Cannabinoid receptor 2 promotes the intracellular degradation of HMGB1 via the autophagy-lysosome pathway in macrophage.
Cannabinoid receptor 2 promotes the intracellular degradation of HMGB1 via the autophagy-lysosome pathway in macrophage.
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DOI：
10.1016/j.intimp.2019.106007
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发表时间：
2019-12
影响因子：
5.6
通讯作者：
Huiting Zhou;Rao Du;Gang Li;Z. Bai;Jin Ma;Chenmei Mao;Jian Wang;Huan Gui
中科院分区：
文献类型：
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作者：
Huiting Zhou;Rao Du;Gang Li;Z. Bai;Jin Ma;Chenmei Mao;Jian Wang;Huan Gui
高迁移率组框1 （HMGB1）是许多炎性疾病的晚期炎症介质。细胞外HMGB1可与多种膜受体结合，激活下游信号分子，促进炎症，导致细胞和组织损伤。在我们之前的工作中，我们发现大麻素受体Ⅱ（CB2R）在体内和体外脂多糖（LPS）诱导的脓毒症模型中抑制HMGB1的表达，但其潜在机制尚不清楚。本研究旨在探讨CB2R抑制HMGB1的可能途径。本研究发现CB2R特异性激动剂GW405833 （GW）可以诱导细胞内HMGB1降解，而不影响腹膜巨噬细胞中HMGB1 mRNA的表达。然后我们观察到自噬抑制剂3-甲基腺嘌呤（3-MA）而不是蛋白酶体抑制剂MG-132 （MG）可以阻断gw诱导的HMGB1降解，这表明自噬溶酶体而不是泛素化途径参与了这一过程。进一步研究表明，GW可以通过提高LC3Ⅱ水平和降低p62蛋白表达来促进巨噬细胞自噬通量的完整性。研究还发现，抑制自噬可阻断gw诱导的巨噬细胞HMGB1核易位。GW可上调组织蛋白酶B （CTSB）的表达，抑制CTSB可阻断GW诱导的HMGB1降解。综上所述，在巨噬细胞中，激活CB2R可通过自噬-溶酶体途径促进HMGB1的胞内降解。
High mobility group box 1 (HMGB1) is a late phase inflammatory mediator in many inflammatory diseases. Extracellular HMGB1 could bind to many membrane receptors to activate downstream signaling molecules and promote inflammation resulting in cell and tissue damage. In our previous work, we found cannabinoid receptor Ⅱ(CB2R) inhibited the expression of HMGB1 in lipopolysaccharide (LPS)-induced septic modelsin vivoandin vitro, but the underlying mechanism is still unclear. The present study was aimed to explore the possible pathway through which CB2R suppressed HMGB1. Here, we found that the specific agonist of CB2R, GW405833 (GW) could induce intracellular HMGB1 degradation without influencing HMGB1 mRNA in peritoneal macrophages. Then we observed that autophagy inhibitor 3-methyladenine (3-MA) but not proteasome inhibitor MG-132 (MG) could block GW-induced HMGB1 degradation, which indicated that the autophagy-lysosome but not the ubiquitination pathway was involved in this process. Further study showed that GW could promote the integrity of autophagy flux in macrophages in terms of increased level of LC3Ⅱand decreased expression of p62 protein. It also observed that inhibition of autophagy blocked GW-induced nuclear translocation of HMGB1 in macrophages. GW could up-regulate expression of Cathepsin B (CTSB), and inhibition of CTSB blocked GW-induced HMGB1 degradation. In summary, all the data showed that activation of CB2R could promote the intracellular degradation of HMGB1 via the autophagy-lysosome pathway in macrophage.