MondoA–Thioredoxin-Interacting Protein Axis Maintains Regulatory T-Cell Identity and Function in Colorectal Cancer Microenvironment

Lu, Ying; Li, Yangyang; Liu, Qi; Tian, Na; Du, Peng; Zhu, Fangming; Han, Yichao; Liu, Xinnan; Liu, Xisheng; Peng, Xiao; Wang, Xiaoxia; Wu, Yuchen; Tong, Lingfeng; Li, Yakui; Zhu, Yemin; Wu, Lifang; Zhang, Ping; Xu, Ye; Chen, Hanbei; Li, Bin; Tong, Xuemei

doi:10.1053/j.gastro.2021.04.041

Cited by 65 publications

(55 citation statements)

References 37 publications

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“…TXNIP is a regulator of oxidative stress [13] and has been studied in many diseases such as pancreatic cancer [12,36], but how ERS regulates oxidative stress in AP is still unknown. A previous study demonstrated that TXNIP is regulated by p-IRE1α in hepatocytes [37].…”

Section: Discussionmentioning

confidence: 99%

Drug D, a Diosgenin Derive, Inhibits L-Arginine-Induced Acute Pancreatitis through Meditating GSDMD in the Endoplasmic Reticulum via the TXNIP/HIF-1α Pathway

et al. 2022

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Acute pancreatitis (AP) is one of the most common causes of hospitalization for gastrointestinal diseases, with high morbidity and mortality. Endoplasmic reticulum stress (ERS) and Gasdermin D (GSDMD) mediate AP, but little is known about their mutual influence on AP. Diosgenin has excellent anti-inflammatory and antioxidant effects. This study investigated whether Diosgenin derivative D (Drug D) inhibits L-arginine-induced acute pancreatitis through meditating GSDMD in the endoplasmic reticulum (ER). Our studies were conducted in a mouse model of L-arginine-induced AP as well as in an in vitro model on mouse pancreatic acinar cells. The GSDMD accumulation in ER was found in this study, which caused ERS of acinar cells. GSDMD inhibitor Disulfiram (DSF) notably decreased the expression of GSDMD in ER and TXNIP/HIF-1α signaling. The molecular docking study indicated that there was a potential interaction between Drug D and GSDMD. Our results showed that Drug D significantly inhibited necrosis of acinar cells dose-dependently, and we also found that Drug D alleviated pancreatic necrosis and systemic inflammation by inhibiting the GSDMD accumulation in the ER of acinar cells via the TXNIP/HIF-1α pathway. Furthermore, the level of p-IRE1α (a marker of ERS) was also down-regulated by Drug D in a dose-dependent manner in AP. We also found that Drug D alleviated TXNIP up-regulation and oxidative stress in AP. Moreover, our results revealed that GSDMD-/- mitigated AP by inhibiting TXNIP/HIF-1α. Therefore, Drug D, which is extracted from Dioscorea zingiberensis, may inhibit L-arginine-induced AP by meditating GSDMD in the ER by the TXNIP /HIF-1α pathway.

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Section: Discussionmentioning

confidence: 99%

Drug D, a Diosgenin Derive, Inhibits L-Arginine-Induced Acute Pancreatitis through Meditating GSDMD in the Endoplasmic Reticulum via the TXNIP/HIF-1α Pathway

et al. 2022

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“…This opposite role of Treg cells might be due to their extremely high heterogeneity in intestines. Single-cell RNA sequencing analysis on intratumoral Tregs from CRC patients revealed Treg cells with low activity of the MondoA-thioredoxin-interacting protein (TXNIP) axis and increased glucose uptake ( 137 ). Treg cells with low MondoA-TXNIP axis are Th17-like and hyperglycolytic, which promote tumor growth.…”

Section: Subsets Of Tissue Resident Treg Cells: Characteristics and F...mentioning

confidence: 99%

Tissue Resident Foxp3+ Regulatory T Cells: Sentinels and Saboteurs in Health and Disease

2022

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Foxp3+ regulatory T (Treg) cells are a CD4 T cell subset with unique immune regulatory function that are indispensable in immunity and tolerance. Their indisputable importance has been investigated in numerous disease settings and experimental models. Despite the extensive efforts in determining the cellular and molecular mechanisms operating their functions, our understanding their biology especially in vivo remains limited. There is emerging evidence that Treg cells resident in the non-lymphoid tissues play a central role in regulating tissue homeostasis, inflammation, and repair. Furthermore, tissue-specific properties of those Treg cells that allow them to express tissue specific functions have been explored. In this review, we will discuss the potential mechanisms and key cellular/molecular factors responsible for the homeostasis and functions of tissue resident Treg cells under steady-state and inflammatory conditions.

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“…It is worthy to note that intestinal bile acids (BAs) produced by hepatocytes have been recently shown to modulate homeostasis and function of Tregs expressing retinoic acid receptor-related orphan receptor γ (RORγ) in the colon ( 153 ). Despite the importance of RORγ-expressing Tregs in preventing intestinal inflammation ( 154 , 155 ), elevation of glycolysis can convert them to pathogenic Tregs in facilitating the progression of CRC ( 156 ). MondoA is a transcription factor that suppresses glycolysis of colonic Tregs through inducing thioredoxin-interacting protein (TXNIP).…”

Section: Diversification Of Treg Cell Metabolism and Functional Adapt...mentioning

confidence: 99%

“…MondoA is a transcription factor that suppresses glycolysis of colonic Tregs through inducing thioredoxin-interacting protein (TXNIP). Deletion of MondoA in Tregs augments their glycolysis and conversion to IL-17-producing Tregs, which promote CRC progression ( 156 ). Thus, food antigens, commensal microbiota, intestinal cytokines, and metabolites constitutes complex networks to orchestrate functional diversity and metabolic fitness of intestinal Tregs in maintaining the balance between protective immunity and immune tolerance in the gastrointestinal tract.…”

Section: Diversification Of Treg Cell Metabolism and Functional Adapt...mentioning

confidence: 99%

Regulation of Treg Cell Metabolism and Function in Non-Lymphoid Tissues

Yang

2022

Front. Immunol.

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Regulator T cells (Tregs) play pivotal roles in maintaining immune tolerance and regulating immune responses against pathogens and tumors. Reprogramming of cellular metabolism has been determined as a crucial process that connects microenvironmental cues and signaling networks to influence homeostasis and function of tissue Tregs. In adaptation to a variety of non-lymphoid tissues, Tregs coordinate local immune signals and signaling networks to rewire cellular metabolic programs to sustain their suppressive function. Altered Treg metabolism in turn shapes Treg activation and function. In light of the advanced understanding of immunometabolism, manipulation of systemic metabolites has been emerging as an attractive strategy aiming to modulate metabolism and function of tissue Tregs and improve the treatment of immune-related diseases. In this review, we summarize key immune signals and metabolic programs involved in the regulation of tissue Tregs, review the mechanisms underlying the differentiation and function of Tregs in various non-lymphoid tissues, and discuss therapeutic intervention of metabolic modulators of tissue Tregs for the treatment of autoimmune diseases and cancer.

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MondoA–Thioredoxin-Interacting Protein Axis Maintains Regulatory T-Cell Identity and Function in Colorectal Cancer Microenvironment

Cited by 65 publications

References 37 publications

Drug D, a Diosgenin Derive, Inhibits L-Arginine-Induced Acute Pancreatitis through Meditating GSDMD in the Endoplasmic Reticulum via the TXNIP/HIF-1α Pathway

Drug D, a Diosgenin Derive, Inhibits L-Arginine-Induced Acute Pancreatitis through Meditating GSDMD in the Endoplasmic Reticulum via the TXNIP/HIF-1α Pathway

Tissue Resident Foxp3+ Regulatory T Cells: Sentinels and Saboteurs in Health and Disease

Regulation of Treg Cell Metabolism and Function in Non-Lymphoid Tissues

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