Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Osteoporosis Center, Centre for Bone and Arthritis Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Immunol Cell Biol. 2024 Aug;102(7):578-592. doi: 10.1111/imcb.12773. Epub 2024 May 10.
Women are more prone to develop rheumatoid arthritis, with peak incidence occurring around menopause. Estrogen has major effects on the immune system and is protective against arthritis. We have previously shown that treatment with estrogen inhibits inflammation and joint destruction in murine models of arthritis, although the mechanisms involved remain unclear. Fibroblastic reticular cells (FRCs) are specialized stromal cells that generate the three-dimensional structure of lymph nodes (LNs). FRCs are vital for coordinating immune responses from within LNs and are characterized by the expression of the chemokine CCL19, which attracts immune cells. The aim of this study was to determine whether the influence of estrogen on innate and adaptive immune cells in arthritis is mediated by estrogen signaling in FRCs. Conditional knockout mice lacking estrogen receptor α (ERα) in CCL19-expressing cells (Ccl19-CreERα) were generated and tested. Ccl19-CreERα mice and littermate controls were ovariectomized, treated with vehicle or estradiol and subjected to the 28-day-long antigen-induced arthritis model to enable analyses of differentiated T- and B-cell populations and innate cells in LNs by flow cytometry. The results reveal that while the response to estradiol treatment in numbers of FRCs per LN is significantly reduced in mice lacking ERα in FRCs, estrogen does not inhibit joint inflammation or markedly affect immune responses in this arthritis model. Thus, this study validates the Ccl19-CreERα strain for studying estrogen signaling in FRCs within inflammatory diseases, although the chosen arthritis model is deemed unsuitable for addressing this question.
女性更容易患类风湿关节炎，发病高峰出现在绝经前后。雌激素对免疫系统有重要影响，可预防关节炎。我们之前已经表明，雌激素治疗可抑制关节炎小鼠模型中的炎症和关节破坏，尽管涉及的机制仍不清楚。纤维网状细胞（FRC）是专门的基质细胞，可生成淋巴结（LN）的三维结构。FRC 对于协调 LN 内的免疫反应至关重要，其特征是表达趋化因子 CCL19，该因子可吸引免疫细胞。本研究旨在确定雌激素对关节炎中固有和适应性免疫细胞的影响是否通过 FRC 中的雌激素信号转导介导。生成并测试了缺乏 CCL19 表达细胞（Ccl19-CreERα）中雌激素受体 α（ERα）的条件性敲除小鼠。Ccl19-CreERα 小鼠和同窝对照小鼠接受卵巢切除术，用载体或雌二醇处理，并进行 28 天抗原诱导的关节炎模型，以通过流式细胞术分析 LN 中分化的 T 和 B 细胞群以及固有细胞。结果表明，尽管缺乏 FRC 中 ERα 的小鼠 LN 中 FRC 数量对雌二醇治疗的反应明显降低，但雌激素并未抑制关节炎症或在该关节炎模型中显著影响免疫反应。因此，尽管选择的关节炎模型被认为不适合解决这个问题，但本研究验证了 Ccl19-CreERα 品系可用于研究炎症性疾病中的 FRC 中的雌激素信号。
