Circulating monocytes accelerate acute liver failure by IL‐6 secretion in monkey

Abstract

Acute liver failure (ALF) is associated with high mortality, and a poor understanding of the underlying pathophysiology has resulted in a lack of effective treatments so far. Here, using an amatoxin‐induced rhesus monkey model of ALF, we panoramically revealed the cellular and molecular events that lead to the development of ALF. The challenged monkeys with toxins underwent a typical course of ALF including severe hepatic injury, systemic inflammation and eventual death. Adaptive immune was not noticeably disturbed throughout the progress of ALF. A systematic examination of serum factors and cytokines revealed that IL‐6 increase was the most rapid and drastic. Interestingly, we found that IL‐6 was mainly produced by circulating monocytes. Furthermore, ablation of monocyte‐derived IL‐6 in mice decreased liver injury and systemic inflammation following chemical injection. Our findings reveal a critical role of circulating monocytes in initiating and accelerating ALF, indicating a potential therapeutic target in clinical treatment for ALF.

Peripheral infusion of human umbilical cord mesenchymal stem cells rescues acute liver failure lethality in monkeys

“…We previously established a non-human primate ( Macaca mulatta ) model of ALF, in which we induced ALF with a single intraperitoneal injection of low-dose α-amatoxin and lipopolysaccharide (LPS) [ 9 , 10 ]. Following the injection of toxins, the monkeys displayed changes in clinical features, hepatic indexes, histopathology, imaging, and life span that are typical features of the progress observed in the clinical ALF [ 9 ]. Moreover, monkey is a species with metabolic and physiological properties similar to those of humans, indicating that our animal model is appropriate for exploring the pathophysiology of ALF and for evaluating potential therapeutic strategies.…”

Exosomes derived from human umbilical cord mesenchymal stem cells ameliorate IL-6-induced acute liver injury through miR-455-3p

“…Our previous in vitro study demonstrated that when cocultured with hUC-MSCs, LPS-stimulated macrophages tremendously decreased the production of inflammatory factors, especially IL-6 [2]. To validate that hUC-MSCs regulate macrophage activation by exosomes, Exos-IL6 were added into the culture medium.…”

“…[1]. Previously, we established an amanitin-induced acute liver failure model in monkeys, which comprehensively revealed the pathophysiological process of ALF [2]. After the induction of toxins, the initial injury of the liver is not serious, but a secondary uncontrolled systemic inflammatory response syndrome (SIRS) is the leading cause of multiple organ failure and death in animals [2].…”

“…Previously, we established an amanitin-induced acute liver failure model in monkeys, which comprehensively revealed the pathophysiological process of ALF [2]. After the induction of toxins, the initial injury of the liver is not serious, but a secondary uncontrolled systemic inflammatory response syndrome (SIRS) is the leading cause of multiple organ failure and death in animals [2]. Most strikingly, bone marrow-derived circulating monocytes are activated, characterized by overexpression of IL-6, before the occurrence of a cytokine storm and significant liver damage.…”

“…We previously established a toxin-induced nonhuman primate model of ALF [2]. In this model, we found that early peripheral infusion of human umbilical cord mesenchymal stem cells (hUC-MSCs) significantly rescued the monkeys from lethal ALF.…”