Abstract
Background: 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.Objective: 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.Methods: Anti-HMGB1 antibody, rHMGB1, or LY294002 (PI3K inhibitor) was administered in a murine model of lipopolysaccharide (LPS)-induced ALI. For in vitro 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.Results: 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.Conclusions: HMGB1/PI3K/Akt/mTOR signaling participates in the pathological process of ALI by regulating the maturation and functions of DCs.
Highlights
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a complex clinical syndrome characterized by persistent hypoxemia due to pulmonary interstitial edema, damage and disruption of the alveolar–capillary barrier, and widespread inflammation in the lung [1, 2]
High-mobility group box 1 protein (HMGB1) upregulated the expression of PI3K, Akt, and mTOR mRNA and phosphorylated proteins in bone marrow-derived dendritic cells (BMDCs)
Previous studies have shown that HMGB1 regulates the PI3K/Akt/mTOR pathway in myocardial ischemia reperfusion injury and the ALI mouse model [9, 27]
Summary
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a complex clinical syndrome characterized by persistent hypoxemia due to pulmonary interstitial edema, damage and disruption of the alveolar–capillary barrier, and widespread inflammation in the lung [1, 2]. Previous studies have shown that an excessive inflammatory response storm plays a vital role in the pathological process of ALI/ARDS [1]. HMGB1 induces an inflammatory response through the phosphatidylinositol 3′kinase/protein kinase B/mammalian target of the rapamycin (PI3K/AKT/mTOR) pathway [9]. 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 to activate the nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) pathways and 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. Studies have shown that the activation of the PI3K/AKT/mTOR signaling pathway may regulate the function and maturation of DCs
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