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

Abstract

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 CD11bGr1 MDSCs mediates the protection against IMH; mTOR with rapamycin and mTOR-deficient CD11bGr1 MDSCs are suppressive immune modulators that result in less IFN-γ-producing T1 cells and more Foxp3 T 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.

Myeloid‐derived suppressor cells: Roles in the tumor microenvironment and tumor radiotherapy

“…SIRT1‐HIF‐1α axis plays an important role in regulating cellular metabolism. In our research, we found that SIRT1‐HIF‐1α axis is associated with the differentiation of several types of immune cells, including Th9 and MDSCs. Our team research showed that SIRT1 can deregulate function and differentiation of MDSCs through orchestrating HIF‐1α‐dependent glycolysis .…”

High expression of ID1 in monocytes is strongly associated with phenotypic and functional MDSC markers in advanced melanoma

“…mTOR downregulation induces Smad and consequently also ID1 expression. mTOR downregulation has also been established as a stimulator for iNOS production [38]. With regards to our data, the hypothesis could then be formed that iNOS production by MDSC is regulated through the mTOR/Smad/ID1 pathway.…”

Early-life undernutrition reprograms CD4+ T-cell glycolysis and epigenetics to facilitate asthma

“…Quantitative PCR was performed, as previously described, 35 and primers for Rpl13a, Il2, Il4, Il5, Il13, Il9, Il10, Il17, Tgfb, Ifng, c-Myc, hexokinase 1 (Hk2), lactate dehydrogenase A (Ldha), pyruvate kinase muscle (Pkm), and triose phosphate isomerase (Tpi; see Table E2 in this article's Online Repository at www.jacionline.org) were from Primer Bank. Data were normalized to Rpl13a, and results were shown as fold induction relative to expression levels in PBS-treated or naive tissues, as previously indicated.…”

“…Western blot analyses were performed, as previously described. 35,37 The first antibodies used were as follows: phosphorylated signal transducer and activator of transcription 6 (Tyr641), S6 (2F9), 4E-BP1 (236B4), S6K1 (108D2), AKT (D9E), AKT (D25E6), anti-c-Myc (D3N8F; Cell Signaling Technology, Danvers, Mass), and anti-b-actin (AC-15; Sigma). Band intensity was determined by using ImageJ software (National Institutes of Health, Bethesda, Md).…”