The Roles of Myeloid Derived Suppressor Cells in Sepsis.

Literature has demonstrated the severity of sepsis, vascular permeability changes through the blood vessels, causing multiple organ failure and even death! By preliminary data and updated references, we hypothesized that septic patients with high monocytic myeloid derived suppressor cell (M-MDSC) could cause a high vascular permeability, multi-organs dysfunction, suppress T cell function via Th17 and may cause death from sepsis! Our research team has found and published that two subtypes of MDSCs in septic patients: granulocytic MDSC (G-MDSC) and monocytic MDSC (M-MDSC), which could reflect the treatment response and prognosis of sepsis! This study is designed to isolate subtypes of MDSCs from septic patients, explore the correlation of MDSC and vascular permeability, T- cell function, Th17 pathway, and differentiation of MDSC to prognosis and phenomenon above in sepsis. From our preliminary data, we found that both subtypes of MDSCs increased in septic patients. Interestingly, patients with high M-MDSC had a worse prognosis, meanwhile patients with lower M-MDSC had a better prognosis. In vitro study model with HUVEC endothelial cell model, G-MDSC could reverse the vascular permeability change by M-MDSC, and T- cells functions! According to our preliminary data, we hypothesized that G-MDSC, which may secret some factors (X factors) to improve endothelial permeability, oxygenation and organ perfusion. Meanwhile, these cells differentiation (to G-MDSC or M-MDSC) could interfere the vascular permeability, T cell immunity, and Th17 function. Further more, the differentiation of MDSC may reverse the effects of endothelial barrier disruption from sepsis cascades by M-MDSC and T cell functions. By the previous references, the Dectin-1/Syk/Card9 pathway may be the effects of MDSCs to interfere T cells via IL17, and the differentiation of MDSC may be related to ROR pathway. The pathway has proved in other diseases, we hypothesized it could be similar in sepsis. The first year we will work to explore correlation of 2 subtypes MDSCs and T cell function and related cytokines and molecules (IL17, Dectin- 1/Syk/Card9) and vascular permeability factor (e.g., VEGF, VEGFR, thrombin, thrombomodulin, angiopoietin, MMP, etc.), and sepsis prognosis in septic patients. By in vitro HUVEC endothelial cell model, we will recognize the phenomenon of our preliminary data and hypotheses. The second year we will try to find out the x factor by proteomics to prove our hypothesis. Further more, the X factor will be validated to reverse vascular permeability of endothelial cells from the model in vitro. At the same time, its downstream signaling of endothelial cells will be also studied via ELISA, immunostaning, and confocal microscope with fluorescence! Bone marrow-derived progenitor cells (BMPC) could prevent thrombin-induced increase in lung vascular permeability. Therefore, thrombin pathway could be x factor between MDSC and endothelial cells permeability. From the study, we could understand the impacts of subtypes of MDSC on the endothelial cells and the prognosis of septic patients. Additionally, the differentiation of MDSC may be related to ROR pathway. The pathway has proved in other diseases, we hypothesized it could be similar in sepsis. The novel treatments of sepsis may be developed from the study!

Project ID:PC10507-0402
External Project ID:MOST105-2314-B182-045