氯膦酸二钠脂质体清除肝脏巨噬细胞助力肝纤维化恢复研究

中文摘要：

最近的数据表明，即使在肝硬化的后期，肝纤维化也可以消退，将免疫反应从促炎性转变为可恢复性谱被认为是一个有前途的选择。控制炎症表型变化并因此可能逆转肝纤维化的免疫调节网络鲜为人知。在这里，我们表明，在从终末期纤维化患者获得的精确切割的人肝切片和小鼠模型中，使用药物或抗体驱动的方法抑制粘膜相关不变 T细胞 （MAIT） ，限制纤维化进展，甚至消退纤维化，在慢性毒性或非酒精性脂肪性肝炎 （NASH） 诱导的肝损伤后。结合 RNA 测序、体内功能研究（在雄性小鼠中进行）和共培养实验的机制研究表明，MAIT 细胞-单核细胞/巨噬细胞相互作用的破坏通过增加恢复性 Ly6C^lo 的比率而牺牲促纤维化 Ly6C^hi 单核细胞衍生的巨噬细胞并促进两个亚群中的自噬表型。因此，我们的数据表明，MAIT 细胞活化和肝脏巨噬细胞随之而来的表型转变是肝纤维化的重要致病特征，可以靶向抗纤维化治疗。

英文摘要：

Recent data have shown that liver fibrosis can regress even at later stages of cirrhosis and shifting the immune response from pro-inflammatory towards a resolutive profile is considered as a promising option. The immune regulatory networks that govern the shift of the inflammatory phenotype and thus potential reversal of liver fibrosis are lesser known. Here we show that in precision-cut human liver slices obtained from patients with end-stage fibrosis and in mouse models, inhibiting Mucosal-Associated Invariant T (MAIT) cells using pharmacological or antibody-driven approaches, limits fibrosis progression and even regresses fibrosis, following chronic toxic- or non-alcoholic steatohepatitis (NASH)-induced liver injury. Mechanistic studies, combining RNA sequencing, in vivo functional studies (performed in male mice) and co-culture experiments indicate that disruption of the MAIT cell-monocyte/macrophage interaction results in resolution of fibrosis both by increasing the frequency of restorative Ly6C^lo at the expenses of pro-fibrogenic Ly6C^hi monocyte-derived macrophages and promoting an autophagic phenotype in both subsets. Thus, our data show that MAIT cell activation and the consequential phenotype shift of liver macrophages are important pathogenic features of liver fibrosis and could be targeted by anti-fibrogenic therapy.

论文信息：

论文题目：MAIT cell inhibition promotes liver fibrosis regression via macrophage phenotype reprogramming

期刊名称：Nature Communications

时间期卷：14, Article number: 1830 (2023)

在线时间：2023年4月1日

DOI：doi.org/10.1038/s41467-023-37453-5

产品信息：

货号：CP-005-005

规格：5ml+5ml

品牌：Liposoma

产地：荷兰

名称：Clodronate Liposomes and Control Liposomes

办事处：Target Technology（靶点科技）

Clodronate Liposomes氯膦酸盐脂质体助力肝脏纤维化模型研究，荷兰Liposoma巨噬细胞清除剂Clodronate Liposomes见刊于Nature Communications：

氯膦酸二钠脂质体清除肝脏巨噬细胞助力肝纤维化恢复研究

Liposoma巨噬细胞清除剂Clodronate Liposomes氯膦酸二钠脂质体的材料和方法：

Macrophage depletion by clodronate liposomes

To deplete macrophages, C57BL/6 J mice with established fibrosis were given one i.v injection of liposome-encapsulated clodronate (Clodronate Liposomes, 0.1 ml/10 g, B#C23J0518, Liposoma). Liposome-encapsulated PBS was used as control (B#P24J0518, Liposoma). Ac-6-FP was then administered daily until the sacrifice at day 1, day 2, or day 4 following the last CCl4 injection. Timeline of injections shown in Fig. 3g（见下图） were created with BioRender® software.