Abstract
Extracellular vesicles (EVs) have emerged as important vectors of intercellular dialogue. High mobility group box protein 1 (HMGB1) is a typical damage-associated molecular pattern (DAMP) molecule, which is cytotoxic and leads to cell death and tissue injury. Whether EVs are involved in the release of HMGB1 in lipopolysaccharide (LPS)-induced acute liver injuries need more investigation. EVs were identified by transmission electron microscopy, nanoparticle tracking analysis (NTA), and western blotting. The co-localization of HMGB1, RAGE (receptor for advanced glycation end-products), EEA1, Rab5, Rab7, Lamp1 and transferrin were detected by confocal microscopy. The interaction of HMGB1 and RAGE were investigated by co-immunoprecipitation. EVs were labeled with the PKH67 and used for uptake experiments. The pyroptotic cell death was determined by FLICA 660-YVAD-FMK. The expression of NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasomes were analyzed by western-blot or immunohistochemistry. Serum HMGB1, ALT (alanine aminotransferase), AST (aspartate aminotransferase), LDH (lactate dehydrogenase) and MPO (myeloperoxidase) were measured using a commercial kit. The extracellular vesicle HMGB1 was detected in the serums of sepsis patients. Macrophages were found to contribute to HMGB1 release through the EVs. HMGB1-RAGE interactions participated in the loading of HMGB1 into the EVs. These EVs shuttled HMGB1 to target cells by transferrin-mediated endocytosis leading to hepatocyte pyroptosis by the activation of NLRP3 inflammasomes. Moreover, a positive correlation was verified between the sepsis serum EVs-HMGB1 level and clinical liver damage. This finding provides insights for the development of novel diagnostic and therapeutic strategies for acute liver injuries.
Highlights
Extracellular vesicles (EVs) have emerged as important vectors of intercellular communication [1, 2]
High mobility group box protein 1 (HMGB1) within the EVs derived from the Raw264.7 cells
The main findings include the following: (1) HMGB1 released by EVs in the serum and macrophages contribute to EVs-HMGB1 release; (2) LPS induces the sorting of HMGB1 into EVs which depend on receptor for advanced glycation end-products (RAGE); () Macrophage-derived EVs shuttle HMGB1 to hepatocytes by transferrin-mediated endocytosis and subsequently promote hepatocyte pyroptosis by activating the NLRP3 inflammasome
Summary
Extracellular vesicles (EVs) have emerged as important vectors of intercellular communication [1, 2]. The role of EVs in sepsis-induced acute liver injuries remains unclear and requires further investigation. Damage associated molecular pattern (DAMP) molecules have key roles in the progression of lipopolysaccharide (LPS)-induced acute liver injuries. Active secretion always requires two steps: the translocation of nuclear HMGB1 to the cytoplasm and the gradual induction of programmed, pro-inflammatory cell death that enables cytoplasmic HMGB1 to reach the extracellular space [6]. The neutralization of inflammation by HMGB1-specific antibodies prevents endotoxin-induced lethality [8, 9]. It is unknown whether EVs are involved in the release of HMGB1 in LPS-induced acute liver injuries
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