mTOR signaling disruption from myeloid‐derived suppressive cells protects against immune‐mediated hepatic injury through the HIF1α‐dependent glycolytic pathway

mTOR negatively controls suppressive functions of MDSCs in immune‐mediated hepatic injury mouse models. The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct innate and adaptive immune responses. Myeloid‐derived suppressive cells (MDSCs) are a heterogeneous cell population that plays a crucial regulatory effect in immune‐related diseases. However, whether mTOR signaling affects the functions of MDSCs remains largely unexplored. Here, we show that mTOR signaling is a pivotal, negative determinant of MDSC function in immune‐mediated hepatic injury (IMH) diseases. In the context of IMH, the blocking of mTOR with rapamycin or mTOR‐deficient CD11b+Gr1+ MDSCs mediates the protection against IMH; mTOR with rapamycin and mTOR‐deficient CD11b+Gr1+ MDSCs are suppressive immune modulators that result in less IFN‐γ‐producing TH1 cells and more Foxp3+ Tregs. Mechanistically, mTOR activity down‐regulation in MDSCs induced iNOS expressions and NO productions. Pharmacologic inhibitions of iNOS completely eliminate MDSC‐suppressive function and lose their inducible effects on T cell differentiation. Importantly, HIF1α‐dependent glycolytic activity is responsible for mTOR‐deficient, increased MDSC functional changes in IMH inflammation. Thus, these data demonstrate that mTOR acts as a fundamental “rheostat” in MDSCs to link immunologic signals to glycolytic pathways and functional fitness and highlights a central role of metabolic programming of MDSC‐suppressive activity in protecting against immune hepatic injuries.