Sun Qi, Lu Zhihua, Ma Lei, Xue Dong, Liu Chang, Ye Changchun, Huang Wenbo, Dang Yueyan, Li Fanni
Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Department of General Surgery, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China.
Front Oncol. 2023 May 8;13:1190229. doi: 10.3389/fonc.2023.1190229. eCollection 2023.
Given the key role of integrins in maintaining intestinal homeostasis, anti-integrin biologics in inflammatory bowel disease (IBD) are being investigated in full swing. However, the unsatisfactory efficacy and safety of current anti-integrin biologics in clinical trials limit their widespread use in clinic. Therefore, it is particularly important to find a target that is highly and specifically expressed in the intestinal epithelium of patients with IBD.
The function of integrin αvβ6 in IBD and colitis-associated carcinoma (CAC) with the underlying mechanisms has been less studied. In the present study, we detected the level of integrin β6 within inflammation including colitis tissues in human and mouse. To investigate the role of integrin β6 in IBD and CAC, integrin β6 deficient mice were hence generated based on the construction of colitis and CAC model.
We noted that integrin β6 was significantly upregulated in inflammatory epithelium of patients with IBD. Integrin β6 deletion not only reduced infiltration of pro-inflammatory cytokines, but also attenuated disruption of tight junctions between colonic epithelial cells. Meanwhile, lack of integrin β6 affected macrophage infiltration in mice with colitis. This study further revealed that lack of integrin β6 could inhibit tumorigenesis and tumor progression in CAC model by influencing macrophage polarization, which was also involved in attenuating the degree of intestinal symptoms and inflammatory responses in mice suffering from colitis.
The present research provides a potentially new perspective and option for the treatment of IBD and CAC.
鉴于整合素在维持肠道稳态中的关键作用，炎症性肠病（IBD）中的抗整合素生物制剂正在全面研究中。然而，目前抗整合素生物制剂在临床试验中的疗效和安全性不尽人意，限制了它们在临床上的广泛应用。因此，找到一个在IBD患者肠上皮中高度特异性表达的靶点尤为重要。
整合素αvβ6在IBD和结肠炎相关癌（CAC）中的功能及其潜在机制研究较少。在本研究中，我们检测了人和小鼠炎症组织（包括结肠炎组织）中整合素β6的水平。为了研究整合素β6在IBD和CAC中的作用，基于结肠炎和CAC模型的构建，制备了整合素β6缺陷小鼠。
我们注意到整合素β6在IBD患者的炎症上皮中显著上调。整合素β6的缺失不仅减少了促炎细胞因子的浸润，还减轻了结肠上皮细胞间紧密连接的破坏。同时，整合素β6的缺失影响了结肠炎小鼠中的巨噬细胞浸润。本研究进一步揭示，整合素β6的缺失可通过影响巨噬细胞极化抑制CAC模型中的肿瘤发生和肿瘤进展，这也参与减轻结肠炎小鼠的肠道症状和炎症反应程度。
本研究为IBD和CAC的治疗提供了一个潜在的新视角和选择。
