M2-like macrophages exert hepatoprotection in acute-on-chronic liver failure through inhibiting necroptosis-S100A9-necroinflammation axis

Abstract

Necroptosis has emerged as a novel and crucial player in acute and chronic liver diseases. Necroptotic cells lead to the release of DAMPs including S100A9, followed by the development of necroinflammation. We previously have documented the beneficial hepatoprotection conferred by M2-like macrophages in acute-on-chronic liver failure (ACLF) in vitro and in vivo, namely, M2-like macrophages protect hepatocytes against apoptosis. Herein, we integrated necroptosis, S100A9, and necroinflammation into this hepatoprotection, and hypothesized M2-like macrophages exert a hepatoprotective effect through inhibiting necroptosis-S100A9-necroinflammation axis. To testify this hypothesis, control mice were pre-treated with necroptosis or S100A9 inhibitors followed by D-GalN/LPS challenge. The extent of liver injury and M1/M2 macrophage activation was assessed. Necroptosis signaling and S100A9 expression were analysed and compared in control and fibrotic mice with or without acute insult. To document the pivotal role of M2-like macrophages in necroptosis and S100A9 inhibition, loss-of-function and gain-of-function experiments were performed. In addition, necroinflammation and its dependence on necroptosis and S100A9 were analysed. Moreover, the inhibitory effects of M2-like macrophages on necroinflammation were investigated in vivo and in vitro. We found that: firstly, the inhibition of necroptosis signaling and S100A9 expression alleviated D-GalN/LPS-induced hepatic damage, which was accompanied by M2-like macrophage activation; secondly, fibrosis inhibited necroptosis signaling and S100A9 expression, which could be attributed to M2-like macrophage activation; thirdly, S100A9 may function as a downstream player of necroptosis signaling; fourthly, fibrosis suppressed necroptosis- and S100A9-dependent necroinflammation; and finally, M2-like macrophages inhibited NLRP3 inflammasome activation and resultant necroinflammation via IL-10. Therefore, M2-like macrophages exert a beneficial hepatoprotection by inhibiting necroptosis-S100A9-necroinflammation axis in ACLF. Our findings provide novel insight for treating ACLF patients by specially targeting this signaling axis.

Oyster-Derived Tyr-Ala (YA) Peptide Prevents Lipopolysaccharide/D-Galactosamine-Induced Acute Liver Failure by Suppressing Inflammatory, Apoptotic, Ferroptotic, and Pyroptotic Signals

“…LPS/D-GalN-injected mice used as an ALF model in this study are also referred to as models for fulminant liver failure (FLF), acute liver injury (ALI), and acute hepatitis. Previous studies reported that liver damage in LPS/D-GalN-injected mouse models is induced by multiple complex mechanisms, such as inflammation, apoptosis, necrosis, autophagy, pyroptosis, necroptosis, and ferroptosis [14][15][16][17][18][19]. However, most previous studies using LPS/D-GalN-injected mouse models analyzed one or two of the mechanisms mentioned above and reported that many hepatoprotectants proposed in those studies modulate the analyzed mechanisms.…”

“…GSDMD is a pore-forming protein that promotes pyroptosis and the release of pro-inflammatory cytokines [43]. GSDMD-mediated hepatocyte pyroptosis extends the inflammatory response to ALF by upregulating monocyte chemotactic protein 1/CC chemokine receptor-2 to recruit macrophages [17,18]. YA pre-administration also decreased the upregulation of GSDMD, caspase 1 activation, C-terminal of GSDMD cleavage in the LPS/D-GalN induced ALF model.…”

“…The LPS/D-GalN model shows typical hepatocellular death manifested by necrosis, apoptosis, autophagy, and inflammatory responses [14][15][16]. Although many studies have not been conducted, recent studies reported that cell death mechanisms by ferroptosis, pyroptosis, and necroptosis are involved in liver injury in the LPS/D-GalN model [17][18][19]. Substances that regulate signals related to the hepatocyte death mechanism are expected to be helpful in the prevention and treatment of LPS/D-GalN-induced liver injury.…”

The Immune Pathogenesis of Acute-On-Chronic Liver Failure and the Danger Hypothesis

“…Serum S100A12 may reflect the oxidative stress and inflammation levels of HBV-ACLF patients, and an increase in S100A12 may be an important biological index of poor prognosis ( 58 ). Others have found that M2 macrophages can alleviate liver injury and play a protective role in ACLF mice by inhibiting the S100A9 protein-related necrotic inflammation axis, which provides new insight for the treatment of ACLF patients ( 98 ). In addition, in children with pediatric acute liver failure (PALF), the serum S100 β level may correlate positively with the severity of the disease ( 94 ).…”

Hepatoprotective Effect of Mitochondria-Targeted Antioxidant Mito-TEMPO against Lipopolysaccharide-Induced Liver Injury in Mouse

“…Septic liver injury, as a common clinical feature, is regarded as an independent indicator of mortality [ 4 ]. In addition, liver dysfunction is strongly associated with poor survival of sepsis patients; damaged hepatocytes could release damage-associated molecular patterns to trigger systemic inflammatory responses, exacerbating the dysfunction of the liver and other organs [ 5 ]. Therefore, effective protection of liver function is crucial for the treatment of sepsis and the improvement of patient prognosis.…”