University of Queensland and Princess Alexandra Hospital, Brisbane, Queensland, Australia.
Arthritis Rheumatol. 2014 Jul;66(7):1755-67. doi: 10.1002/art.38638.
Spondyloarthritides (SpA) occur in 1% of the population and include ankylosing spondylitis (AS) and arthropathy of inflammatory bowel disease (IBD), with characteristic spondylitis, arthritis, enthesitis, and IBD. Genetic studies implicate interleukin-23 (IL-23) receptor signaling in the development of SpA and IBD, and IL-23 overexpression in mice is sufficient for enthesitis, driven by entheseal-resident T cells. However, in genetically prone individuals, it is not clear where IL-23 is produced and how it drives the SpA syndrome, including IBD or subclinical gut inflammation of AS. Moreover, it is unclear why specific tissue involvement varies between patients with SpA. We undertook this study to determine the location of IL-23 production and its role in SpA pathogenesis in BALB/c ZAP-70(W163C)-mutant (SKG) mice injected intraperitoneally with β-1,3-glucan (curdlan).
Eight weeks after curdlan injection in wild-type or IL-17A(-/-) SKG or BALB/c mice, pathology was scored in tissue sections. Mice were treated with anti-IL-23 or anti-IL-22. Cytokine production and endoplasmic reticulum (ER) stress were determined in affected organs.
In curdlan-treated SKG mice, arthritis, enthesitis, and ileitis were IL-23 dependent. Enthesitis was specifically dependent on IL-17A and IL-22. IL-23 was induced in the ileum, where it amplified ER stress, goblet cell dysfunction, and proinflammatory cytokine production. IL-17A was pathogenic, while IL-22 was protective against ileitis. IL-22+CD3- innate-like cells were increased in lamina propria mononuclear cells of ileitis-resistant BALB/c mice, which developed ileitis after curdlan injection and anti-IL-22.
In response to systemic β-1,3-glucan, intestinal IL-23 provokes local mucosal dysregulation and cytokines driving the SpA syndrome, including IL-17/IL-22-dependent enthesitis. Innate IL-22 production promotes ileal tolerance.
脊柱关节炎（SpA）在人群中的发病率为 1%，包括强直性脊柱炎（AS）和炎症性肠病（IBD）的关节病，具有特征性的脊柱炎、关节炎、肌腱炎和 IBD。遗传研究表明白细胞介素-23（IL-23）受体信号在 SpA 和 IBD 的发展中起作用，而在小鼠中过度表达 IL-23 足以通过附着点 resident T 细胞引起附着点炎。然而，在遗传易感个体中，尚不清楚 IL-23 是在哪里产生的，以及它如何驱动 SpA 综合征，包括 IBD 或 AS 的亚临床肠道炎症。此外，尚不清楚为什么 SpA 患者的特定组织受累不同。我们进行这项研究是为了确定 IL-23 的产生部位及其在 BALB/c ZAP-70(W163C)-突变（SKG）小鼠中 SpA 发病机制中的作用，这些小鼠被腹腔内注射β-1,3-葡聚糖（凝乳酶）。
在野生型或 IL-17A(-/-)SKG 或 BALB/c 小鼠腹腔注射凝乳酶 8 周后，对组织切片进行病理学评分。用抗 IL-23 或抗 IL-22 治疗小鼠。检测受影响器官中的细胞因子产生和内质网（ER）应激。
在凝乳酶处理的 SKG 小鼠中，关节炎、附着点炎和回肠炎依赖于 IL-23。附着点炎特别依赖于 IL-17A 和 IL-22。IL-23 在回肠中被诱导，在回肠中它放大了内质网应激、杯状细胞功能障碍和促炎细胞因子的产生。IL-17A 具有致病性，而 IL-22 则对回肠炎具有保护作用。在回肠炎抵抗 BALB/c 小鼠的固有层单核细胞中，IL-22+CD3-固有样细胞增加，这些小鼠在腹腔注射凝乳酶和抗 IL-22 后发展为回肠炎。
对系统性β-1,3-葡聚糖的反应中，肠道 IL-23 引发局部黏膜失调和细胞因子驱动 SpA 综合征，包括依赖于 IL-17/IL-22 的附着点炎。先天的 IL-22 产生促进回肠耐受。
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