Abstract
Acetaminophen (APAP)-induced liver injury (AILI) is the most frequent cause of acute liver failure; but the underlying mechanisms still remain obscure. Macrophages and endoplasmic reticulum (ER) stress play an important role in the pathogenesis of AILI. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a newly identified 18-kDa soluble protein, whose expression and secretion are stimulated by ER stress. To investigate the role of myeloid cell MANF in the pathogenesis of AILI, we assayed serum and liver samples from AILI model mice and patients with drug-induced liver injury (DILI). We demonstrated that the levels of MANF were elevated in patients with DILI and in mice with AILI. Moreover, myeloid-specific MANF knockout mice were generated and used. It was observed that a delayed liver recovery from myeloid-specific MANF gene knockout mice following APAP overdose compared to that from wild-type mice. MANF deficiency in myeloid cells resulted in increased infiltrating monocyte-derived macrophages (MoMFs) but reduced restorative Ly6Clow macrophages after APAP treatment. MANF supplementation increased restorative Ly6Clow macrophages and subsequently alleviated liver injury. Moreover, MANF could enhance IL-10 expression and phagocytosis in macrophages via p38 MAPK pathway. Altogether, MANF seems to be a critical immune modulator in promoting liver repair via reducing and reprogramming MoMFs. MANF perhaps promoted the phenotype conversion of pro-inflammatory MoMFs to pro-restorative Ly6Clow MoMFs via p38 MAPK pathway, particularly through enhancing IL-10 and phagocytosis.
Highlights
Drug-induced liver injury (DILI) is one of the major causes of liver diseases around the world
Increased Mesencephalic astrocyte-derived neurotrophic factor (MANF) expression in DILI patients and an APAP-induced liver injury (AILI) mouse recombinant human MANF (rhMANF) enhances restorative macrophage percentage in vivo model To investigate the role of MANF in DILI, we first examined MANF expression in DILI patients
Considering that liver macrophages may be stimulated by damage-associated molecular patterns (DAMP)-derived from APAP damaged hepatocytes in vivo, we further examined whether rhMANF could downregulate macrophage-mediated inflammatory response
Summary
Drug-induced liver injury (DILI) is one of the major causes of liver diseases around the world. In Western society, the main cause of acute liver injury is acetaminophen (APAP) overdose [1]. APAP is metabolized by hepatic cytochrome P450 enzymes (mainly CYP2E1) into a reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI) which is detoxified by glutathione (GSH) [2]. Excessive formation of NAPQI causes depletion of hepatic glutathione in APAP overdose and subsequently leads to oxidative stress and hepatocyte damage [3]. N-acetylcysteine is the only clinically approved antidote for APAP overdose patients. The efficacy of N-acetylcysteine dramatically decreases 8 h after APAP ingestion [4, 5]. The development of new approaches to treat APAP-induced liver failure, at the late phase of injury is required
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
