The Role of Dectin-1-Akt-RNF146 Pathway in β-Glucan Induced Immune Trained State of Monocyte in Sepsis.

Background: Sepsis is regarded as a dysregulated immune response to infections. Recent study showed partially reversal of immunosuppression by trained immunity, which fosters an enhanced immune response towards a secondary challenge. However, the role of trained immunity in sepsis has not been fully understood. Methods: We profiled the characteristics of peripheral blood mononuclear cells from septic patients using single-cell RNA sequencing (scRNA-seq) analyses. Murine double-hit models (pretreatment or post-treatment of β-glucan in septic mice) and murine monocyte/macrophage cell line RAW264.7 were used then. Results: scRNA-seq revealed that Ring finger protein 146 (RNF146) and protein kinase B (Akt) were downregulated in the immunosuppression period of septic patients and were verified to be decreased in bone marrow and spleen monocytes from septic mice. While β-glucan pretreatment improved the immunosuppressed state in septic mice and increased dectin-1/Akt/RNF146 expressions in monocytes, along with the increased survival rate, inflammatory factors and aerobic glycolysis, indicating a change from immunosuppression to immune training. Moreover, RNF146 regulated dectin-1-Akt-mTOR signaling in the trained immune state of murine monocyte/macrophage RAW264.7 cell line and the expression of RNF146 was dependent on dectin-1-Akt activation. The inhibition of dectin-1 by its antagonist laminarin downregulated Akt-RNF146 signaling and partially reversed β-glucan induced trained immunity in septic mice. Conclusion: RNF146 and Akt are downregulated in the immunosuppression period of sepsis, while increased after β-glucan pretreatment induced trained immunity in septic mice. Moreover, RNF146 regulates the immune trained state of monocyte through dectin-1-Akt-mTOR pathway, suggesting a possible target in reversal of immunosuppression in sepsis.