中文摘要：

NOD樣受體蛋白3（NLRP3）炎癥小體在人類急性和慢性肝病中發(fā)揮著至關(guān)重要的作用。然而，NLRP3在肝臟再生中的作用及其細(xì)胞特異性貢獻(xiàn)仍不清楚。在這里，我們發(fā)現(xiàn)，在70%部分肝切除（PHx）小鼠模型和臨床數(shù)據(jù)中，NLRP3在肝臟再生早期階段高度激活。全球性NLRP3缺失或藥理學(xué)阻斷NLRP3顯著增強(qiáng)了肝臟再生，而NLRP3過(guò)表達(dá)在PHx后則損害了肝臟再生。此外，與肝細(xì)胞特異性敲除（Nlrp3Δhep）不同，髓系特異性敲除Nlrp3的小鼠（Nlrp3Δmye）顯示肝臟再生明顯改善，與對(duì)照組（Nlrp3fl/fl）相比有顯著差異。在機(jī)制上，Nlrp3缺失促進(jìn)了髓系-上皮-受體酪氨酸激酶（MerTK）介導(dǎo)的凋亡細(xì)胞清除作用，從而誘導(dǎo)巨噬細(xì)胞向促修復(fù)的Ly6C低表型轉(zhuǎn)化。值得注意的是，通過(guò)MCC950抑制NLRP3能夠有效逆轉(zhuǎn)高脂飲食小鼠PHx后肝臟再生受損的情況。我們的研究結(jié)果為術(shù)后肝衰竭的預(yù)防和治療提供了潛在的治療策略。

英文摘要：

The NOD-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in human acute and chronic liver diseases. However, the role and cell-specific contribution of NLRP3 in liver regeneration remains unclear. Here, we found that NLRP3 was highly activated during the early stage of liver regeneration via 70% partial hepatectomy (PHx) mice model and clinical data. Global NLRP3 depletion or pharmacologically blocking NLRP3 significantly enhanced liver regeneration, while NLRP3 overexpression impaired it after PHx. Furthermore, mice with myeloid-specific knockout of Nlrp3 (Nlrp3Δmye), rather than hepatocyte-specific knockout (Nlrp3Δhep), showed improved liver regeneration compared to control (Nlrp3fl/fl). Mechanistically, deficiency of Nlrp3 promoted myeloid-epithelial-reproductive tyrosine kinase (MerTK)–mediated efferocytosis, thereby inducing macrophages toward a pro-reparative Ly6Clo phenotype. Notably, NLRP3 inhibition by MCC950 effectively reversed the impairment of liver regeneration after PHx in mice fed a high-fat diet. Our findings provide a potential therapeutic strategy for the prevention and treatment of post-hepatectomy liver failure.

論文信息：

論文題目：NLRP3 inflammasome constrains liver regeneration through impairing MerTK-mediated macrophage efferocytosis

期刊名稱：Science Advances

時(shí)間期卷：Vol 1, Issue 1(2025)

在線時(shí)間：2025年1月1日

DOI：doi.org/10.1126/sciadv.adq5786

產(chǎn)品信息：

貨號(hào)：CP-005-005

規(guī)格：5ml+5ml

品牌：Liposoma

產(chǎn)地：荷蘭

名稱：Clodronate Liposomes&Control Liposomes

辦事處：靶點(diǎn)科技

Clodronate Liposomes氯膦酸鹽脂質(zhì)體在小鼠創(chuàng)肝臟再生模型種清除肝臟巨噬細(xì)胞。荷蘭Liposoma巨噬細(xì)胞清除劑ClodronateLiposomes見(jiàn)刊于Science Advances：NLRP3 炎癥小體通過(guò)抑制 MerTK 介導(dǎo)的巨噬細(xì)胞胞葬作用，進(jìn)而限制肝臟再生。

Liposoma巨噬細(xì)胞清除劑Clodronate Liposomes氯膦酸二鈉脂質(zhì)體清除巨噬細(xì)胞的材料和方法：

To generate the PHx model, mice were subjected to 70% PHx as our previous description . For macrophage depletion, 200 μl of CLs (Liposoma) and control liposomes were intraperitoneally injected 4 hours before PHx. For hepatic NLRP3 overexpression, the mice were injected with AAV8-NLRP3 (AAV-OE) or AAV-8-NTC (AAV-BL) (General Biology) at a dosage of 1 × 1012 vector genomes (vg) per mouse intravenously 20 days before PHx operation. For NLRP3 inhibition, MCC950 (TargetMol, no. T3701) was administrated intraperitoneally to a concentration of 20 μg/kg 2 hours before PHx. For MerTK inhibition, UNC2025 (TargetMol, no. T7007) was administrated intraperitoneally to a concentration of 50 mg/kg 2 hours before and 24 hours after PHx. For IL-1β inhibition, IL-1β neutralizing antibody (R&D Systems, no. AF-401-NA) was administrated intraperitoneally to a concentration of 10 mg/kg 4 hours before PHx. For macrophage depletion, CLs (200 μl; Yeasen, no. 40337ES08) and control liposomes (200 μl; Yeasen, no. 40338ES08) were administered by tail vein injection 4 hours before PHx. The mice were humanly euthanized at indicated time after PHx. Blood and liver tissue samples were collected for examination. All animal experiments were approved by the Ethics Committee Medical College of Qingdao University (approval no. QDU-AEC-2021151).

巨噬細(xì)胞清除材料和方法文獻(xiàn)截圖：