Abstract
BackgroundAcetaminophen (APAP) overdose is one of the major etiologies of liver failure. Hepatocyte necrosis induced by toxic metabolites of APAP can activate proinflammatory responses, including elastase-expressing neutrophils, to exacerbate liver injury. Myeloid-derived suppressor cells (MDSCs) increased in inflammation can inhibit proinflammatory responses. Our aim is to investigate the role of MDSC in APAP-induced liver failure and the possible therapeutic application.MethodsBLAB/c mice were injected with a sublethal/lethal dose of APAP as the murine model of liver failure. MDSCs were defined as CD11b+Gr-1+ cells with the ability of T-cell suppression.ResultsA sublethal challenge of APAP could increase the intrahepatic MDSC and protect mice against subsequent lethal challenge of APAP, lipopolysaccharide (LPS)/D-galatosamine or concanavalin A. This protection was lost if MDSCs were depleted and inducible nitric oxide synthase (iNOS) was the key molecule in this MDSC-mediated protection. Taking advantage of these observations, different bone marrow-derived MDSCs (BM-MDSCs) were generated. Among different cytokine-treated BM-MDSCs, tumor necrosis factor alpha/LPS-primed MDSCs (TNF-α/LPS MDSCs) had the strongest liver-protection ability after adoptive transfer. Further mechanistic explorations showed, iNOS-expressing TNF-α/LPS MDSCs induced the apoptosis of activated neutrophil and decreased the intrahepatic infiltration of elastase-expressing neutrophil. Moreover, we generated MDSCs from human peripheral blood mononuclear cells (PBMCs) with similar phenotype.ConclusionWe demonstrated the protective role of MDSCs and therapeutic effect of TNF-α/LPS MDSCs in APAP-induced liver failure. MDSC might protect against the APAP-induced liver failure by reducing the intrahepatic infiltration of activated neutrophil to limit inflammation. Therefore, a therapeutic role of MDSCs for APAP-induced liver failure was proposed.
Highlights
Acetaminophen (N-acetyl-p-aminophenol or APAP) is a widely used antipyretic and analgesic drug
To investigate the possible underlying immune mechanisms in APAP-induced liver injury (AILI), we focused on the role of Myeloid-derived suppressor cells (MDSCs), due to their significant increase and regulation of immune responses in several inflammatory conditions [15, 18]
The liver injury was reduced and the serum ALT levels were in the normal range on day 7 after sublethal APAP challenge, the frequencies of CD11b+Gr-1+ cells increased in the liver, and continually increased in the spleen and blood up to 14 days, but did not increase during the whole course in the bone marrow compartment (Figures 1A, B)
Summary
Acetaminophen (N-acetyl-p-aminophenol or APAP) is a widely used antipyretic and analgesic drug. APAP overdose is the most common etiology of drug-induced liver injury in the U.S and Europe with no apparent decline in the past 20 years [1, 2]. The pathogenesis of APAP-induced liver failure includes APAP-induced hepatocyte necrosis and the subsequent inflammatory responses. Neutrophils are one of the most abundant immune cells in the initial necroinflammatory phase in APAP-induced liver injury [9, 10]. Regulating inflammatory responses focusing on neutrophils or monocytes/macrophages could be a way to reduce hepatotoxicity and mortality induced by APAP overdose. Acetaminophen (APAP) overdose is one of the major etiologies of liver failure. Hepatocyte necrosis induced by toxic metabolites of APAP can activate proinflammatory responses, including elastase-expressing neutrophils, to exacerbate liver injury. Our aim is to investigate the role of MDSC in APAPinduced liver failure and the possible therapeutic application
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