Baicalin inhibits necroptosis by decreasing oligomerization of phosphorylated MLKL and mitigates caerulein-induced acute pancreatitis in mice

•Baicalin dose-dependently inhibits necroptosis in murine macrophages.•The phosphorylation levels of either RIPK3 or MLKL are unaffected by baicalin.•Baicalin suppresses oligomerization of phosphorylated MLKL by reducing ROS.•Baicalin mitigates the severity of caerulein-induced acute pancreatitis in...

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Veröffentlicht in:International immunopharmacology 2022-07, Vol.108, p.108885-108885, Article 108885
Hauptverfasser: Huang, Yuan-Ting, Liang, Qi-Qi, Zhang, Hong-Rui, Chen, Si-Yuan, Xu, Li-Hui, Zeng, Bo, Xu, Rong, Shi, Fu-Li, Ouyang, Dong-Yun, Zha, Qing-Bing, He, Xian-Hui
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Sprache:eng
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Zusammenfassung:•Baicalin dose-dependently inhibits necroptosis in murine macrophages.•The phosphorylation levels of either RIPK3 or MLKL are unaffected by baicalin.•Baicalin suppresses oligomerization of phosphorylated MLKL by reducing ROS.•Baicalin mitigates the severity of caerulein-induced acute pancreatitis in mice. Necroptosis is a form of regulated necrosis mainly controlled by receptor-interacting protein kinases 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL). Necroptosis has important roles in defensing against pathogenic infections, but it is also implicated in various inflammatory diseases including pancreatitis. Baicalin, a flavonoid from Scutellaria baicalensis Georgi, has been shown to possess anti-inflammatory and anti-pyroptosis properties, yet it is unclear whether baicalin can inhibit necroptosis and confer protection against necroptosis-related diseases. Here we reported that baicalin significantly inhibited necroptosis in macrophages induced by lipopolysaccharide plus pan-caspase inhibitor (IDN-6556), or by tumor-necrosis factor-α in combination with LCL-161 (Smac mimetic) and IDN-6556 (TSI). Mechanistically, baicalin did not inhibit the phosphorylation of RIPK1, RIPK3 and MLKL, nor membrane translocation of p-MLKL, during necroptotic induction, but instead inhibited p-MLKL oligomerization that is required for executing necroptosis. As intracellular reactive oxygen species (ROS) has been reported to be involved in p-MLKL oligomerization, we assessed the effects of N-acetyl-L-cysteine (NAC), an ROS scavenger, on necroptosis and found that NAC significantly attenuated TSI-induced necroptosis and intracellular ROS production concomitantly with reduced levels of oligomerized p-MLKL, mirroring the effect of baicalin. Indeed, inhibitory effect of baicalin was associated with reduced TSI-induced superoxide (indicating mitochondrial ROS) production and increased mitochondrial membrane potential within cells during necroptosis. Besides, oral administration of baicalin significantly reduced the severity of caerulein-induced acute pancreatitis in mice, an animal model of necroptosis-related disease. Collectively, baicalin can inhibit necroptosis through attenuating p-MLKL oligomerization and confers protection against caerulein-induced pancreatitis in mice.
ISSN:1567-5769
1878-1705
DOI:10.1016/j.intimp.2022.108885