The ADA Forsyth Institute, 245 First Street, Cambridge, MA 02142, United States; Department of Oral Surgery, Pathology, and Clinical Dentistry, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
The ADA Forsyth Institute, 245 First Street, Cambridge, MA 02142, United States.
Mol Immunol. 2024 Sep;173:20-29. doi: 10.1016/j.molimm.2024.06.010. Epub 2024 Jul 16.
Sjӧgren's syndrome is a systemic autoimmune disease primarily targeting the salivary and lacrimal glands. Our previous investigations have shown that administration of interleukin-22 (IL-22), an IL-10 family cytokine known for its complex and context-dependent effects on tissues, either protective- or detrimental, to salivary glands leads to hypofunction and pathological changes of salivary glands in C57BL/6 mice and in non-obese diabetic (NOD) mice, the latter being a commonly used model of Sjӧgren's syndrome. This study aims to delineate the pathophysiological roles of endogenously produced IL-22 in the development of salivary gland pathologies and dysfunction associated with Sjӧgren's disease in the NOD mouse model. Our results reveal that neutralizing IL-22 offered a protective effect on salivary gland function without significantly affecting the immune cell infiltration of salivary glands or the autoantibody production. Blockade of IL-22 reduced the levels of phosphorylated STAT3 in salivary gland tissues of NOD mice, while its administration to salivary glands had the opposite effect. Correspondingly, the detrimental impact of exogenously applied IL-22 on salivary glands was almost completely abrogated by a specific STAT3 inhibitor. Moreover, IL-22 blockade led to a downregulation of protein amounts of Ten-Eleven-Translocation 2, a methylcytosine dioxygenase critical for mediating interferon-induced responses, in salivary gland epithelial cells. IL-22 neutralization also exerted a protective effect on the salivary gland epithelial cells that express high levels of surface EpCAM and bear the stem cell potential, and IL-22 treatment in vitro hampered the survival/expansion of these salivary gland stem cells, indicating a direct negative impact of IL-22 on these cells. In summary, this study has uncovered a critical pathogenic role of the endogenous IL-22 in the pathogenesis of Sjögren's disease-characteristic salivary gland dysfunction and provided initial evidence that this effect is dependent on STAT3 activation and potentially achieved through fostering Tet2-mediated interferon responses in salivary gland epithelial cells and negatively affecting the EpCAM salivary gland stem cells.
干燥综合征是一种主要针对唾液腺和泪腺的系统性自身免疫性疾病。我们之前的研究表明，白细胞介素 22（IL-22）是一种白细胞介素 10 家族细胞因子，因其对组织的复杂和依赖于背景的作用而闻名，对唾液腺既有保护作用，也有损害作用，无论是在 C57BL/6 小鼠还是在非肥胖型糖尿病（NOD）小鼠中，给予 IL-22 都会导致唾液腺功能低下和病理改变，后者是干燥综合征的常用模型。本研究旨在阐明内源性产生的 IL-22 在 NOD 小鼠模型中与干燥病相关的唾液腺病理和功能障碍发展中的病理生理作用。我们的结果表明，中和 IL-22 对唾液腺功能具有保护作用，而不会显著影响唾液腺的免疫细胞浸润或自身抗体的产生。阻断 IL-22 可降低 NOD 小鼠唾液腺组织中磷酸化 STAT3 的水平，而其在唾液腺中的给药则产生相反的效果。相应地，外源性应用 IL-22 对唾液腺的有害影响几乎完全被一种特定的 STAT3 抑制剂所消除。此外，IL-22 阻断导致唾液腺上皮细胞中 Ten-Eleven-Translocation 2 的蛋白量下调，Ten-Eleven-Translocation 2 是一种关键的甲基胞嘧啶双加氧酶，可介导干扰素诱导的反应。阻断 IL-22 还对表达高水平表面 EpCAM 并具有干细胞潜能的唾液腺上皮细胞发挥保护作用，体外 IL-22 处理会阻碍这些唾液腺干细胞的存活/扩增，表明 IL-22 对这些细胞有直接的负面影响。总之，本研究揭示了内源性 IL-22 在干燥病特征性唾液腺功能障碍发病机制中的关键致病作用，并提供了初步证据表明，这种作用依赖于 STAT3 激活，并可能通过促进唾液腺上皮细胞中的 Tet2 介导的干扰素反应和负性影响 EpCAM 唾液腺干细胞来实现。
