Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510000, China.
Guangdong Provincial Key Laboratory of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510000, China; Department of Gastroenterology, Yuebei People's Hospital, Shantou University Medical College, Shaoguan 512026, China.
Biochim Biophys Acta Mol Basis Dis. 2024 Oct;1870(7):167279. doi: 10.1016/j.bbadis.2024.167279. Epub 2024 Jun 4.
Ulcerative colitis (UC) is a major inflammatory bowel disease (IBD) characterized by intestinal epithelium damage. Recently, Lipocalin-2 (LCN2) has been identified as a potential fecal biomarker for patients with UC. However, further investigation is required to explore its pro-inflammatory role in UC and the underlying mechanism. The biological analysis revealed that Lcn2 serves as a putative signature gene in the colon mucosa of patients with UC and its association with the capsase/pyroptosis signaling pathway in UC. In wild-type mice with DSS-induced colitis, LCN2 overexpression in colon mucosa via in vivo administration of Lcn2 overexpression plasmid resulted in exacerbation of colitis symptoms and epithelium damage, as well as increased expression levels of pyroptosis markers (cleaved caspase1, GSDMD, IL-1β, HMGB1 and IL-18). Additionally, we observed downregulation in the expression levels of pyroptosis markers following in vivo silencing of LCN2. However, the pro-inflammatory effect of LCN2 overexpression was effectively restrained in GSDMD-KO mice. Moreover, single-cell RNA-sequencing analysis revealed that Lcn2 was predominantly expressed in the intestinal epithelial cells (IECs) within the colon mucosa of patients with UC. We found that LCN2 effectively regulated pyroptosis events by modulating the NF-κB/NLRP3/GSDMD signaling axis in NCM460 cells stimulated by LPS and ATP. These findings demonstrate the pro-inflammatory role of LCN2 in colon epithelium and provide a potential target for inhibiting pyroptosis in UC.
溃疡性结肠炎（UC）是一种主要的炎症性肠病（IBD），其特征为肠道上皮损伤。最近，脂钙素-2（LCN2）被鉴定为 UC 患者的潜在粪便生物标志物。然而，需要进一步研究来探索其在 UC 中的促炎作用及其潜在机制。生物学分析表明，Lcn2 作为 UC 患者结肠黏膜中的一个假定特征基因，与 UC 中的 caspase/焦亡信号通路相关。在 DSS 诱导的结肠炎野生型小鼠中，通过体内给予 LCN2 过表达质粒，在结肠黏膜中过表达 LCN2 导致结肠炎症状和上皮损伤加剧，以及焦亡标志物（裂解的 caspase1、GSDMD、IL-1β、HMGB1 和 IL-18）的表达水平升高。此外，我们观察到体内沉默 LCN2 后焦亡标志物的表达水平下调。然而，GSDMD-KO 小鼠中 LCN2 的促炎作用得到了有效抑制。此外，单细胞 RNA 测序分析显示，Lcn2 在 UC 患者的结肠黏膜中主要在肠道上皮细胞（IECs）中表达。我们发现 LCN2 通过调节 LPS 和 ATP 刺激的 NCM460 细胞中的 NF-κB/NLRP3/GSDMD 信号轴有效调节焦亡事件。这些发现表明 LCN2 在结肠上皮中的促炎作用，并为抑制 UC 中的焦亡提供了一个潜在的靶点。
