All-trans-retinoic Acid Restores Immunosuppression In Sepsis By Inhibiting Expansion And Activation Of Myeloid-Derived Suppressor Cells.

Background:Sepsis is a systemic, deleterious host response to widespread infection. The immune response in sepsis can be characterized by a cytokine-mediated hyper-inflammatory phase and a subsequent immune-suppressive phase, in which patients fail to eradicate invading pathogens and are susceptible to opportunistic organisms. Secondary infections due to post-sepsis immunosuppression are a major cause of death in patients with sepsis. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that are elevated in the number and activated during sepsis. MDSCs possess immune-suppressive activities via suppressing T-cell proliferation and activation. All-trans-retinoic acid (ATRA) has been proved by a series of in vitro, in vivo experiments and clinical trials to cause MDSCs to differentiate into normal functioning mature immune cells such as dendritic cells (DC), macrophages and neutrophils. However, all these studies have been carried out in cancer field and there is no evidence in sepsis. The present study aims to investigate how ATRA affects the immune STATe and prognosis of sepsis through modulating the accumulation and function of MDSCs, as well as the involving signal transduction molecules.Methods:A murine cecal ligation and puncture (CLP) model was established. Three and seven days after CLP, surviving mice underwent secondary pulmonary infection by intranasal inoculation of nonlethal dose of P. aeruginosa. The effects of ATRA on the survival rate of CLP and "two-hit" models, the accumulation, morphological characterization, activity and cytokine secration of CLP-induced MDSC, apoptosis and proliferation of CD4+T lymphocytes, delayed type hypersensitivity (DTH) reaction, cytokine levels in resum and expression of signal transduction molecules were determined.Results:ATRA significantly decreased the number and percentage of MDSC in spleen, bone marrow and peripheral blood in septic mice post CLP. ATRA inhibited arginase activity and down-regulated the NO expression of splenic CD11b+/Gr-1+cells, as well as ameliorate the secration balance of pro-/anti-imflamation cytokine by them. These changes led to the decrease in level of immune-suppressive cytokines, the promotion in proliferation and inhibition in apoptosis of CD4+T cells at7days after CLP. It was also characterized by restored DTH response, prolonged surviving period and increased survival rate in ATRA-treated group. This effect could be counteracted by adoptive transfer of CD11b-Gr-1+cells isolated from septic mice and achieved by depletion of Gr-1+cells through Gr-1antibody. Phosphorylation level of signal transducers and activators of transcription (STAT)-3, STAT-6and AKT were defected to determine the underlying signal pathways during the modulation of ATRA in MDSCs, but the change was only found in p-STAT3.Conclusion:Taken together, our results demonstrate that ATRA restores immune-competence in sepsis by modulating the accumulation and function of MDSCs and thus represents an additional potential strategy in the treatment of the immunosuppressive state of sepsis.