ATP Triggers Human Th9 Cell Differentiation via Nitric Oxide-Mediated mTOR-HIF1α Pathway

Roy, Suyasha; Awasthi, Amit

doi:10.3389/fimmu.2019.01120

Cited by 21 publications

(25 citation statements)

References 53 publications

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“…HIF1α plays an essential role in the differentiation and functions of Th cells 35 . HIF1α acts as one of the key metabolic checkpoints in differentiation and functions of Th9, Th17, and Tregs 23 , 36 – 38 . HIF1α regulates the expression of glycolytic genes and metabolic reprogramming of T cells from oxidative phosphorylation (OxPhos) to aerobic glycolysis 39 .…”

Section: Introductionmentioning

confidence: 99%

EGFR-HIF1α signaling positively regulates the differentiation of IL-9 producing T helper cells

et al. 2021

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Interleukin 9 (IL-9)-producing helper T (Th9) cells are essential for inducing anti-tumor immunity and inflammation in allergic and autoimmune diseases. Although transcription factors that are essential for Th9 cell differentiation have been identified, other signaling pathways that are required for their generation and functions are yet to be explored. Here, we identify that Epidermal Growth Factor Receptor (EGFR) is essential for IL-9 induction in helper T (Th) cells. Moreover, amphiregulin (Areg), an EGFR ligand, is critical for the amplification of Th9 cells induced by TGF-β1 and IL-4. Furthermore, our data show that Areg-EGFR signaling induces HIF1α, which binds and transactivates IL-9 and NOS2 promoters in Th9 cells. Loss of EGFR or HIF1α abrogates Th9 cell differentiation and suppresses their anti-tumor functions. Moreover, in line with its reliance on HIF1α expression, metabolomics profiling of Th9 cells revealed that Succinate, a TCA cycle metabolite, promotes Th9 cell differentiation and Th9 cell-mediated tumor regression.

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Section: Introductionmentioning

confidence: 99%

EGFR-HIF1α signaling positively regulates the differentiation of IL-9 producing T helper cells

et al. 2021

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“…But we haven't looked at other cellular targets as EGFR is the most prominent and well-studied target for Gefitinib. Interestingly, Salmonella exploit EGFR for its entry and subsequently internalization through flagellin in gut of the host (48)(49)(50)(51)(52). Since Gefitinib blocks EGFR phosphorylation, it is possible that Salmonella entry and uptake by host cells require EGFR activation (Figure 3G) (31,48,49,(53)(54)(55).…”

Section: Discussionmentioning

confidence: 99%

“…Previous reports demonstrated that blocking of EGFR signaling suppresses mTOR pathway. In addition, Rapamycin treatment affects EGF/EGFR signaling and causes diverse physiological changes within the cell (48)(49)(50)60). Several studies indicated that mTOR play a pivotal role in the replication of intracellular pathogens (37,53).…”

Section: Discussionmentioning

confidence: 99%

Gefitinib Results in Robust Host-Directed Immunity Against Salmonella Infection Through Proteo-Metabolomic Reprogramming

et al. 2021

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The global rise of antibiotic-resistant strains of Salmonella has necessitated the development of alternative therapeutic strategies. Recent studies have shown that targeting host factors may provide an alternative approach for the treatment of intracellular pathogens. Host-directed therapy (HDT) modulates host cellular factors that are essential to support the replication of the intracellular pathogens. In the current study, we identified Gefitinib as a potential host directed therapeutic drug against Salmonella. Further, using the proteome analysis of Salmonella-infected macrophages, we identified EGFR, a host factor, promoting intracellular survival of Salmonella via mTOR-HIF-1α axis. Blocking of EGFR, mTOR or HIF-1α inhibits the intracellular survival of Salmonella within the macrophages and in mice. Global proteo-metabolomics profiling indicated the upregulation of host factors predominantly associated with ATP turn over, glycolysis, urea cycle, which ultimately promote the activation of EGFR-HIF1α signaling upon infection. Importantly, inhibition of EGFR and HIF1α restored both proteomics and metabolomics changes caused by Salmonella infection. Taken together, this study identifies Gefitinib as a host directed drug that holds potential translational values against Salmonella infection and might be useful for the treatment of other intracellular infections.

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“…TME is adenosine triphosphate (ATP) rich [ 160 ]. Roy and Awasthi showed that the extracellular ATP (eATP) induced the production of NO, which potentiated the mTOR-HIF1 α -mediated metabolic signaling pathway to promote differentiation of human Th9 cells and secretion of IL-9 [ 161 ].…”

Section: Roles Of Th9 Cells and Treg Cells In Asthma And Cancermentioning

confidence: 99%

Critical Roles of Balanced T Helper 9 Cells and Regulatory T Cells in Allergic Airway Inflammation and Tumor Immunity

Huang

Dong

2021

Journal of Immunology Research

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CD4+T helper (Th) cells are important mediators of immune responses in asthma and cancer. When counteracted by different classes of pathogens, naïve CD4+T cells undergo programmed differentiation into distinct types of Th cells. Th cells orchestrate antigen-specific immune responses upon their clonal T-cell receptor (TCR) interaction with the appropriate peptide antigen presented on MHC class II molecules expressed by antigen-presenting cells (APCs). T helper 9 (Th9) cells and regulatory T (Treg) cells and their corresponding cytokines have critical roles in tumor and allergic immunity. In the context of asthma and cancer, the dynamic internal microenvironment, along with chronic inflammatory stimuli, influences development, differentiation, and function of Th9 cells and Treg cells. Furthermore, the dysregulation of the balance between Th9 cells and Treg cells might trigger aberrant immune responses, resulting in development and exacerbation of asthma and cancer. In this review, the development, differentiation, and function of Th9 cells and Treg cells, which are synergistically regulated by various factors including cytokine signals, transcriptional factors (TFs), costimulatory signals, microenvironment cues, metabolic pathways, and different signal pathways, will be discussed. In addition, we focus on the recent progress that has helped to achieve a better understanding of the roles of Th9 cells and Treg cells in allergic airway inflammation and tumor immunity. We also discuss how various factors moderate their responses in asthma and cancer. Finally, we summarize the recent findings regarding potential mechanisms for regulating the balance between Th9 and Treg cells in asthma and cancer. These advances provide opportunities for novel therapeutic strategies that are aimed at reestablishing the balance of these cells in the diseases.

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ATP Triggers Human Th9 Cell Differentiation via Nitric Oxide-Mediated mTOR-HIF1α Pathway

Cited by 21 publications

References 53 publications

EGFR-HIF1α signaling positively regulates the differentiation of IL-9 producing T helper cells

EGFR-HIF1α signaling positively regulates the differentiation of IL-9 producing T helper cells

Gefitinib Results in Robust Host-Directed Immunity Against Salmonella Infection Through Proteo-Metabolomic Reprogramming

Critical Roles of Balanced T Helper 9 Cells and Regulatory T Cells in Allergic Airway Inflammation and Tumor Immunity

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