氯膦酸二鈉脂質體清除肝臟巨噬細胞助力肝纖維化恢復研究

中文摘要：

最近的數據表明，即使在肝硬化的后期，肝纖維化也可以消退，將免疫反應從促炎性轉變為可恢復性譜被認為是一個有前途的選擇?？刂蒲装Y表型變化并因此可能逆轉肝纖維化的免疫調節網絡鮮為人知。在這里，我們表明，在從終末期纖維化患者獲得的精確切割的人肝切片和小鼠模型中，使用藥物或抗體驅動的方法抑制粘膜相關不變 T細胞 （MAIT） ，限制纖維化進展，甚至消退纖維化，在慢性毒性或非酒精性脂肪性肝炎 （NASH） 誘導的肝損傷后。結合 RNA 測序、體內功能研究（在雄性小鼠中進行）和共培養實驗的機制研究表明，MAIT 細胞-單核細胞/巨噬細胞相互作用的破壞通過增加恢復性 Ly6C^lo 的比率而犧牲促纖維化 Ly6C^hi 單核細胞衍生的巨噬細胞并促進兩個亞群中的自噬表型。因此，我們的數據表明，MAIT 細胞活化和肝臟巨噬細胞隨之而來的表型轉變是肝纖維化的重要致病特征，可以靶向抗纖維化治療。

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.

論文信息：

論文題目：MAIT cell inhibition promotes liver fibrosis regression via macrophage phenotype reprogramming

期刊名稱：Nature Communications

時間期卷：14, Article number: 1830 (2023)

在線時間：2023年4月1日

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

產品信息：

貨號：CP-005-005

規格：5ml+5ml

品牌：Liposoma

產地：荷蘭

名稱：Clodronate Liposomes and Control Liposomes

辦事處：Target Technology（靶點科技）

Clodronate Liposomes氯膦酸鹽脂質體助力肝臟纖維化模型研究，荷蘭Liposoma巨噬細胞清除劑Clodronate Liposomes見刊于Nature Communications：

氯膦酸二鈉脂質體清除肝臟巨噬細胞助力肝纖維化恢復研究

Liposoma巨噬細胞清除劑Clodronate Liposomes氯膦酸二鈉脂質體的材料和方法：

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（見下圖） were created with BioRender® software.