反应。然而，ABIN1 在溃疡性结肠炎发病机制中的作用尚不清楚。
通过检测临床 UC 标本中 ABIN1 和坏死性凋亡相关基因（RIPK1、RIPK3 和 MLKL）的 mRNA 和蛋白表达水平，研究 ABIN1 与坏死性凋亡之间的关系。随后，利用葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎模型验证 ABIN1 在体内的作用。此外，我们建立了 ABIN1 增益和缺失功能检测在 CACO-2 细胞中，以确认体外 UC 中的机制。
我们发现 ABIN1、RIPK1、RIPK3 和 MLKL 在 UC 样本和 DSS 诱导的结肠炎中上调。在肠上皮细胞系中受到 TNF-刺激时，ABIN1 的过表达可显著抑制肠道炎症模型中的坏死性凋亡，同时降低促炎细胞因子如 IL1B、IL6、IL8 和 TNF-的表达。用 Nec-1s 阻断 RIPK1 可显著缓解结肠炎和细胞死亡，其表型与 ABIN1 过表达相同。
因此，ABIN1 的失调可能与 UC 中不受控制的坏死性凋亡和炎症有关，并负调控溃疡性结肠炎的发生和发展。ABIN1 的激活可能被视为 UC 的一种治疗策略。
