Dehydrozaluzanin C- derivative protects septic mice by alleviating over-activated inflammatory response and promotes the phagocytosis of macrophages

In the course of sepsis, excessive inflammatory response can lead to cytokine storm. The severity of cytokine storm is closely related with poor prognosis. Dehydrozaluzanin C-derivative (DHZD) is a modified compound from Magnolia officinalis. Here, we demonstrated that DHZD ameliorated tissue damage (lung, kidney and liver) and excessive inflammatory response induced by LPS challenge or the infection of Carbapenem-resistant Klebsiella pneumoniae (CRKP). In LPS-induced sepsis model, DHZD could reduce the secretion of inflammatory factors IL-6, TNF-α, etc. and increased the survival rate. In vitro experiments, DHZD also decreased LPS-stimulated expression of IL-6, TNF-α and MCP-1 via PI3K/Akt/p70S6K signaling pathway in macrophages, etc., might accounting for the decreased tissue damage and its protective role in vivo. Interestingly, the combined treatment group of DXM and DHZD had higher survival rate and lower level of IL-6 than those of DXM-treated group. The combination of DHZD and DXM played a synergistically role to decrease IL-6 secretion in sera. DHZD not only improved the hypothermic symptoms of acute peritonitis induced by CRKP, but also inhibited heat-killed CRKP-induced inflammatory response in macrophages. Similar to that of DXM-treated group, the proportions of phagocytic cell types, e.g., neutrophils and monocytes/macrophages in lungs were upregulated by DHZD. What’s more, the phagocytic receptor CD36 was increased by DHZD in macrophages, which was accompanied by increased bacterial phagocytosis in clathrin- and actin-dependent manner. In short, DHZD is a potential drug candidate with host-directed immunomodulatory effects during bacterial infection through increasing the numbers and the phagocytic ability of phagocytes and decreasing their inflammatory responses together.