The effect of artesunate to reverse CLP-induced sepsis immunosuppression mice with secondary infection is tightly related to reducing the apoptosis of T cells via decreasing the inhibiting receptors and activating MAPK/ERK pathway.

T cells play an important role in regulating immune system balance. Sepsis-associated immunosuppression causes apoptosis of T cells and a decrease in their number. Previously, artesunate was found to have an immunomodulatory effect on immunosuppression in model mice with cecal ligation and puncture (CLP)-induced sepsis. In the present study, mouse sepsis models of CLP and CLP with secondary infection were established and treated with artesunate in order to examine the effect of artesunate on adaptive immune response in sepsis-related immunosuppression. The results showed that artesunate treatment could increase the survival rate of CLP mice with secondary Pseudomonas aeruginosa infection, increase the bacterial clearance rate, and also increase the level of the pro-inflammatory cytokine TNF-α. In addition, artesunate resulted in an increase in the number of T cells, CD4+ T cells and CD8+ T cells, and inhibited CD4+ and CD8+ T-cell apoptosis. Artesunate was also found to inhibit the expression of the inhibitory receptors of PD-1, CTLA-4, and BTLA, but it did not affect the expression of Tim-3. Additionally, artesunate significantly increased the phosphorylated ERK level of CD4+ T cells and CD8+ T cells and inhibited mitochondrial pathway-mediated apoptosis in CLP mice with Pseudomonas aeruginosa infection. These findings reveal that artesunate has an immunomodulatory effect on the adaptive immune response in sepsis. These effects include an increase in the numbers of T cells, CD4+ T cells, and CD8+ T cells through inhibition of the expression of inhibitory receptors and promotion of the MAPK/ERK pathway.

The Anti-Sepsis Effect of Isocorydine Screened from Guizhou Ethnic Medicine is Closely Related to Upregulation of Vitamin D Receptor Expression and Inhibition of NFκB p65 Translocation into the Nucleus.

Background: The anti-inflammatory application of Guizhou ethnic medicine in the Karst area of China is mainly based on folk medicine experience, and there has been a lack of systematic research, leading to limited application of Guizhou ethnic medicine. Purpose: To evaluate the anti-inflammatory effects of compounds extracted from Guizhou ethnic medicine in the Karst area and investigate their molecular mechanisms. Methods and Results: Preliminarily, the anti-inflammatory effects of 181 compounds extracted from Guizhou ethnic medicine were screened in lipopolysaccharide (LPS)-stimulated peritoneal macrophages and the 41 compounds with anti-inflammatory effects were selected. Then, these 41 compounds with anti-inflammatory effects were investigated for their druggability and 18 compounds were selected. Thirdly, compound Hx-150, named isocorydine, was selected as the candidate compound. In vitro and in vivo, isocorydine inhibited LPS-induced TNF-α and IL-6 release from LPS-treated mouse peritoneal macrophages. Isocorydine decreased TNF-α, IL-6, and IL-1ß levels in the blood, lung, and spleen, and ameliorated lung tissue damage. Mechanistically, isocorydine had no effect on the mRNA expressions and protein levels of Tlr4, Myd88, and Traf6. Isocorydine also had no effect on the expression of RelA (encoding NFκB p65) mRNA, but inhibited phosphorylation of IκBα and NFκB p65 in the TLR4-mediated signaling pathway. Furthermore, isocorydine increased the cytoplasmic level of NFκB p65 and decreased its nuclear level in LPS-treated macrophages. Importantly, isocorydine upregulated Vdr mRNA (encoding the vitamin D receptor) expression and increased the nuclear VDR protein level. Conclusion: Many compounds from Guizhou ethnic medicine had potential anti-inflammatory activities. Among them, isocorydine has a strong anti-sepsis effect, which is tightly related to its upregulation of VDR expression and inhibition of NFκB p65 translocation into the nucleus, leading to reduced pro-inflammatory cytokines release and protection for LPS-challenged mice.