Li Yichen, Lin Xutao, Wang Wenxia, Wang Wenyu, Cheng Sijing, Huang Yibo, Zou Yifeng, Ke Jia, Zhu Lixin
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Department of Colorectal Surgery, The Sixth Affiliated Hospital, Guangdong Institute of Gastroenterology, Sun Yat-sen University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Department of Gastrointestinal Endoscopy, The Sixth Affiliated Hospital, Guangdong Institute of Gastroenterology, Sun Yat-sen University, Guangzhou, China.
Front Microbiol. 2022 Jun 2;13:926915. doi: 10.3389/fmicb.2022.926915. eCollection 2022.
NLRP3 inflammasome is implicated in the pathogenesis of inflammatory bowel diseases (IBD). Since guanylate-binding protein 5 (GBP5) induces the NLRP3 inflammasome activity, we aim to investigate the potential role of GBP5 in IBD pathogenesis. The expression of GBP5, NLRP3 inflammasome, and related cytokines and chemokines was examined in two cohorts of IBD patients and healthy controls, by microarray transcriptome analysis and quantitative real-time PCR. Cellular localization of GBP5 in colonic biopsies was examined by immunohistochemistry and immunofluorescence with confocal microscopy. For functional studies, was induced by interferon γ or silenced by siRNA or CRISPR/CAS9 technique, and inflammatory activities were evaluated at mRNA and protein levels. We found that the expression of was elevated in colonic mucosa in two geographically and culturally distinct IBD cohorts. In colonic tissues of IBD patients, GBP5 expression was mainly confined to immune cells and the levels of expression were correlated with those of the inflammatory cytokines and chemokines. In cultured T and macrophage cells, the expression of proinflammatory cytokines and chemokines was increased when was induced, while deficiency leads to decreased expression of proinflammatory mediators including gasdermin D, caspase 1, cytokines, and chemokines. We conclude that GBP5 is required in the expression of many proinflammatory cytokines and chemokines in intestinal immune cells. In addition, GBP5 may upregulate inflammatory reactions through an inflammasome-mediated mechanism. Since GBP5 plays a proinflammatory role at the early steps of the inflammatory cascades of IBD pathogenesis, and is implicated in IBD patients of distinct genetic and environmental backgrounds, targeting GBP5 could be an effective strategy for the management of IBD.
NLRP3炎性小体与炎症性肠病（IBD）的发病机制有关。由于鸟苷酸结合蛋白5（GBP5）可诱导NLRP3炎性小体活性，我们旨在研究GBP5在IBD发病机制中的潜在作用。通过微阵列转录组分析和定量实时PCR，检测了两组IBD患者和健康对照中GBP5、NLRP3炎性小体以及相关细胞因子和趋化因子的表达。通过免疫组织化学和共聚焦显微镜免疫荧光检查结肠活检组织中GBP5的细胞定位。对于功能研究，通过干扰素γ诱导或采用siRNA或CRISPR/CAS9技术使其沉默，并在mRNA和蛋白质水平评估炎症活性。我们发现，在两个地理位置和文化背景不同的IBD队列中，结肠黏膜中GBP5的表达均升高。在IBD患者的结肠组织中，GBP5表达主要局限于免疫细胞，且GBP5表达水平与炎性细胞因子和趋化因子的水平相关。在培养的T细胞和巨噬细胞中，诱导GBP5时促炎细胞因子和趋化因子的表达增加，而GBP5缺乏则导致包括gasdermin D、半胱天冬酶1、细胞因子和趋化因子在内的促炎介质表达降低。我们得出结论，肠道免疫细胞中许多促炎细胞因子和趋化因子的表达需要GBP5。此外，GBP5可能通过炎性小体介导的机制上调炎症反应。由于GBP5在IBD发病机制的炎症级联反应早期发挥促炎作用，且与不同遗传和环境背景的IBD患者有关，靶向GBP5可能是治疗IBD的有效策略。
