Modified Xi-Jiao-Di-Huang Decoction Alleviates Sepsis via Regulating Macrophage Polarization by Inhibiting the PIM2/NF-κB Pathway

Fan Ge,1,* Fang Tian,2,* Yeyan Zhu,1 Qixiang Yan,1 Qimeng Sun,1 Jun Lu1 1Department of Intensive Care Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 2Department of Central Laboratory, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun Lu, Department of Intensive Care Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, No. 155 Hanzhong Road, Nanjing, Jiangsu Province, 210029, People’s Republic of China, Tel + 8613813865758, Email [email protected]: Modified Xi-Jiao-Di-Huang decoction (MXJDH) has significant clinical efficacy for the treatment of sepsis; however, its mechanism of action remains unclear. The purpose of this study was to investigate the protective effects of MXJDH in septic mice and explore its mechanism of action.Methods: Utilizing UPLC-Q-TOF-MS, we identified the primary constituents of the compound MXJDH. Subsequently, we created a mouse model for sepsis, observing their overall condition, including specific symptoms and behavior. We also monitored key inflammatory markers and pathological changes in their organs. Flow cytometry was then employed to assess the polarization of macrophages. Transcriptome sequencing was used to identify genes with altered expression patterns. We investigated the connection between MXJDH and the Pim2/NF-κB signaling pathway, a crucial regulatory mechanism in inflammation. Finally, we examined the expression and tissue distribution of macrophages in the sepsis-induced mice.Results: MXJDH effectively reduces inflammation in sepsis mice, leading to a progressive recovery of organ functions. Moreover, MXJDH facilitates the conversion of macrophages from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype. This transformation is potentially mediated through the Pim2/NF-κB signaling pathway. By suppressing Pim2 expression, MXJDH mitigates the nuclear translocation of NF-κB, thereby modulating the expression of downstream inflammatory mediators. The role of MXJDH in regulating macrophage polarization has also been confirmed in sepsis mouse tissues.Conclusion: MXJDH regulates macrophage polarization, inhibits CRS, and alleviates sepsis by inhibiting the Pim2/NF-κB signaling pathway.Keywords: modified Xi-Jiao-Di-Huang decoction, sepsis, macrophage polarization, PIM2/NF-κB pathway