Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), UNLP, CONICET, CIC PBA, Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata, Argentina.
Innate Immunity Laboratory, Immunology Program, Faculty of Medicine, Biomedical Sciences Institute, Universidad de Chile, Santiago, Chile.
Front Immunol. 2020 Oct 8;11:581445. doi: 10.3389/fimmu.2020.581445. eCollection 2020.
Initially described as Th2 promoter cytokine, more recently, IL-33 has been recognized as an alarmin, mainly in epithelial and endothelial cells. While localized in the nucleus acting as a gene regulator, it can be also released after injury, stress or inflammatory cell death. As proinflammatory signal, IL-33 binds to the surface receptor ST2, which enhances mast cell, Th2, regulatory T cell, and innate lymphoid cell type 2 functions. Besides these Th2 roles, free IL-33 can activate CD8 T cells during ongoing Th1 immune responses to potentiate its cytotoxic function. Celiac Disease (CD) is a chronic inflammatory disorder characterized by a predominant Th1 response leading to multiple pathways of mucosal damage in the proximal small intestine. By immunofluorescence and western blot analysis of duodenal tissues, we found an increased expression of IL-33 in duodenal mucosa of active CD (ACD) patients. Particularly, locally digested IL-33 releases active 18/21kDa fragments which can contribute to expand the proinflammatory signal. Endothelial (CD31) and mesenchymal, myofibroblast and pericyte cells from microvascular structures in villi and crypts, showed IL-33 nuclear location; while B cells (CD20) showed a strong cytoplasmic staining. Both ST2 forms, ST2L and sST2, were also upregulated in duodenal mucosa of CD patients. This was accompanied by increased number of CD8ST2 T cells and the expression of T-bet in some ST2 intraepithelial lymphocytes and cells. IL-33 and sST2 mRNA levels correlated with IRF1, an IFN induced factor relevant in responses to viral infections and interferon mediated proinflammatory responses highly represented in duodenal tissues in ACD. These findings highlight the potential contribution of IL-33 and its fragments to exacerbate the proinflammatory circuit and potentiate the cytotoxic activity of CD8 T cells in CD pathology.
最初被描述为 Th2 启动细胞因子，最近，IL-33 被认为是警报素，主要存在于上皮细胞和内皮细胞中。虽然它在细胞核中定位于充当基因调节剂，但在损伤、应激或炎症细胞死亡后也可以释放。作为前炎性信号，IL-33 与表面受体 ST2 结合，增强肥大细胞、Th2、调节性 T 细胞和先天淋巴样细胞 2 型的功能。除了这些 Th2 作用外，游离的 IL-33 可以在持续的 Th1 免疫反应中激活 CD8 T 细胞，增强其细胞毒性功能。乳糜泻 (CD) 是一种慢性炎症性疾病，其特征是主要 Th1 反应导致近端小肠黏膜的多种途径损伤。通过对十二指肠组织的免疫荧光和 Western blot 分析，我们发现活动期 CD (ACD) 患者的十二指肠黏膜中 IL-33 表达增加。特别是，局部消化的 IL-33 释放出活性的 18/21kDa 片段，可有助于扩大前炎性信号。来自绒毛和隐窝中小血管结构的内皮 (CD31) 和间充质、肌纤维母细胞和周细胞显示 IL-33 的核定位；而 B 细胞 (CD20) 显示出强烈的细胞质染色。CD 患者的十二指肠黏膜中，ST2 的两种形式，ST2L 和 sST2，也上调。这伴随着 CD8ST2 T 细胞数量的增加和一些 ST2 上皮内淋巴细胞和 细胞中 T-bet 的表达。IL-33 和 sST2 mRNA 水平与 IRF1 相关，IRF1 是一种 IFN 诱导因子，与病毒感染和干扰素介导的炎症反应相关，在 ACD 中的十二指肠组织中高度表达。这些发现强调了 IL-33 及其片段可能加剧炎症回路，并增强 CD 病理学中 CD8 T 细胞的细胞毒性活性。
