Immunomodulatory signaling imposes tight regulations on metabolic programs within immune cells and consequentially determines immune response outcomes. Although the glucocorticoid receptor (GR) has been recently implicated in regulating the function of myeloid-derived suppressor cells (MDSCs), whether the dysregulation of GR in MDSCs is involved in immune-mediated hepatic diseases and how GR regulates the function of MDSCs in such a context remains unknown. Here, we revealed the dysregulation of GR expression in MDSCs during innate immunological hepatic injury (IMH) and found that GR regulates the function of MDSCs through modulating HIF1 alpha-dependent glycolysis. Pharmacological modulation of GR by its agonist (dexamethasone, Dex) protects IMH mice against inflammatory injury. Mechanistically, GR signaling suppresses HIF1 alpha and HIF1 alpha-dependent glycolysis in MDSCs and thus promotes the immune suppressive activity of MDSCs. Our studies reveal a role of GR-HIF1 alpha in regulating the metabolism and function of MDSCs and further implicate MDSC GR signaling as a potential therapeutic target in hepatic diseases that are driven by innate immune cell-mediated systemic inflammation.
[1]Fudan Univ, Sch Basic Med Sci, Dept Immunol, Shanghai 200032, Peoples R China;
[2]Beijing Normal Univ, Coll Life Sci, Key Lab Cell Proliferat & Regulat Biol, Minist Educ,Inst Cell Biol, Xinjiekouwaidajie 19, Beijing 100875, Peoples R China;
[3]Beijing Inst Microbiol & Epidemiol, State Key Lab Pathogen & Biosecur, Beijing 100071, Peoples R China;
[4]Chinese Acad Sci, Inst Zool, State Key Lab Membrane Biol, Beijing 100101, Peoples R China;
[5]Ohio State Univ, Nationwide Childrens Hosp, Ctr Childhood Canc & Blood Dis Hematol Oncol, Columbus, OH 43205 USA;
[6]Ohio State Univ, Nationwide Childrens Hosp, BMT, Res Inst, Columbus, OH 43205 USA
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