SOCS3 ablation enhances DC-derived Th17 immune response against Candida albicans by activating IL-6/STAT3 in vitro

Shi, Dongmei; Jia, Yongsheng; Wang, Qiong; Li, Dongmei; Zheng, Hailin; Mei, Huan; Liu, Weida

doi:10.1016/j.lfs.2019.03.009

Cited by 16 publications

(14 citation statements)

References 34 publications

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“…Similar results were obtained from experiments measuring the IL-6 protein levels in these cells (Figure 5C). The observations are consistent with studies that both mRNA and protein levels of IL-6 enhanced in SOCS3-knockdown cells (45, 46), and suggest that persistent activation of STAT3 may be responsible for the reduced expression of IL-6. Consistently, we observed that inactivation of STAT3 by inhibitor S3I-201 (Figure 5D), or knockdown of STAT3 by shRNA caused a significant increase in IL-6 mRNA levels in WSN infected A549 cells (Figures 5E,F and Figure S5B).…”

Section: Resultssupporting

confidence: 91%

Influenza Virus-Induced Robust Expression of SOCS3 Contributes to Excessive Production of IL-6

Yan

Chen

et al. 2019

Front. Immunol.

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Influenza A virus (IAV) remains a major public health threat in the world, as indicated by the severe pneumonia caused by its infection annually. Interleukin-6 (IL-6) involved excessive inflammatory response to IAV infection profoundly contributes to the virus pathogenesis. However, the precise mechanisms underlying such a response are poorly understood. Here we found from both in vivo and in vitro studies that IAV not only induced a surge of IL-6 release, but also greatly upregulated expression of suppressor of cytokine signaling-3 (SOCS3), the potent suppressor of IL-6-associated signal transducer and activator of transcription 3 (STAT3) signaling. Interestingly, there existed a cytokine-independent mechanism of the robust induction of SOCS3 by IAV at early stages of the infection. Furthermore, we employed SOCS3-knockdown transgenic mice (TG), and surprisingly observed from virus challenge experiments using these mice that disruption of SOCS3 expression provided significant protection against IAV infection, as evidenced by attenuated acute lung injury, a higher survival rate of infected animals and lower viral load in infected tissues as compared with those of wild-type littermates under the same condition. The activity of nuclear factor-kappa B (NFκB) and the expression of its target gene IL-6 were suppressed in SOCS3-knockdown A549 cells and the TG mice after infection with IAV. Moreover, we defined that enhanced STAT3 activity caused by SOCS3 silencing was important for the regulation of NFκB and IL-6. These findings establish a critical role for IL-6-STAT3-SOCS3 axis in the pathogenesis of IAV and suggest that influenza virus may have evolved a strategy to circumvent IL-6/STAT3-mediated immune response through upregulating SOCS3.

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Section: Resultssupporting

confidence: 91%

Influenza Virus-Induced Robust Expression of SOCS3 Contributes to Excessive Production of IL-6

Yan

Chen

et al. 2019

Front. Immunol.

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“…SOCS3 is a negative regulator of STAT3/RORγt signaling pathway, which is essential for the inhibition of Th17 cell differentiation (Ding 2017 ). Previous studies demonstrated that SOCS3-mediated IL-6/STAT3 signaling pathway regulates multiple cytokine signaling pathways in autoimmune and infectious diseases (Shi 2019 ). Our previous study found that miR-206 directly targets SOCS3 and Foxp3 to facilitate Th17 differentiation and repress Treg differentiation in vitro .…”

Section: Discussionmentioning

confidence: 99%

“…The differentiation of Th17 cells involves the activation and phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the downstream regulation of retinoid-related orphan receptor γt (RORγt) (Singh 2014 ). Suppressor of cytokine signaling-3 (SOCS3) is considered a key signaling molecule that regulates Th17 cell differentiation by negatively regulating STAT3-activating cytokines (Shi 2019 ). Meanwhile, Treg cells expressing the transcription factor fork head transcriptional factor 3 (Foxp3) have a crucial role in the induction of immunosuppression (Kawai et al 2018 ).…”

Section: Introductionmentioning

confidence: 99%

MiR-206 regulates the Th17/Treg ratio during osteoarthritis

Yang

et al. 2021

Mol Med

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Background The present study aimed to determine the functional role of miR-206 in T helper 17 (Th17)/regulatory T (Treg) cell differentiation during the development of osteoarthritis (OA). Methods Patients with OA and healthy controls were recruited for investigating the association between miR-206 and Th17/Treg ratio. Transfection experiments were conducted in CD4+ T cells to verify the mechanism of miR-206 on the balance of Treg/Th17. OA model was constructed to detect the clinical score, histopathological changes and Treg/Th17 ratio. OA model was induced in rats to verify the effect of miR-206 inhibition on Th17/Treg immunoregulation. Results High expression of miR-206 was positively correlated with peripheral Th17/Treg imbalance in patients with OA. The interactions between miR-206 and the 3′ untranslated regions (3'-UTR) of suppressor of cytokine signaling-3 (SOCS3) and fork head transcriptional factor 3 (Foxp3) were confirmed by luciferase reporter assays. MiR-206 disturbed the Th17/Treg balance by targeting SOCS3 and Foxp3. In vivo assay demonstrated that antagomiR directed against miR-206 restored Th17/Treg balance during the development of OA. Conclusion MiR-206 contributed to the progression of OA by modulating Th17/Treg imbalance, suggesting that miR-206 inhibition might be a promising therapeutic strategy for the treatment of OA.

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“…Previous research showed that SOCS3 deficiency promotes M1 macrophage polarization and inflammation ( 39 ). In addition, SOCS3 ablation could enhance DC-derived Th17 immune response by activating IL-6/STAT3 ( 40 ). These findings indicated that abnormally deficient SOCS3 might function in the regulation and recruitment of immune infiltrating cells, and thereby induce inflammation involved in OLF.…”

Section: Discussionmentioning

confidence: 99%

Deciphering Obesity-Related Gene Clusters Unearths SOCS3 Immune Infiltrates and 5mC/m6A Modifiers in Ossification of Ligamentum Flavum Pathogenesis

et al. 2022

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BackgroundOssification of ligamentum flavum (OLF) is an insidious and debilitating heterotopic ossifying disease with etiological heterogeneity and undefined pathogenesis. Obese individuals predispose to OLF, whereas the underlying connections between obesity phenotype and OLF pathomechanism are not fully understood. Therefore, this study aims to explore distinct obesity-related genes and their functional signatures in OLF.MethodsThe transcriptome sequencing data related to OLF were downloaded from the GSE106253 in the Gene Expression Omnibus (GEO) database. The obesity-related differentially expressed genes (ORDEGs) in OLF were screened, and functional and pathway enrichment analysis were applied for these genes. Furthermore, protein-protein interactions (PPI), module analysis, transcription factor enrichment analysis (TFEA), and experiment validation were used to identify hub ORDEGs. The immune infiltration landscape in OLF was depicted, and correlation analysis between core gene SOCS3 and OLF-related infiltrating immune cells (OIICs) as well as 5mC/m6A modifiers in OLF was constructed.ResultsNinety-nine ORDEGs were preliminarily identified, and functional annotations showed these genes were mainly involved in metabolism, inflammation, and immune-related biological functions and pathways. Integrative bioinformatic algorithms determined a crucial gene cluster associated with inflammatory/immune responses, such as TNF signaling pathway, JAK-STAT signaling pathway, and regulation of interferon-gamma-mediated signaling. Eight hub ORDEGs were validated, including 6 down-regulated genes (SOCS3, PPARG, ICAM-1, CCL2, MYC, and NT5E) and 2 up-regulated genes (PTGS2 and VEGFA). Furthermore, 14 differential OIICs were identified by ssGSEA and xCell, and SOCS3 was overlapped to be the core gene, which was associated with multiple immune infiltrates (dendritic cells, macrophage, and T cells) and six m6A modifiers as well as four 5mC regulators in OLF. Reduced SOCS3 and FTO expression and up-regulated DNMT1 level in OLF were validated by Western blotting.ConclusionThis study deciphered immune/inflammatory signatures of obesity-related gene clusters for the first time, and defined SOCS3 as one core gene. The crosstalk between 5mC/m6A methylation may be a key mediator of SOCS3 expression and immune infiltration. These findings will provide more insights into molecular mechanisms and therapeutic targets of obesity-related OLF.

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SOCS3 ablation enhances DC-derived Th17 immune response against Candida albicans by activating IL-6/STAT3 in vitro

Cited by 16 publications

References 34 publications

Influenza Virus-Induced Robust Expression of SOCS3 Contributes to Excessive Production of IL-6

Influenza Virus-Induced Robust Expression of SOCS3 Contributes to Excessive Production of IL-6

MiR-206 regulates the Th17/Treg ratio during osteoarthritis

Deciphering Obesity-Related Gene Clusters Unearths SOCS3 Immune Infiltrates and 5mC/m6A Modifiers in Ossification of Ligamentum Flavum Pathogenesis

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