Animal Biochemistry Division, ICAR-NDRI, India 132001; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW 2052, Australia; Mark Wainwright Analytical Centre, Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, NSW 2052, Australia; Steno Diabetes Center Copenhagen, DK-2730 Herlev, Denmark.
Life Sci. 2023 Aug 15;327:121868. doi: 10.1016/j.lfs.2023.121868. Epub 2023 Jun 15.
The intestinal tract is the largest immune organ in the human body, comprising a complex network of immune cells and epithelial cells that perform a variety of functions such as nutrient absorption, digestion, and waste excretion. Maintenance of homeostasis and effective responses to injury in the colonic epithelium are crucial for maintaining homeostasis between these two cell types. The onset and perpetuation of gut inflammation, characterizing inflammatory bowel diseases (IBD), are triggered by constitutive dysregulation of cytokine production. IL-33 is a newly characterized cytokine that has emerged as a critical modulator of inflammatory disorders. IL-33 is constitutively expressed in the nuclei of different cell types such as endothelial, epithelial, and fibroblast-like cells. Upon tissue damage or pathogen encounter, IL-33 is released as an alarmin and signals through a heterodimer receptor that consists of serum Stimulation-2 (ST2) and IL-1 receptor accessory protein (IL-1RAcP). IL-33 has the ability to induce Th2 cytokine production and enhance both Th1 and Th2, as well as Th17 immune responses. Exogenous administration of IL-33 in mice caused pathological changes in most mucosal tissues such as the lung and the gastrointestinal (GI) tract associated with increased production of type 2 cytokines and chemokines. In vivo and in vitro, primary studies have exhibited that IL-33 can activate Th2 cells, mast cells, or basophils to produce type 2 cytokines such as IL-4, IL-5, and IL-13. Moreover, several novel cell populations, collectively referred to as "type 2 innate lymphoid cells" were identified as being IL-33 responsive and are thought to be important for initiating type 2 immunity. Nevertheless, the underlying mechanisms by which IL-33 promotes type 2 immunity in the GI tract remain to be fully understood. Recently, it has been discovered that IL-33 plays important roles in regulatory immune responses. Highly suppressive ST2 + FoxP3+ Tregs subsets regulated by IL-33 were identified in several tissues, including lymphoid organs, gut, lung, and adipose tissues. This review aims to comprehensively summarize the current knowledge on IL-33's role in the gut immune system, its crosstalk, and regulation. The article will provide insights into the potential applications of IL-33-based therapies in the treatment of gut inflammatory disorders.
肠道是人体最大的免疫器官，由复杂的免疫细胞和上皮细胞网络组成，具有多种功能，如营养吸收、消化和废物排泄。维持肠道上皮细胞的内稳态和对损伤的有效反应对于维持这两种细胞类型之间的平衡至关重要。肠道炎症的发作和持续，其特征是炎症性肠病（IBD），是由细胞因子产生的固有失调触发的。IL-33 是一种新鉴定的细胞因子，已成为炎症性疾病的关键调节剂。IL-33 在不同的细胞类型（如内皮细胞、上皮细胞和成纤维细胞样细胞）的核中持续表达。在组织损伤或病原体接触后，IL-33 作为警报素释放，并通过由血清刺激 2（ST2）和白细胞介素 1 受体辅助蛋白（IL-1RAcP）组成的异二聚体受体信号传递。IL-33 能够诱导 Th2 细胞因子的产生，并增强 Th1 和 Th2 以及 Th17 免疫反应。在小鼠中给予外源性 IL-33 会导致大多数黏膜组织（如肺和胃肠道（GI）道）发生病理变化，与 2 型细胞因子和趋化因子的产生增加有关。在体内和体外，初步研究表明，IL-33 可以激活 Th2 细胞、肥大细胞或嗜碱性粒细胞产生 IL-4、IL-5 和 IL-13 等 2 型细胞因子。此外，还鉴定出一些新的细胞群，统称为“2 型先天淋巴样细胞”，它们对 IL-33 有反应，被认为对启动 2 型免疫很重要。然而，IL-33 促进 GI 道 2 型免疫的潜在机制仍有待充分了解。最近，人们发现 IL-33 在调节免疫反应中发挥着重要作用。在包括淋巴器官、肠道、肺和脂肪组织在内的几种组织中，发现了受 IL-33 调节的高度抑制性 ST2+FoxP3+Treg 亚群。本文旨在全面总结目前关于 IL-33 在肠道免疫系统中的作用、相互作用和调节的知识。本文将为基于 IL-33 的治疗方法在治疗肠道炎症性疾病中的潜在应用提供见解。
