All-trans-retinoic acid restores CD4+T cell response after sepsis by inhibiting the expansion and activation of myeloid-derived suppressor cells

Background: Patients are susceptible to immunosuppression in late-stage of sepsis, in which myeloid-derived suppressor cells (MDSCs) is an important contributor. This study aims to investigate whether all-trans-retinoic acid (ATRA), which has been proved to inhibit MDSCs generation in cancer, will ameliorate sepsis-induced immuno-suppression through modulating MDSCs. Methods: A clinically relevant two-hit'' model of sepsis, the cecal ligation and puncture (CLP) model and secondary pneumonia model, were established in mice. The effects of ATRA on the mortality, the bacterial burden, the expansion and activity of CLP-induced MDSCs, as well as the function of CD4+ T cells were evaluated. Results: In CLP model, ATRA was found to reduce frequency of MDSCs in spleen of mice and inhibit activity of MDSCs by regulating the generation and activity of arginase-1 and iNOS, and the secretion of immune-supressive cytokines. ATRA administration eventually reduced mortality of secondary infection by Legionella pneumophila in CLP-surviving mice, which might be associated with the restoration of CD4+ T cells proliferating and secreting activity. Conclusion: ATRA can restore CD4+ T cells dysfunction in sepsis by modulating the expansion and function of MDSCs and therefore provides a potential therapy that targets the immunosuppressive state of sepsis.

Automated summary

ATRA can reduce the frequency and activity of MDSCs in the spleen of mice by regulating the expression of arginase-1 and iNOS, as well as the secretion of immune-suppressive cytokines. The administration of ATRA ultimately decreased mortality in CLP-surviving mice with secondary infection, potentially due to the restoration of CD4+ T cell function.