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.
Highlights
Acute liver failure (ALF) is a complicated clinical syndrome that consists of metabolic and immunological dysfunction, hepatic encephalopathy, coagulopathy, sepsis and, eventually, multi-organ failure
We reported that the early excessive activation of circulating monocytes, rather than the resident Kupffer cells, plays a critical role in the augmentation of systemic inflammation, which act as a potential therapeutic target for this lethal syndrome
After excluding the possibility that circulating lymphocytes contributed to the elevation of IL-6 levels (Figure 4F), we investigated whether circulating monocytes (c-Mos) secreted IL-6 before undergoing hepatic migration
Summary
Acute liver failure (ALF) is a complicated clinical syndrome that consists of metabolic and immunological dysfunction, hepatic encephalopathy, coagulopathy, sepsis and, eventually, multi-organ failure. We previously established a non-human primate (Macaca mulatta) model of ALF, in which we induced ALF with a single intraperitoneal injection of lowdose a-amatoxin and lipopolysaccharide (LPS).[17] Amatoxin is an alkaloid derived from poisonous mushrooms that selectively inhibits RNA polymerase II.[18] When taken up by hepatocytes, amatoxin is released in its original form in the bile and appears in the enterohepatic circulation. Before it is fully cleared within 24 hours, amatoxin repeatedly damages hepatocytes without causing clear injury to extrahepatic organs. We reported that the early excessive activation of circulating monocytes, rather than the resident Kupffer cells, plays a critical role in the augmentation of systemic inflammation, which act as a potential therapeutic target for this lethal syndrome
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