Background: Sepsis is a life-threatening organ dysfunction disease caused by a dysregulated host response to infection. Rutaecarpine is an important alkaloid component of Evodia rutaecarpa. There has been no study on the therapeutic effects of rutaecarpine in sepsis.
Methods: Mice were randomly assigned into four groups: sham, sepsis, sepsis plus vehicle and sepsis plus rutaecarpine groups. Mice in sepsis were administered CLP surgery. Rutaecarpine or vehicle was injected intraperitoneally 1 h after CLP. The liver damage, bacterial infection, survival rate and weight loss were observed, and changes in the ratio of peritoneal resident macrophages were analyzed by flow cytometry and immunofluorescence microscopy. Western blotting was used to identify the levels of NF-κB signaling pathway, ER stress and apoptosis related proteins. TUNEL and Annexin V/PI assay were used to detect the apoptosis of liver tissues and peritoneal resident macrophages, respectively. ELISA and qRT-PCR were used to detect the inflammatory factors.
Results: Rutaecarpine alleviated weight loss, bacterial infection and liver injury, and regulated inflammation homeostasis, enhancing survival rate induced by sepsis. Population of peritoneal resident macrophages (CD11b+F4/80hiMHCIIlow) was significantly decreased in sepsis mice, which was resulted from ER stress-induced apoptosis through caspase-12 signaling pathway. Rutaecarpine restored the ratio of peritoneal resident macrophages and the level of GATA6 in CD11b+ peritoneal macrophages. Rutaecarpine could also attenuate sepsis-induced inflammatory responses through inhibiting the activation of ER stress/NF-κB pathway.
Conclusion: Rutaecarpine ameliorated sepsis-induced peritoneal resident macrophages apoptosis and inflammation responses through inhibition of ER stress-mediated caspase-12 and NF-κB pathways. Our study provided new insights for drug development against sepsis.
Keywords: Apoptosis; Endoplasmic reticulum stress; Inflammation; Peritoneal resident macrophages; Rutaecarpine; Sepsis.
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