Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Pharmacology, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland.
Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland; Department of Microbiology and Immunology, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland.
Cell Mol Gastroenterol Hepatol. 2024;18(3):101367. doi: 10.1016/j.jcmgh.2024.101367. Epub 2024 Jun 6.
BACKGROUND & AIMS: Siglec-H is a receptor specifically expressed in mouse plasmacytoid dendritic cells (pDCs), which functions as a negative regulator of interferon-α production and plays a critical role in pDC maturation to become antigen-presenting cells. The function of pDCs in autoimmune and inflammatory diseases has been reported. However, the effect of Siglec-H expression in pDCs in liver inflammation and diseases remains unclear.
Using the model of concanavalin A-induced acute liver injury (ALI), we investigated the Siglec-H/pDCs axis during ALI in BDCA2 transgenic mice and Siglec-H mice. Anti-BDCA2 antibody, anti-interleukin (IL)-21R antibody, and Stat3 inhibitor were used to specifically deplete pDCs, block IL21 receptor, and inhibit Stat3 signaling, respectively. Splenocytes and purified naive CD4 T cells and bone marrow FLT3L-derived pDCs were cocultured and stimulated with phorbol myristate acetate/ionomycin and CD3/CD28 beads, respectively.
Data showed that specific depletion of pDCs aggravated concanavalin A-induced ALI. Remarkably, alanine aminotransferase, hyaluronic acid, and proinflammatory cytokines IL6 and tumor necrosis factor-α levels were lower in the blood and liver of Siglec-H knockout mice. This was associated with attenuation of both interferon-γ/Th1 response and Stat1 signaling in the liver of Siglec-H knockout mice while intrahepatic IL21 and Stat3 signaling pathways were upregulated. Blocking IL21R or Stat3 signaling in Siglec-H knockout mice restored concanavalin A-induced ALI. Finally, we observed that the Siglec-H-null pDCs exhibited immature and immunosuppressive phenotypes (CCR9CD40), resulting in reduction of CD4 T-cell activation and promotion of IL21CD4 T cells in the liver.
During T-cell-mediated ALI, Siglec-H-null pDCs enhance immune tolerance and promote IL21CD4 T cells in the liver. Targeting Siglec-H/pDC axis may provide a novel approach to modulate liver inflammation and disease.
Siglec-H 是一种特异性表达于小鼠浆细胞样树突状细胞（pDCs）的受体，作为干扰素-α产生的负调节剂发挥作用，并在 pDC 成熟为抗原呈递细胞的过程中发挥关键作用。已有报道称 pDCs 在自身免疫和炎症性疾病中发挥作用。然而，Siglec-H 在肝炎症和疾病中的 pDC 表达的影响尚不清楚。
我们使用伴刀豆球蛋白 A 诱导的急性肝损伤（ALI）模型，在 BDCA2 转基因小鼠和 Siglec-H 小鼠中研究了 Siglec-H/pDCs 轴在 ALI 中的作用。抗-BDCA2 抗体、抗白细胞介素（IL）-21R 抗体和 Stat3 抑制剂分别用于特异性耗竭 pDCs、阻断 IL21 受体和抑制 Stat3 信号传导。脾细胞和纯化的幼稚 CD4 T 细胞以及骨髓 FLT3L 衍生的 pDCs 分别与佛波醇肉豆蔻酸乙酸/离子霉素和 CD3/CD28 珠共培养和刺激。
数据显示，特异性耗竭 pDCs 可加重伴刀豆球蛋白 A 诱导的 ALI。值得注意的是，Siglec-H 敲除小鼠的血液和肝脏中的丙氨酸氨基转移酶、透明质酸和促炎细胞因子 IL6 和肿瘤坏死因子-α水平较低。这与 Siglec-H 敲除小鼠肝脏中干扰素-γ/Th1 反应和 Stat1 信号的减弱有关，而肝内 IL21 和 Stat3 信号通路被上调。在 Siglec-H 敲除小鼠中阻断 IL21R 或 Stat3 信号可恢复伴刀豆球蛋白 A 诱导的 ALI。最后，我们观察到 Siglec-H 缺失的 pDCs 表现出不成熟和免疫抑制表型（CCR9CD40），导致 CD4 T 细胞活化减少，并促进肝内 IL21CD4 T 细胞。
在 T 细胞介导的 ALI 中，Siglec-H 缺失的 pDCs 增强免疫耐受并促进肝内 IL21CD4 T 细胞。靶向 Siglec-H/pDC 轴可能为调节肝炎症和疾病提供一种新方法。
