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.
Highlights
Acute-on-chronic liver failure (ACLF) refers to a severe acute deterioration of the established chronic liver disease, and usually develops after an acute insult[1,2]
We documented the critical role of necroptosis and S100A9 in D-GalN/LPSinduced acute liver injury through the application of specific inhibitors; secondly, we analyzed the correlation between necroptosis or S100A9 inhibition and macrophage M1/M2 activation; thirdly, we demonstrated the inhibitory effects of fibrotic liver on necroptosis and S100A9 using mouse models of hepatic fibrosis and fibrosis regression; fourthly, the pivotal roles of M2-like macrophages in inhibiting necroptosis and S100A9 were verified through depleting and adoptively transferring M2-like macrophages; fifthly, the inhibitory effects of fibrosis on necroinflammation triggered by necroptosis and mediated by S100A9 were confirmed; we dissected the role and possible mechanism by which M2like macrophages suppressed the necroinflammation through in vivo and in vitro experiments
Necroptosis inhibition alleviates acute liver injury, which is accompanied by M2-like activation of macrophages First, we documented the existence of necroptosis in
Summary
Acute-on-chronic liver failure (ACLF) refers to a severe acute deterioration of the established chronic liver disease, and usually develops after an acute insult[1,2]. Several new modes of cell death, named regulated necrosis, have been discovered and characterized, including necroptosis, pyroptosis and ferroptosis[8,9,10,11]. An increasing number of studies explore the possible effects of this cell death mode in acute and chronic liver injury. It remains conflicting and controversial whether necroptosis exists or not and its possible contribution to the pathogenesis of diverse liver diseases[14,17,18,19,20]
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