Huanrong Liu

SIRT1 Limits the Function and Fate of Myeloid-Derived Suppressor Cells in Tumors by Orchestrating HIF-1α–Dependent Glycolysis

Myeloid-derived suppressor cells (MDSC) display an immature phenotype that may assume a classically activated (M1) or alternatively activated phenotype (M2) in tumors. In this study, we investigated metabolic mechanisms underlying the differentiation of MDSCs into M1 or M2 myeloid lineage and their effect on cancer pathophysiology. We found that SIRT1 deficiency in MDSCs directs a specific switch to M1 lineage when cells enter the periphery from bone marrow, decreasing the suppressive function in favor of a proinflammatory M1 phenotype associated with tumor cell attack. Glycolytic activation through the mTOR-hypoxia-inducible factor-1α (HIF-1α) pathway was required for differentiation to the M1 phenotype, which conferred protection against tumors. Our results define the essential nature of a SIRT1-mTOR/HIF-1α glycolytic pathway in determining MDSC differentiation, with implications for metabolic reprogramming as a cancer therapeutic approach.

Kinase AKT controls innate immune cell development and function

The critical roles of kinase AKT in tumour cell proliferation, apoptosis and protein synthesis have been widely recognized. But AKT also plays an important role in immune modulation. Recent studies have confirmed that kinase AKT can regulate the development and functions of innate immune cells (neutrophil, macrophage and dendritic cell). Studies have shown that different isoforms of kinase AKT have different effects in regulating immunity‐related diseases, mainly through the mammalian target of rapamycin‐dependent or ‐independent pathways. The purpose of this review is to illustrate the immune modulating effects of kinase AKT on innate immune cell development, survival and function.

Dexamethasone potentiates myeloid-derived suppressor cell function in prolonging allograft survival through nitric oxide

Whereas GCs have been demonstrated to be beneficial for transplantation patients, the pharmacological mechanisms remain unknown. Herein, the role of GR signaling was investigated via a pharmacological approach in a murine allogeneic skin transplantation model. The GC Dex, a representative GC, significantly relieved allograft rejection. In Dex‐treated allograft recipient mice, CD11b+Gr1+ MDSCs prolonged graft survival and acted as functional suppressive immune modulators that resulted in fewer IFN‐γ‐producing Th1 cells and a greater number of IL‐4‐producing Th2 cells. In agreement, Dex‐treated MDSCs promoted reciprocal differentiation between Th1 and Th2 in vivo. Importantly, the GR is required in the Dex‐induced MDSC effects. The blocking of GR with RU486 significantly diminished the expression of CXCR2 and the recruitment of CD11b+Gr1+ MDSCs, thereby recovering the increased MDSC‐suppressive activity induced by Dex. Mechanistically, Dex treatment induced MDSC iNOS expression and NO production. Pharmacologic inhibition of iNOS completely eliminated the MDSC‐suppressive function and the effects on T cell differentiation. This study shows MDSCs to be an essential component in the prolongation of allograft survival following Dex or RU486 treatment, validating the GC–GR–NO signaling axis as a potential therapeutic target in transplantation.

Dendritic cell SIRT1–HIF1α axis programs the differentiation of CD4+ T cells through IL-12 and TGF-β1

Significance Naive CD4+ T cells differentiate into diverse effector and regulatory subsets to orchestrate immunity and tolerance. Whereas the mechanism of T-cell intrinsic signals has been extensively studied, how T-cell lineage differentiation is controlled by innate immune signals remains unknown. Here we used loss-of-function mouse systems, combined with other complementary approaches and models, to define the role of dendritic cell (DC) sirtuin 1 (SIRT1) as a key regulator in orchestrating the orientation of T-cell differentiation via HIF1α signaling in a mammalian target of rapamycin–independent manner. DC-expressed SIRT1, a type III histone deacetylase, programmed reciprocal T helper 1 (TH1) and regulatory T-cell (Treg) differentiation by modulating IL-12–STAT4 and TGF-β1–SMAD3 axes and cytokine receptor expressions at the DC–T-cell interface. The differentiation of naive CD4+ T cells into distinct lineages plays critical roles in mediating adaptive immunity or maintaining immune tolerance. In addition to being a first line of defense, the innate immune system also actively instructs adaptive immunity through antigen presentation and immunoregulatory cytokine production. Here we found that sirtuin 1 (SIRT1), a type III histone deacetylase, plays an essential role in mediating proinflammatory signaling in dendritic cells (DCs), consequentially modulating the balance of proinflammatory T helper type 1 (TH1) cells and antiinflammatory Foxp3+ regulatory T cells (Treg cells). Genetic deletion of SIRT1 in DCs restrained the generation of Treg cells while driving TH1 development, resulting in an enhanced T-cell–mediated inflammation against microbial responses. Beyond this finding, SIRT1 signaled through a hypoxia-inducible factor-1 alpha (HIF1α)-dependent pathway, orchestrating the reciprocal TH1 and Treg lineage commitment through DC-derived IL-12 and TGF-β1. Our studies implicates a DC-based SIRT1–HIF1α metabolic checkpoint in controlling T-cell lineage specification.

Targeting S1P1 Receptor Protects against Murine Immunological Hepatic Injury through Myeloid-Derived Suppressor Cells

Although FTY720 may alter migration and homing of lymphocytes via sphingosine-1-phosphate (S1P) receptors, our recent studies indicated that FTY720 directly controls the differentiation of Th1 cells to regulatory T cells (Tregs) by targeting S1P1. However, the pharmacological function of FTY720 in immunological hepatic injury remains unknown. In this study, the role and regulatory signaling pathway of S1P receptor were investigated using a pharmacological approach in immune-mediated hepatic injury (IMH). In the context of IMH, FTY720 significantly ameliorated mortality and hepatic pathology. In FTY720-treated mice, recruited CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) mediate protection against IMH and are functional suppressive immune modulators that result in fewer IFN-γ–producing Th1 cells and more Foxp3+ Tregs. In agreement, FTY720-treated MDSCs promote the reciprocal differentiation between Th1 cells and Tregs in vitro and in vivo. Mechanistically, FTY720 treatment induced inducible NO synthase expression and NO production in MDSCs. Pharmacologic inhibition of inducible NO synthase completely eliminates MDSC suppressive function and eradicates their inducible effects on T cell differentiation. Finally, the mTOR inhibitor, rapamycin, photocopies the effects of FTY720 on MDSCs, implicating mTOR as a downstream effector of S1P1 signaling. This study identifies MDSCs as an essential component that provides protection against IMH following FTY720 or rapamycin treatment, validating the S1P1–mTOR signaling axis as a potential therapeutic target in hepatic injury.

Modulation of TSC-mTOR signaling on immune cells in immunity and autoimmunity.

The mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase which has a central role in the regulation of cell growth and metabolism. In the study of the mTOR signaling pathway, tuberous sclerosis complex (TSC) 1/2 complex is identified as a critical regulator of mTOR activity. TSC1/2 plays important roles for immune cell homeostasis and differentiation by negative control of mTOR signaling pathway. TSC1/2–mTOR pathway is proving to be a central point in regulating immune function of diverse immune cells. In this review, we discuss the function of TSC1/2–mTOR to direct the innate and adaptive immune cell development and function. Furthermore, we focus on the role of TSC1/2–mTOR signaling pathway in immune cell mediated diseases, especially autoimmunity. J. Cell. Physiol. 229: 17–26, 2014.

mTOR limits the recruitment of CD11b+Gr1+Ly6Chigh myeloid-derived suppressor cells in protecting against murine immunological hepatic injury

The mTOR pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct the innate and adaptive immune responses. 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 unknown. Here, we show that mTOR signaling is a pivotal negative determinant of MDSC recruitment in IMH disease. In the context of IMH, inhibition of mTOR with rapamycin in CD11b+Gr1+ MDSCs mediates protection against IMH and serves as a functional, suppressive immune modulator that results in increased CD11b+Gr1+Ly6Chigh MDSC recruitment to inflammatory sites. In agreement with this, mTOR down‐regulation promotes CD11b+Gr1+Ly6Chigh MDSC migration in vitro and in vivo. Mechanistically, mTOR activity down‐regulation in MDSCs induced iNOS expression and NO production. Pharmacologic inhibition of iNOS completely eliminated MDSC recruitment. This study identifies MDSCs as an essential component for protection against IMH following rapamycin treatment. Rapamycin treatment or mTOR inhibition promotes CD11b+Gr1+Ly6Chigh MDSC recruitment and is critically required for protection against hepatic injury. This study further validates the targeting of mTOR signaling as a potential therapeutic approach to IMH‐related diseases.

Kinase AKT1 Negatively Controls Neutrophil Recruitment and Function in Mice

Neutrophils are critically involved in host defense and inflammatory injury. However, intrinsic signaling mechanisms controlling neutrophil recruitment and activities are poorly defined. In this article, we showed that protein kinase AKT1 (also known as PKBα) is the dominant isoform expressed in neutrophils and is downregulated upon bacterial infection and neutrophil activation. AKT1 deficiency resulted in severe disease progression accompanied by recruitment of neutrophils and enhanced bactericidal activity in the acute inflammatory lung injury (ALI) and the Staphylococcus aureus infection mouse models. Moreover, the depletion of neutrophils efficiently reversed the aggravated inflammatory response, but adoptive transfer of AKT1−/− neutrophils could potentiate the inflammatory immunity, indicating an intrinsic effect of the neutrophil in modulating inflammation in AKT1−/− mice. In the ALI model, the infiltration of neutrophils into the inflammatory site was associated with enhanced migration capacity, whereas inflammatory stimuli could promote neutrophil apoptosis. In accordance with these findings, neutralization of CXCR2 attenuated neutrophil infiltration and delayed the occurrence of inflammation. Finally, the enhanced bactericidal activity and inflammatory immunity of AKT-deficient neutrophils were mediated by a STAT1-dependent, but not a mammalian target of rapamycin–dependent, pathway. Thus, our findings indicated that the AKT1–STAT1 signaling axis negatively regulates neutrophil recruitment and activation in ALI and S. aureus infection in mice.

Glucocorticoid receptor promotes the function of myeloid-derived suppressor cells by suppressing HIF1α-dependent glycolysis

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 HIF1α-dependent glycolysis. Pharmacological modulation of GR by its agonist (dexamethasone, Dex) protects IMH mice against inflammatory injury. Mechanistically, GR signaling suppresses HIF1α and HIF1α-dependent glycolysis in MDSCs and thus promotes the immune suppressive activity of MDSCs. Our studies reveal a role of GR-HIF1α 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.

Cellular metabolism modulation in T lymphocyte immunity

T lymphocytes are a central component, and play an important role in controlling immunity and immunological diseases. Recent studies have shown that T cell metabolism is highly dynamic and has a tremendous impact on the modulation of T lymphocyte immunity. Specific metabolic pathways meet energy and biosynthetic requirements that can support specific T cell functional activities in immunity and immunological diseases. This review summarizes the recent progresses about the modulatory role of cell metabolism in T cell development, differentiation, activation and function in immunity. These might provide new opportunities to modulate the immune responses and treat clinical immunological diseases. This article is protected by copyright. All rights reserved.