Abstract
Inflammation is a key contributor to various types of acute and chronic liver disease. We recently reported that lack of Nur77, an orphan nuclear receptor, contributes to the pathogenesis of inflammatory diseases including inflammatory bowel disease and sepsis. However, whether Nur77 plays a critical role in liver inflammation remains to be fully understood. Employing in vivo acute liver inflammation model in wild-type (Nur77+/+) and Nur77-/- mice, we here found that Nur77 deficiency dramatically increased the production of pro-inflammatory cytokines and accelerated liver injury induced by poly (I:C)/D-GalN in Nur77-/- mice. Mechanistically, Nur77 acts as a negative regulator of NF-κB signaling by inducing the expression of ubiquitin-editing enzyme A20, a novel target gene of Nur77. Notably, in inflammatory cells, overexpression of A20 enhanced, whereas knockdown of A20 by siRNA approach impaired, the inhibitory effect of Nur77 on poly (I:C)-triggered inflammation. Collectively, our data suggest that the orphan nuclear receptor Nur77 plays a protective role in poly (I:C)-triggered liver inflammation by inducing A20, thus making it a promising target for the prevention and treatment of liver inflammation.
Highlights
Inflammation contributes to the pathogenesis of acute and chronic liver diseases induced by different etiologies, such as drug toxicity and viral infection [1]
To explore the biological function of Nur77 in liver inflammation, we induced acute liver inflammation in mice by injection of poly (I:C)/D-GalN. These Nur77/- mice exhibited a significant increase in inflammatory infiltrates in hepatocytes and severe hepatocyte destruction not observed in wild-type control mice (Figure 1A). poly (I:C)/D-GalN injection induced significant hepatocyte cell death in Nur77-/- mice, as indicated by PARP cleavage (Figure 1B)
Nur77 prevents atherosclerosis via regulation of the polarization of macrophages [7], and it exerts a protective effect against inflammatory bowel disease by modulating Toll-like receptor (TLR) signaling [11]
Summary
Inflammation contributes to the pathogenesis of acute and chronic liver diseases induced by different etiologies, such as drug toxicity and viral infection [1]. Strong liver inflammation results in sudden increased recruitment of inflammatory cells to the liver to initiate and drive inflammatory response by producing proinflammatory cytokines and chemokines, such as tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), interferon beta (IFN-β) and monocyte-chemoattractant protein-1 (MCP-1) [1]. These inflammatory mediators can led to hepatocytic cell death through activation of cell death signaling [1]. Despite the great effort that has been made to understand the role of inflammation in acute and chronic liver diseases, the molecular mechanism underlying liver inflammation is not completely understood
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