NOD1 Agonist Protects Against Lipopolysaccharide and D-Galactosamine-Induced Fatal Hepatitis Through the Upregulation of A20 Expression in Hepatocytes

Abstract

Increasing evidence suggests that NODs are involved in liver diseases; however, the underlying mechanisms remain obscure. In the present study, we analyzed the effect of NOD1 agonist pretreatment on acute liver failure induced by lipopolysaccharide (LPS) in D-galactosamine (D-GalN)-sensitized mice. We found that pretreatment with the NOD1 agonist markedly reduced LPS/D-GalN-induced mortality, elevation of serum ALT levels, and hepatocyte apoptosis. The protective effect of NOD1 agonist was independent of tumor necrosis factor (TNF)-α inhibition. NOD1 agonist pretreatment also attenuated TNF-α/D-GalN-induced apoptotic liver damage. The anti-apoptotic protein A20 expression was more pronounced in NOD1 agonist pretreated mice than in controls, and knockdown of A20 abrogated the protective effect of NOD1 agonist on LPS/D-GalN-induced liver injury and hepatocyte apoptosis. Further experiments showed that NOD1 agonist-induced A20 upregulation required the presence of kupffer cells and TNF-α. Taken together, our data strongly indicate that NOD1 is involved in the regulation of liver injury and could be a potential therapeutic target for liver diseases.

The Pathophysiology of Hepatic Encephalopathy at the Level of Gut-Liver-Brain Axis: The Role of Resident Innate Immune Cells

“…The HSCs progress liver fibrosis through a signaling pathway dependent on TGFβ, NLRP3 inflammasome-Caspase1-IL1β, and WNT/β-catenin [125][126][127]. Like intestinal Mϕ, KCs express PRRs on their surface, including TLR, RIG-like receptors, C-type lectin receptors (CLR), and nucleotide-binding oligomerization domain (NOD)-like receptors that recognize DAMPs and PAMPs [128][129][130]. For instance, activation of TLR4 in response to circulatory LPS through activation of myeloid differentiation factor 88 and overexpression of NF-kβ induces the production of pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, TNFα, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) [129,[131][132][133].…”

Activation of NOD1 and NOD2 in the development of liver injury and cancer

“…In contrast to the sensitizing action of NOD2, pre-activation of NOD1 by the NOD1 ligand C14-Tri-LAN-Gly markedly inhibited the development of ALF induced by D-Gal/LPS (33). Suppression of ALF by NOD1 activation was associated with enhanced expression of A20 in hepatocytes (33). Given that A20 removes polyubiquitin chains from RIPK2, it is likely that NOD1 suppresses ALF through RIPK2 deubiquitination (22).…”

“…Injection of D-galactosamine (D-Gal) in combination with lipopolysaccharide (LPS) is widely used to induce acute liver failure (ALF) ( 33 , 34 ). Recent studies have highlighted the importance of RIPK2 polyubiquitination in this model.…”

Advances in the Study of the Ubiquitin-Editing Enzyme A20

“…Furthermore, A20 upregulation inhibits intestinal epithelial cell apoptosis in Crohn’s disease ( Zhou et al, 2019 ) by affecting the functions of tumor necrosis factor receptor 1 (TNFR1), TNFR1-associated death domain protein (TRADD) and RIPK1. In a mouse model with hepatic damage, A20 inhibited the apoptosis of hepatocytes and immune inflammation through the NF-κB signaling pathway, playing a role in the chronic rejection of allogeneic liver transplantation ( Li et al, 2019 ; Jia et al, 2021 ). Although it is fully recognized that A20 is a key regulator that can prevent cells from apoptosis, the mechanism by which it does are still not completely elucidated.…”