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

Liu, Guangwei; Bi, Yujing; Xue, Lixiang; Zhang, Yan; Yang, Hui; Chen, Xi; Lu, Yun; Zhang, Zhengguo; Liu, Huanrong; Wang, Xiao; Wang, Ruoning; Chu, Yiwei; Yang, Ruifu

doi:10.1073/pnas.1420419112

Cited by 107 publications

(122 citation statements)

References 68 publications

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“…The lack of SIRT1 in DCs reduced critical cytokine production, including IFNβ and IL-12, which we suggest contributed to a pathological Th2/Th17 immune response within the airways. Previous studies examining DC-specific KO mice reported no changes in DC maturation, differentiation, or development compared to WT DCs (39, 40), in agreement with our observations. Thus, our data indicate that SIRT1 has a unique role in modulating DC cytokine production in the context of a viral infection, such as RSV (12).…”

Section: Discussionsupporting

confidence: 93%

Sirtuin 1 Regulates Dendritic Cell Activation and Autophagy during Respiratory Syncytial Virus–Induced Immune Responses

Owczarczyk

Schaller

Reed

et al. 2015

The Journal of Immunology

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Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infection in children worldwide. Sirtuin 1 (SIRT1), an NAD+ dependent deacetylase, has been associated with the induction of autophagy and the regulation of inflammatory mediators. We found that Sirt1 was upregulated in mouse lung after RSV infection. Infected animals that received EX-527, a selective SIRT1 inhibitor, displayed exacerbated lung pathology, with increased mucus production, elevated viral load, and enhanced Th2 cytokine production. Gene expression analysis of isolated cell populations revealed that Sirt1 was most highly upregulated in RSV-treated dendritic cells (DCs). Upon RSV infection, EX-527-treated DCs, Sirt1 siRNA-treated DCs, or DCs from conditional knockout (Sirt1f/f-CD11c–Cre+) mice showed downregulated inflammatory cytokine gene expression and attenuated autophagy. Finally, RSV infection of Sirt1f/f-CD11c–Cre+ mice resulted in altered lung and lymph node cytokine responses, leading to exacerbated pathology. These data indicate that SIRT1 promotes DC activation associated with autophagy-mediated processes during RSV infection, thereby directing efficient antiviral immune responses.

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Section: Discussionsupporting

confidence: 93%

Sirtuin 1 Regulates Dendritic Cell Activation and Autophagy during Respiratory Syncytial Virus–Induced Immune Responses

Owczarczyk

Schaller

Reed

et al. 2015

The Journal of Immunology

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“…ϩ differentiation toward Th1-like T cells (59). Again, these experiments must be performed in a tumoral context to gain insights into the consequences of HIF-1 stabilization in DCs in CD4 ϩ T cell differentiation.…”

Section: Hypoxia Potentiates Treg Cell Immunosuppressive Functionmentioning

confidence: 99%

Hypoxia: a key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia

Noman

Hasmim

Messai

et al. 2015

American Journal of Physiology-Cell Physiology

329

310

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-The tumor microenvironment is a complex system, playing an important role in tumor development and progression. Besides cellular stromal components, extracellular matrix fibers, cytokines, and other metabolic mediators are also involved. In this review we outline the potential role of hypoxia, a major feature of most solid tumors, within the tumor microenvironment and how it contributes to immune resistance and immune suppression/tolerance and can be detrimental to antitumor effector cell functions. We also outline how hypoxic stress influences immunosuppressive pathways involving macrophages, myeloid-derived suppressor cells, T regulatory cells, and immune checkpoints and how it may confer tumor resistance. Finally, we discuss how microenvironmental hypoxia poses both obstacles and opportunities for new therapeutic immune interventions.hypoxia; hypoxia-inducible factor; tumor microenvironment; myeloid cells; lymphoid cells; immune suppression; cancer stem cells; programmed death-ligand 1; epithelial-mesenchymal transition; circulating tumor cells; autophagy and antitumor immune response IT HAS BECOME INCREASINGLY apparent that malignant cells exist in a complex cellular and extracellular microenvironment that plays key roles in the initiation and maintenance of the malignant phenotype. Among the microenvironmental factors that play a dominant role in neoplasia, hypoxia is believed to be one of the most relevant in the neoplastic response of tumor cells. It is widely appreciated that the majority of malignancies create a hostile hypoxic microenvironment that can hamper cellmediated immunity and dampen the efficacy of the immune response. Poorly vascularized and hypoxic zones inside solid tumors contribute to immune tolerance of tumor cells by impeding the homing of immunocompetent cells into tumors and inhibiting their antitumor efficacy. Several regulatory mechanisms can occur concurrently within the hypoxic tumor microenvironment, resulting in multiple redundant levels of immune cell plasticity and suppression, tumor plasticity, and functional heterogeneity. Hypoxic stress clearly plays a crucial role in tumor promotion and immune escape by controlling angiogenesis and favoring immune suppression and tumor resistance. Like other therapeutic attempts, immunotherapy is heavily hampered by the morphologically aberrant tumor microvasculature, preventing migration of immune effector cells into established tumors. Many strategies are emerging for changing the immunosuppressive nature of the tumor to a microenvironment able to support antitumor immunity. The identification of ways to induce a permissive and less hostile tumor microenvironment to avoid tumor resistance and immune suppression is of major interest and pertinence. Hypoxia as an Integral Component of the Tumor MicroenvironmentAll life on Earth depends on O 2 , and all physiological and pathological processes of a living cell rely principally on O 2 (103). Hypoxia is characterized by lack of O 2 , and hypoxic tissues are inadequately oxygenated (107). A p...

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“…Indeed, the blockade of glycolysis inhibits Th17 cell generation while stimulating Foxp3+ Treg cell development [66]. Finally, HIF-1α signaling in antigen presenting cells has been shown to modulate their ability to promote the differentiation of Th1 cells and Foxp3+ Tregs [70]. Collectively, these findings suggest that, besides its direct role in cancer cell metabolism, HIF-1α is an important factor in the control of tumor-specific immunity.…”

Section: Hif-1αmentioning

confidence: 99%

Role of AHR and HIF-1α in Glioblastoma Metabolism

Gabriely

Wheeler

Takenaka

et al. 2017

Trends in Endocrinology & Metabolism

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Glioblastoma (GBM) progression is associated with metabolic remodeling in both glioma and immune cells, resulting in the use of aerobic glycolysis as the main source energy and biosynthetic molecules. The transcription factor HIF-1α drives this metabolic reorganization. Oxygen levels as well as other factors control the activity of HIF-1α. In addition, the ligand-activated transcription factor AHR modulates tumor-specific immunity and can also participate in metabolic remodeling. AHR activity is regulated by tryptophan derivatives present in the tumor microenvironment. Thus, the tumor microenvironment, signaling via HIF-1α and AHR, regulates the metabolism of gliomas and immune cells, modulating tumor-specific immunity and consequently, tumor growth. Here, we will review the roles of HIF-1α and AHR in cancer and immune cell metabolism in glioblastoma.

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

Cited by 107 publications

References 68 publications

Sirtuin 1 Regulates Dendritic Cell Activation and Autophagy during Respiratory Syncytial Virus–Induced Immune Responses

Sirtuin 1 Regulates Dendritic Cell Activation and Autophagy during Respiratory Syncytial Virus–Induced Immune Responses

Hypoxia: a key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia

Role of AHR and HIF-1α in Glioblastoma Metabolism

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

Cited by 107 publications

References 68 publications

Sirtuin 1 Regulates Dendritic Cell Activation and Autophagy during Respiratory Syncytial Virus–Induced Immune Responses

Sirtuin 1 Regulates Dendritic Cell Activation and Autophagy during Respiratory Syncytial Virus–Induced Immune Responses

Hypoxia: a key player in antitumor immune response. A Review in the Theme: Cellular Responses to Hypoxia

Role of AHR and HIF-1α in Glioblastoma Metabolism

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