Zhao Yu-Xin, Sun Ying-Yin, Li Liang-Yun, Li Xiao-Feng, Li Hai-di, Chen Xin, Xia Ran, Yang Ying-Li, Jiang Xin-Yu, Zuo Long-Quan, Meng Xiao-Ming, Wang Hua, Huang Cheng, Li Jun
Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032, China.
Acta Pharmacol Sin. 2025 Jan;46(1):134-146. doi: 10.1038/s41401-024-01333-5. Epub 2024 Jul 11.
Macrophage polarization is vital to mounting a host defense or repairing tissue in various liver diseases. Excessive activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome is related to the orchestration of inflammation and alcohol-associated liver disease (ALD) pathology. Rab GTPases play critical roles in regulating vesicular transport. In this study we investigated the role of Rab11b in ALD, aiming to identify effective therapeutic targets. Here, we first demonstrated a decreased expression of Rab11b in macrophages from ALD mice. Knockdown of Rab11b by macrophage-specific adeno-associated virus can alleviate alcohol induced liver inflammation, injury and steatosis. We found that LPS and alcohol stimulation promoted Rab11b transferring from the nucleus to the cytoplasm in bone marrow-derived macrophages (BMDM) cells. Rab11b specifically activated the NLRP3 inflammasome in BMDMs and RAW264.7 cells to induce M1 macrophage polarization. Rab11b overexpression in BMDMs inhibited autophagic flux, leading to the suppression of LC3B-mediated NLRP3 degradation. We conclude that impaired Rab11b could alleviate alcohol-induced liver injury via autophagy-mediated NLRP3 degradation.
巨噬细胞极化对于在各种肝脏疾病中启动宿主防御或修复组织至关重要。含3个吡啉结构域的NLR家族（NLRP3）炎性小体的过度激活与炎症及酒精性肝病（ALD）病理过程的调控有关。Rab GTP酶在调节囊泡运输中起关键作用。在本研究中，我们调查了Rab11b在ALD中的作用，旨在确定有效的治疗靶点。在此，我们首先证明了ALD小鼠巨噬细胞中Rab11b表达降低。通过巨噬细胞特异性腺相关病毒敲低Rab11b可减轻酒精诱导的肝脏炎症、损伤和脂肪变性。我们发现脂多糖（LPS）和酒精刺激促进Rab11b从骨髓来源的巨噬细胞（BMDM）细胞核转移至细胞质。Rab11b特异性激活BMDM和RAW264.7细胞中的NLRP3炎性小体以诱导M1巨噬细胞极化。BMDM中Rab11b过表达抑制自噬流，导致LC3B介导的NLRP3降解受到抑制。我们得出结论，Rab11b功能受损可通过自噬介导的NLRP3降解减轻酒精诱导的肝损伤。
