Rap1 prevents colitogenic Th17 cell expansion and facilitates Treg cell differentiation and distal TCR signaling

Ishihara, Sayaka; Sato, Tsuyoshi; Fujikado, Noriyuki; Miyazaki, Haruka; Yoshimoto, Takayuki; Yamamoto, Hiromitsu; Fukuda, Shinji; Katagiri, Koko

doi:10.1038/s42003-022-03129-x

Cited by 6 publications

(4 citation statements)

References 83 publications

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“…Imbalances in Th and Treg cells contribute to the development of various diseases [14]. Restoration of the balance of Th17 cells and Treg cells has been shown to improve ALI [15]. Mechanistically, we suggest that AA attenuates ALI by modulating the Th17/Treg balance.…”

Section: Discussionmentioning

confidence: 71%

Abietic acid attenuates LPS-induced acute lung injury by restoring Th17/Treg balance

Li¹,

Liu²,

Liu³

et al. 2022

Trop. J. Pharm Res

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Purpose: To investigate the mechanism of action and effects of abietic acid (AA) in a mouse acute lung injury (ALI) model. Methods: A mouse ALI model was established by lipopolysaccharide (LPS) induction. Lung tissues were examined for histological alterations and scored based on the degree of injury. Myeloperoxidase (MPO), IL-6, IL-1β, and TNF-α levels were measured by enzyme-linked immunosorbent assay (ELISA) while the numbers of Th17 and Treg cells were assessed by immunofluorescence. Protein expression levels of p-STAT3, p-STAT5, RORrt, and FOXP3 were analyzed by immunoblot assay. Expression of peroxisome proliferator-activated receptor γ (PPARγ) was assessed by immunoblot. Results: AA ameliorated LPS-induced lung injury in mice. Furthermore, AA ameliorated LPS-induced pneumonia in mice (p < 0.05) and restored Th17/Treg balance and Th17/Treg transcription factor expression that was altered by LPS induction. AA also activated PPARγ expression to restore Th17/Treg balance (p < 0.05). Conclusion: The results indicate that AA attenuates LPS-induced ALI in mice by restoring Th17/Treg balance. Thus, AA is a potential drug for the management of ALI; however, AA must first be evaluated in clinical studies.

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Section: Discussionmentioning

confidence: 71%

Abietic acid attenuates LPS-induced acute lung injury by restoring Th17/Treg balance

Li¹,

Liu²,

Liu³

et al. 2022

Trop. J. Pharm Res

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“…5 d). The top downregulated pathways included the MAPK and Rap1 pathways, which are associated with the promotion of Treg differentiation (Huang et al 2018 ; Ishihara et al 2022 ) (Fig. 5 e).…”

Section: Resultsmentioning

confidence: 99%

m6A methyltransferase METTL3 programs CD4+ T-cell activation and effector T-cell differentiation in systemic lupus erythematosus

Wei

Zhu

et al. 2023

Mol Med

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Background Systemic lupus erythematosus (SLE) is an autoimmune disorder in which excessive CD4+ T-cell activation and imbalanced effector T-cell differentiation play critical roles. Recent studies have implied a potential association between posttranscriptional N6-methyladenosine (m6A) modification and CD4+ T-cell-mediated humoral immunity. However, how this biological process contributes to lupus is not well understood. In this work, we investigated the role of the m6A methyltransferase like 3 (METTL3) in CD4+ T-cell activation, differentiation, and SLE pathogenesis both in vitro and in vivo. Methods The expression of METTL3 was knocked down and METTL3 enzyme activity was inhibited using siRNA and catalytic inhibitor, respectively. In vivo evaluation of METTL3 inhibition on CD4+ T-cell activation, effector T-cell differentiation, and SLE pathogenesis was achieved using a sheep red blood cell (SRBC)-immunized mouse model and a chronic graft versus host disease (cGVHD) mouse model. RNA-seq was performed to identify pathways and gene signatures targeted by METTL3. m6A RNA-immunoprecipitation qPCR was applied to confirm the m6A modification of METTL3 targets. Results METTL3 was defective in the CD4+ T cells of SLE patients. METTL3 expression varied following CD4+ T-cell activation and effector T-cell differentiation in vitro. Pharmacological inhibition of METTL3 promoted the activation of CD4+ T cells and influenced the differentiation of effector T cells, predominantly Treg cells, in vivo. Moreover, METTL3 inhibition increased antibody production and aggravated the lupus-like phenotype in cGVHD mice. Further investigation revealed that catalytic inhibition of METTL3 reduced Foxp3 expression by enhancing Foxp3 mRNA decay in a m6A-dependent manner, hence suppressing Treg cell differentiation. Conclusion In summary, our findings demonstrated that METTL3 was required for stabilizing Foxp3 mRNA via m6A modification to maintain the Treg differentiation program. METTL3 inhibition contributed to the pathogenesis of SLE by participating in the activation of CD4+ T cells and imbalance of effector T-cell differentiation, which could serve as a potential target for therapeutic intervention in SLE.

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“…We could find ZNF469 as one of the zinc finger protein family members through SDGs. The zinc finger protein family gains the ability to recruit immunosuppressive regulatory T (Treg) cells through a positive feedback loop of Rap1 signaling, which can promote the formation of a microenvironment conducive to tumor metastasis [ 44 ]. Treg cells are an immunosuppressive cell type that can inhibit the activation and attack of other immune cells, thus helping tumor cells to evade immune surveillance.…”

Section: Resultsmentioning

confidence: 99%

Revealing Tissue Heterogeneity and Spatial Dark Genes from Spatially Resolved Transcriptomics by Multiview Graph Networks

Li,

Lu,

Kang

et al. 2023

Research

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Spatially resolved transcriptomics (SRT) is capable of comprehensively characterizing gene expression patterns and providing an unbiased image of spatial composition. To fully understand the organizational complexity and tumor immune escape mechanism, we propose stMGATF, a multiview graph attention fusion model that integrates gene expression, histological images, spatial location, and gene association. To better extract information, stMGATF exploits SimCLRv2 for visual feature exaction and employs edge feature enhanced graph attention networks for the learning potential embedding of each view. A global attention mechanism is used to adaptively integrate 3 views to obtain low-dimensional representation. Applied to diverse SRT datasets, stMGATF is robust and outperforms other methods in detecting spatial domains and denoising data even with different resolutions and platforms. In particular, stMGATF contributes to the elucidation of tissue heterogeneity and extraction of 3-dimensional expression domains. Importantly, considering the associations between genes in tumors, stMGATF can identify the spatial dark genes ignored by traditional methods, which can be used to predict tumor-driving transcription factors and reveal tumor immune escape mechanisms, providing theoretical evidence for the development of new immunotherapeutic strategies.

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Rap1 prevents colitogenic Th17 cell expansion and facilitates Treg cell differentiation and distal TCR signaling

Cited by 6 publications

References 83 publications

Abietic acid attenuates LPS-induced acute lung injury by restoring Th17/Treg balance

Abietic acid attenuates LPS-induced acute lung injury by restoring Th17/Treg balance

m6A methyltransferase METTL3 programs CD4+ T-cell activation and effector T-cell differentiation in systemic lupus erythematosus

Revealing Tissue Heterogeneity and Spatial Dark Genes from Spatially Resolved Transcriptomics by Multiview Graph Networks

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