Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, P.R. China.
Medical Research Center, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, P.R. China.
FASEB J. 2023 Jul;37(7):e22967. doi: 10.1096/fj.202201995RR.
Neutrophils participate in the pathogenesis of ulcerative colitis (UC) through regulating the intestinal homeostasis. Several inflammatory diseases are reported to be regulated by proline-rich tyrosine kinase 2B (PTK2B). However, the role of PTK2B in regulating the function of neutrophils and the pathogenesis of UC remains unknown. In this study, the mRNA and protein levels of PTK2B in the colonic tissues from UC patients were measured by using quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry. TAE226, a PTK2B inhibitor, was used to inhibit the activity of PTK2B in neutrophils, and then, the pro-inflammatory factors were analyzed by using qRT-PCR and ELISA. To determine the role of PTK2B in intestinal inflammation, a dextran sulfate sodium (DSS)-induced colitis model was established in PTK2B gene knockout (PTK2B KO) and wild-type (WT) mice. We found that compared with healthy donor controls, the expression level of PTK2B was significantly elevated in inflamed mucosa from UC patients. In addition, expression of PTK2B was positively correlated with the severity of disease. Pharmacological inhibition of PTK2B could markedly reduce the generation of reactive oxygen species (ROS), myeloperoxidase (MPO), and antimicrobial peptides (S100a8 and S100a9) in neutrophils. The vitro study showed that tumor necrosis factor (TNF)-α is involved in promoting the expression of PTK2B in neutrophils. As expected, UC patients treated with infliximab, an anti-TNF-α agent, showed significantly reduced level of PTK2B in neutrophils, as well as in the intestinal mucosa. Of note, compared with DSS-treated WT mice, DSS-treated PTK2B KO mice showed more severe colitis symptoms. Mechanistically, PTK2B could enhance neutrophil migration by regulating CXCR2 and GRK2 expression via the p38 MAPK pathway. Additionally, mice treated with TAE226 exhibited the same effects. In conclusion, PTK2B is involved in the pathogenesis of UC by promoting the migration of neutrophils and inhibiting mucosal inflammation, highlighting PTK2B as a new potential therapeutic target to treat UC.
中性粒细胞通过调节肠道内稳态参与溃疡性结肠炎（UC）的发病机制。有报道称，几种炎症性疾病受富含脯氨酸的酪氨酸激酶 2B（PTK2B）调节。然而，PTK2B 在调节中性粒细胞功能和 UC 发病机制中的作用尚不清楚。在这项研究中，通过实时定量聚合酶链反应（qRT-PCR）、蛋白质印迹和免疫组织化学测量 UC 患者结肠组织中 PTK2B 的 mRNA 和蛋白水平。使用 PTK2B 抑制剂 TAE226 抑制中性粒细胞中 PTK2B 的活性，然后通过 qRT-PCR 和 ELISA 分析促炎因子。为了确定 PTK2B 在肠道炎症中的作用，在 PTK2B 基因敲除（PTK2B KO）和野生型（WT）小鼠中建立葡聚糖硫酸钠（DSS）诱导的结肠炎模型。我们发现，与健康供体对照相比，UC 患者炎症黏膜中 PTK2B 的表达水平显著升高。此外，PTK2B 的表达与疾病严重程度呈正相关。PTK2B 的药理学抑制可显著减少中性粒细胞中活性氧（ROS）、髓过氧化物酶（MPO）和抗菌肽（S100a8 和 S100a9）的产生。体外研究表明，肿瘤坏死因子（TNF）-α参与促进中性粒细胞中 PTK2B 的表达。不出所料，用抗 TNF-α 药物英夫利昔单抗治疗的 UC 患者，中性粒细胞和肠黏膜中的 PTK2B 水平明显降低。值得注意的是，与 DSS 处理的 WT 小鼠相比，DSS 处理的 PTK2B KO 小鼠表现出更严重的结肠炎症状。机制上，PTK2B 通过调节 p38 MAPK 通路中的 CXCR2 和 GRK2 表达来增强中性粒细胞的迁移。此外，用 TAE226 处理的小鼠也表现出相同的效果。总之，PTK2B 通过促进中性粒细胞迁移和抑制黏膜炎症参与 UC 的发病机制，突显 PTK2B 作为治疗 UC 的新的潜在治疗靶点。
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