Zhengguo Zhang

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.

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.

Intercellular interplay between Sirt1 signalling and cell metabolism in immune cell biology.

Sirtuins are evolutionarily conserved class III histone deacetylases that have been the focus of intense scrutiny and interest since the discovery of Sir2 as a yeast longevity factor. Early reports demonstrated an important role of Sirt1 in aging and metabolism, but its critical regulatory role in the immune system has only been unveiled in recent years. In this review we discuss the latest advances in understanding the regulatory role of Sirt1 in immune responses as well as how Sirt1 translates metabolic cues to immune signals, which would bring new insights into both pathogenesis and potential therapeutic strategies of a variety of immune‐related diseases, such as cancer, microbial infection, autoimmune diseases and transplantation.

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.

The calcineurin-NFAT axis controls allograft immunity in myeloid-derived suppressor cells through reprogramming T cell differentiation.

ABSTRACT While cyclosporine (CsA) inhibits calcineurin and is highly effective in prolonging rejection for transplantation patients, the immunological mechanisms remain unknown. Herein, the role of calcineurin signaling was investigated in a mouse allogeneic skin transplantation model. The calcineurin inhibitor CsA significantly ameliorated allograft rejection. In CsA-treated allograft recipient mice, CD11b+ Gr1+ myeloid-derived suppressor cells (MDSCs) were functional suppressive immune modulators that resulted in fewer gamma interferon (IFN-γ)-producing CD8+ T cells and CD4+ T cells (TH1 T helper cells) and more interleukin 4 (IL-4)-producing CD4+ T cells (TH2) and prolonged allogeneic skin graft survival. Importantly, the expression of NFATc1 is significantly diminished in the CsA-induced MDSCs. Blocking NFAT (nuclear factor of activated T cells) with VIVIT phenocopied the CsA effects in MDSCs and increased the suppressive activities and recruitment of CD11b+ Gr1+ MDSCs in allograft recipient mice. Mechanistically, CsA treatment enhanced the expression of indoleamine 2,3-dioxygenase (IDO) and the suppressive activities of MDSCs in allograft recipients. Inhibition of IDO nearly completely recovered the increased MDSC suppressive activities and the effects on T cell differentiation. The results of this study indicate that MDSCs are an essential component in controlling allograft survival following CsA or VIVIT treatment, validating the calcineurin-NFAT-IDO signaling axis as a potential therapeutic target in transplantation.

Myeloid-derived suppressor cells in immunity and autoimmunity

Myeloid-derived suppressor cells (MDSCs) play a critical role in suppressing immune responses in patients with cancer or severe inflammation. Recent studies have focused on the strong relationship between MDSCs and autoimmune diseases, such as autoimmune hepatitis, inflammatory bowel disease and experimental autoimmune encephalomyelitis. Interestingly, MDSCs appear to serve multifaceted functions in autoimmunity, playing both protective and pathogenic roles. Therefore, although MDSCs may be a functional target for the therapy of autoimmune diseases, the disorders that accompany such treatments should be noted. In this manuscript, we summarize the functions and molecular regulation of MDSCs in immunity and autoimmune disease.

Different effects of tacrolimus on innate and adaptive immune cells in the allograft transplantation

While tacrolimus (FK506) is currently used as immunosuppression therapy in transplant recipient, the immunological mechanism remains unknown. Herein, the immunoregulatory effects of FK506 were investigated in the physiological status and allogeneic skin transplantation. FK506 cannot significantly alter the functions of innate immune cells (macrophages and neutrophils) and adaptive immune cells (T cells) in the physiological status. However, it can effectively delay allogeneic skin‐graft rejection through ameliorating the T cell responses, but not myeloid‐derived innate immune cell responses. Importantly, it did not affect the allograft recipient macrophage innate immune defence capacity to bacteria. In clinics, FK506 treatment can significantly control the cytokine production in T cells, but not non‐T cells. This study shows targeting calcineurin signalling, FK506, to be essential in inducing allograft tolerance, but not to damage the innate defence capacity, validating the immune cell phenotypes as a potential marker in transplantation following FK506 treatment.