Department of Critical Care Medicine, Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Emergency, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medical College of Jinan University, Shenzhen, China.
Front Immunol. 2020 Jun 19;11:1104. doi: 10.3389/fimmu.2020.01104. eCollection 2020.
High-mobility group box 1 protein (HMGB1) was identified as a highly conserved DNA binding nuclear protein, which participates in the processes of acute lung injury (ALI). HMGB1 binds to its specific receptors not only to activate the nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) pathways but also to regulate the activation of the phosphatidylinositol 3'-kinase/protein kinase B/mammalian target of the rapamycin (PI3K/AKT/mTOR) pathway. Mature dendritic cells (DCs) regulate acute lung inflammation and pathological injury in ALI. In addition, studies have shown that the activation of the PI3K/AKT/mTOR signaling pathway may regulate the function and maturation of DCs. Therefore, we speculate that HMGB1/PI3K/Akt/mTOR signaling participates in regulating the pathological process of ALI by regulating the maturation and function of DCs. Anti-HMGB1 antibody, rHMGB1, or LY294002 (PI3K inhibitor) was administered in a murine model of lipopolysaccharide (LPS)-induced ALI. For studies, generated bone marrow-derived dendritic cells (BMDCs) primed by LPS were stimulated with the same reagents. The effects of these different treatments were observed on the expression of PI3K, AKT, and mTOR and on the function of DCs. HMGB1 upregulated the expression of PI3K, Akt, and mTOR mRNA and phosphorylated proteins in BMDCs. The HMGB1/PI3K/Akt/mTOR signaling pathway induced the maturation and antigen-presenting ability of lung DCs, mediated the percentage of myeloid DCs (mDCs), and enhanced the adhesion and chemotactic ability of lung DCs. HMGB1/PI3K/Akt/mTOR signaling participates in the pathological process of ALI by regulating the maturation and functions of DCs.
高迁移率族蛋白 B1（HMGB1）被鉴定为一种高度保守的 DNA 结合核蛋白，参与急性肺损伤（ALI）的过程。HMGB1 通过与其特异性受体结合，不仅激活核因子（NF）-κB 和丝裂原活化蛋白激酶（MAPK）途径，还调节磷脂酰肌醇 3'-激酶/蛋白激酶 B/雷帕霉素的哺乳动物靶标（PI3K/AKT/mTOR）途径的激活。成熟树突状细胞（DCs）调节 ALI 中的急性肺炎症和病理损伤。此外，研究表明，PI3K/AKT/mTOR 信号通路的激活可能调节 DCs 的功能和成熟。因此，我们推测 HMGB1/PI3K/Akt/mTOR 信号通过调节 DCs 的成熟和功能参与调节 ALI 的病理过程。在脂多糖（LPS）诱导的 ALI 小鼠模型中给予抗 HMGB1 抗体、rHMGB1 或 LY294002（PI3K 抑制剂）。在研究中，用 LPS 诱导的骨髓来源的树突状细胞（BMDCs）进行刺激。观察这些不同处理方法对 PI3K、AKT 和 mTOR 的表达以及 DC 功能的影响。HMGB1 上调了 LPS 刺激的 BMDCs 中 PI3K、Akt 和 mTOR mRNA 的表达和磷酸化蛋白。HMGB1/PI3K/Akt/mTOR 信号通路诱导肺 DC 的成熟和抗原呈递能力，介导髓样树突状细胞（mDCs）的百分比，并增强肺 DC 的黏附和趋化能力。HMGB1/PI3K/Akt/mTOR 信号通过调节 DC 的成熟和功能参与 ALI 的病理过程。
