Chen Leilei, Zhu Fengqin, Gao Xizhuang, Yang Yonghong, Jin Guiyuan, Zhou Yaqi, Dong Guanjun, Zhou Guangxi
Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining 272000, China.
Int Immunopharmacol. 2025 Feb 20;148:114122. doi: 10.1016/j.intimp.2025.114122. Epub 2025 Jan 24.
Ulcerative colitis (UC) is a persistent chronic, non-specific inflammatory disease, and macrophages play a crucial role in its pathogenesis. Spleen tyrosine kinase (Syk) is strongly associated with the pathogenesis of several inflammatory diseases. However, the role of Syk in the pathogenesis of UC is still obscure.
Syk expression was analyzed in peripheral blood mononuclear cells (PBMCs) and colonic tissues of UC patients using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunofluorescence. A public database was used to analyze the expression of selected signature genes of interest in UC patients with different expressions of Syk. R788, a small molecule inhibitor of Syk, was used to treat macrophages from mice. The functions of macrophages were assessed using qRT-PCR, flow cytometry, and fluorescence microscopy. Dextran sodium sulfate (DSS)-induced colitis mice model was established to determine the role of Syk in UC.
The Syk levels were markedly increased in PBMCs, colonic tissues, and colonic mucosa lamina propria macrophages from UC patients, and positively related to disease activity. Inhibition of Syk with R788 decreased pro-inflammatory genes expression and increased anti-inflammatory genes expression in peritoneal macrophages and bone marrow macrophages. Blockade of Syk enhanced phagocytosis and bactericidal ability of macrophages. Syk promoted the production of reactive oxygen species of macrophages and M1-type macrophage polarization. Furthermore, inhibition of Syk alleviated intestinal mucosal inflammation in DSS-induced colitis model.
Syk plays a vital role in intestinal inflammation by regulating inflammatory responses of macrophages in UC. Targeting Syk may be a promising therapeutic approach for UC.
溃疡性结肠炎（UC）是一种持续性慢性非特异性炎症性疾病，巨噬细胞在其发病机制中起关键作用。脾酪氨酸激酶（Syk）与多种炎症性疾病的发病机制密切相关。然而，Syk在UC发病机制中的作用仍不清楚。
采用定量逆转录-聚合酶链反应（qRT-PCR）和免疫荧光法分析UC患者外周血单个核细胞（PBMC）和结肠组织中Syk的表达。利用公共数据库分析Syk表达不同的UC患者中感兴趣的选定特征基因的表达。用Syk小分子抑制剂R788处理小鼠巨噬细胞。采用qRT-PCR、流式细胞术和荧光显微镜评估巨噬细胞的功能。建立葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠模型，以确定Syk在UC中的作用。
UC患者的PBMC、结肠组织和结肠黏膜固有层巨噬细胞中Syk水平显著升高，且与疾病活动度呈正相关。用R788抑制Syk可降低腹膜巨噬细胞和骨髓巨噬细胞中促炎基因的表达，增加抗炎基因的表达。阻断Syk可增强巨噬细胞的吞噬和杀菌能力。Syk促进巨噬细胞活性氧的产生和M1型巨噬细胞极化。此外，抑制Syk可减轻DSS诱导的结肠炎模型中的肠道黏膜炎症。
Syk通过调节UC中巨噬细胞的炎症反应在肠道炎症中起重要作用。靶向Syk可能是一种有前景的UC治疗方法。
