Abstract
Acute liver injury (ALI) induced by chemicals or viruses can progress rapidly to acute liver failure (ALF), often resulting in death of patients without liver transplantation. Since liver transplantation is limited due to a paucity of donors, expensive surgical costs, and severe immune rejection, novel therapies are required to treat liver injury. Extracellular vesicles (EVs) are used for cellular communication, carrying RNAs, proteins, and lipids and delivering them intercellularly after being endocytosed by target cells. Recently, it was reported that EVs secreted from human hepatocytes have an ability to modulate the immune responses; however, these roles of EVs secreted from human hepatocytes were studied only with in vitro experiments. In the present study, we evidenced that EVs secreted from human hepatocytes attenuated the CCL4-induced ALI by inhibiting the recruitment of monocytes through downregulation of chemokine receptor in the bone marrow and recruitment of neutrophils through the reduction of C-X-C motif chemokine ligand 1 (CXCL1) and CXCL2 expression levels in the liver.
Highlights
The liver is a highly vascularized large organ responsible for the metabolism of carbohydrates, proteins, and lipids, as well as removal of drugs and toxins from the blood
Chemokine receptor of the bone marrow monocytes was significantly downregulated in the mice treated with the Extracellular vesicles (EVs) from hepatocytes Previously, we reported that the EVs derived from HepG2 cells replicating hepatitis B virus (HBV) are incorporated by Kupffer cells (KCs) in the liver and by bone marrow monocytes (BMMC), which mainly migrated to the intestine to exhibit immunoregulatory functions [21]
We demonstrated that EVs secreted from human hepatocytes potently attenuated the CCL4-induced Acute liver injury (ALI), which depended on resident KC, by inhibiting the recruitment of neutrophils and monocytes via downregulation of chemokines and chemokine receptor in the BM cells, respectively (Fig. 8)
Summary
The liver is a highly vascularized large organ responsible for the metabolism of carbohydrates, proteins, and lipids, as well as removal of drugs and toxins from the blood It acts as a key frontline immune tissue. The EVs secreted from human hepatocytes control under CL treatment (Fig. 3C–E) These results indicated attenuated the CCL4-induced ALI by inhibiting the recruitment that the EVs attenuate the CCL4-induced ALI through the of neutrophils to the liver via reduction of C-X-C motif chemokine macrophages incorporating EVs. ligand 1 (CXCL1) and CXCL2 in the liver and that of monocytes via reduction of chemokine receptor (CCR)-8 and CCR-9 in bone Profile of the expression of proinflammatory cytokines and marrow (BM) cells possibly mediated by docosahexaenoic acid chemokines in the Kupffer cells (DHA), producing potent anti-inflammatory and proresolutive lipid mediators, were enriched with EVs than with hepatocytes.
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