CELL
·
2019
·
IF 36.216
Jiang Dai,Yi-Jiao Huang,Xinhua He,Ming Zhao,Xinzheng Wang,Zhao-Shan Liu,Wen Xue,Hong Cai,Xiao-Yan Zhan,Shao-Yi Huang,Kun He,Hongxia Wang,Na Wang,Zhihong Sang,Tingting Li,Qiu-Ying Han,Jie Mao,Xinwei Diao,Nan Song,Yuan Chen,Wei-Hua Li,Jiang-Hong Man,Ai-Ling Li,Tao Zhou,Zheng-Gang Liu,Xue-Min Zhang,Tao Li
Summary The presence of DNA in the cytoplasm is normally a sign of microbial infections and is quickly detected by cyclic GMP-AMP synthase (cGAS) to elicit anti-infection immune responses. However, chronic activation of cGAS by self-DNA leads to severe autoimmune diseases for which no effective treatment is available yet. Here we report that acetylation inhibits cGAS activation and that the enforced acetylation of cGAS by aspirin robustly suppresses self-DNA-induced autoimmunity. We find that cGAS acetylation on either Lys384, Lys394, or Lys414 contributes to keeping cGAS inactive. cGAS is deacetylated in response to DNA challenges. Importantly, we show that aspirin can directly acetylate cGAS and efficiently inhibit cGAS-mediated immune responses. Finally, we demonstrate that aspirin can effectively suppress self-DNA-induced autoimmunity in Aicardi-Goutières syndrome (AGS) patient cells and in an AGS mouse model. Thus, our study reveals that acetylation contributes to cGAS activity regulation and provides a potential therapy for treating DNA-mediated autoimmune diseases.
研究领域:
免疫学
·
分子生物学
·
药理学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2022
·
IF 6.1
Jianhong Zhou,Xiangxiang Lin,Huiping Shang,Yutuo Zhu,Jinrun Chen,Mengyun Deng,Mali Dai,Dan Lin,Serhii Vakal,Yuqin Wang,Xingyi Li
Noninfectious (autoimmune and immune-mediated) uveitis is one of the primary diseases leading to blindness in the world. Due to the limitation of current first-line drugs for clinical uveitis, novel drugs and targets against uveitis are urgently needed. Ganciclovir (GCV), an FDA-approved antiviral drug, is often used to treat cytomegalovirus-induced retinitis in clinical patients. Recently, GCV was found to suppress neuroinflammation via targeting STING signaling because the STING pathway plays a pivotal role in autoimmune diseases. However, until now, the effect of GCV on non-infectious uveitis has never been explored. In this work, using the rat experimental autoimmune uveitis (EAU) model, we first found STING to be highly expressed in infiltrating cells (CD68 + , CD45 + , and CD4 + ) and retinal glial cells (Iba1 + and GFAP + ) of the immunized retina. More importantly, GCV treatment can significantly suppress the initiation and progression of EAU by inhibiting infiltration of Th17 and inflammatory cells into the retina. Mechanistically, we found that GCV could reverse the levels of pro-inflammatory factors (such as IL-1β) and chemokine-related factors (such as Cxcr3), possibly via targeting the STING pathway. The present results suggest that GCV may be considered as a novel therapeutic strategy against human uveitis.
研究领域:
免疫学
·
眼科学
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药理学
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DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Shuangjie Zhu,Yongqi Cui,Huizheng Hu,Chenxi Zhang,Kan Chen,Zhongyan Shan,Weiping Teng,Jing Li
Autoimmune thyroiditis is among the most prevalent autoimmune endocrine illnesses. However, the pathophysiology has not been determined, and efficacious treatments are still lacking. The current study used network pharmacology analysis and an experimental autoimmune thyroiditis(EAT) mouse model to explore whether dihydroartemisinin (DHA) has therapeutic effects on autoimmune thyroiditis and to investigate the potentially related mechanisms concerning oxidative stress (OS) responses and T-cell immune imbalance. The therapeutic effects of DHA on autoimmune thyroiditis and potentially related processes were first anticipated using network pharmacology analysis and then verified using the EAT model. DHA may influenced the onset of autoimmune thyroiditis by regulating immune imbalance and OS responses, according to network pharmacology analysis. ELISA, immunofluorescence staining, and histopathological examination were used to detect changes in serum thyroid autoantibody levels and intrathyroidal inflammatory infiltration following DHA intervention. RT-PCR was used to determine the spleen’s mRNA expression of typical T-cell cytokines, whereas an OS kit and immunohistochemical staining were used to assess the thyroid’s glutathione (GSH) content, superoxide dismutase (SOD) activity, and Nrf2 protein expression. Furthermore, serum TgAb levels and intrathyroidal inflammatory infiltrates were considerably lower in EAT mice given high-dose DHA than in vehicle-treated controls. In the spleen, IFN-γ, IL-17A, and IL-6 mRNA expressions were dramatically downregulated, while IL-4 and IL-10 were significantly raised. Following high-dose DHA treatment, GSH content, SOD activity, and Nrf2 protein expression levels were markedly increased in thyroid tissue. These findings imply that DHA administration may suppress TgAb formation and reduce intrathyroidal inflammatory cell infiltration by restoring T-cell immune imbalance and increasing antioxidant capacity via the Nrf2 pathway. This study provides important experimental data for DHA’s therapeutic use in patients with autoimmune thyroiditis.
研究领域:
药理学
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免疫学
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内分泌学
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DOI
PubMed
高影响因子
Journal of Neuroinflammation
·
2018
·Vol. 15
·期 1
·1-13
·
IF 5.193
Liu Ru-Tao,Zhang Min,Yang Chun-Lin,Zhang Peng,Zhang Na,Du Tong,Ge Meng-Ru,Yue Long-Tao,Li Xiao-Li,Li Heng,Duan Rui-Sheng
Background With the recognition of the key roles of cellular metabolism in immunity, targeting metabolic pathway becomes a new strategy for autoimmune disease treatment. Guillain-Barré syndrome (GBS) is an acute immune-mediated inflammatory demyelinating disease of the peripheral nervous system, characterized by inflammatory cell infiltration. These inflammatory cells, including activated macrophages, Th1 cells, and Th17 cells, generally undergo metabolic reprogramming and rely mainly on glycolysis to exert functions. This study aimed to explore whether enhanced glycolysis contributed to the pathogenesis of experimental autoimmune neuritis (EAN), a classic model of GBS.Methods Preventive and therapeutic treatments with glycolysis inhibitor, 2-deoxy-d-glucose (2-DG), were applied to EAN rats. The effects of treatments were determined by clinical scoring, weighting, and tissue examination. Flow cytometry and ELISA were used to evaluate T cell differentiation, autoantibody level, and macrophage functions in vivo and in vitro.Results Glycolysis inhibition with 2-DG not only inhibited the initiation, but also prevented the progression of EAN, evidenced by the improved clinical scores, weight loss, inflammatory cell infiltration, and demyelination of sciatic nerves. 2-DG inhibited the differentiation of Th1, Th17, and Tfh cells but enhanced Treg cell development, accompanied with reduced autoantibody secretion. Further experiments in vitro proved glycolysis inhibition decreased the nitric oxide production and phagocytosis of macrophages and suppressed the maturation of dendritic cells (DC).Conclusion The effects of glycolysis inhibition on both innate and adaptive immune responses and the alleviation of animal clinical symptoms indicated that enhanced glycolysis contributed to the pathogenesis of EAN. Glycolysis inhibition may be a new therapy for GBS.
研究领域:
免疫学
·
神经病学
·
代谢途径
·
自身免疫性疾病
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Jun Weng,Geng Miaomiao,Xiaoyu Hu,Yang Hu,Yi Yang,Banbin Xing,Wu Zhiyong,Zigong Wei
TNFα inhibitors have been successfully developed and used in the clinical treatment of autoimmune disorders. However, the use of TNFα blockade may be accompanied by side effects. The cases of bacterial and viral infections, lymphoproliferative disorders, and anti-TNFα-induced lupus, have been reported among the rheumatoid arthritis or Crohn's disease patients treated with TNFα blockers. Therefore, alternative therapeutic strategy is highly desirable. TNFα signaling via TNFR1 induces proinflammatory responses, and selective inhibition of TNFR1 signaling may be beneficial for managing autoimmune diseases. To this end, we developed minibinder proteins targeting soluble ectodomain of TNFR1 (sTNFR1) by de novo computational designing. Top-rated designed minibinders targeting to two hydrophobic sites on sTNFR1 were selected and expressed in E. coli . Purified top-ranked minibinders are thermostable in solution and presented micromolar to sub-micromolar affinity to sTNFR1. All designs showed the potency of blocking TNFα signaling in L929 cell-based assays, and one of the designs targeting to hydrophobic Site I called S1B2 exhibited higher potency than other minibinders with IC 50 of 4.32 nM. Our work provided a new approach to develop TNFR1 antagonist and S1B2 should be a promising lead molecule of TNFR1 antagonist for further development.
研究领域:
生物化学
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免疫学
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药物开发
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DOI
PubMed
高影响因子
Journal of Neuroinflammation
·
2025
·Vol. 22
·期 1
·1-20
·
IF 10.1
Hong Wenxiang,Ma Hongbo,Li Zhibin,Du Yiwen,Xia Wenjing,Yin Han,Huang Han,Sun Zebing,Gai Renhua,Tong Lexian,Zhu Hong,Wang Jincheng,Yang Bo,He Qiaojun,Weng Qinjie,Wang Jiajia
The epigenetic modification of histone H3 lysine 27 trimethylation (H3K27me3) by the embryonic ectoderm development (EED) protein is closely associated with the regulation of transcriptional programs and is implicated in autoimmune diseases. However, the efficacy of targeting H3K27me3 for the treatment of neuroinflammation remains unclear. In this study, we demonstrate that systemic administration of an EED inhibitor diminishes the inflammatory response mediated by dendritic cells (DCs), thereby alleviating experimental autoimmune encephalitis (EAE), a representative mouse model of autoimmune diseases in the central nervous system (CNS). Our findings indicate that EED inhibitors suppress DC migration by upregulating genes in the WNT signaling pathway that are epigenetically marked by H3K27me3. Conversely, inhibiting the WNT pathway partially reverses the impaired DC migration caused by EED inhibitors. Additionally, the genetic deletion of Eed inhibits DC migration and effectively mitigates autoimmune symptoms and inflammatory infiltration into the CNS in EAE. These results highlight EED as a critical regulator of DC migration and suggest its potential as a therapeutic target for autoimmune disorders.
研究领域:
免疫学
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神经科学
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表观遗传学
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自身免疫疾病
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2022
·
IF 6.1
Yuanxing Zhi,Jin Liu,Peihua Kuang,Xin Zhang,Ziwei Xu,Yanshan Chen,Xiuling Lin,Xiaoyan Wu,Pingzheng Zhou,Jianjun Chen
The enzyme cyclic GMP-AMP synthase (cGAS) senses cytosolic DNA and catalyzes the formation of 2′3′-cyclic-GMP-AMP (cGAMP), which in turn triggers interferon (IFN) production. Inappropriate activation of cGAS and production of cGAMP have been linked to a diversity of autoimmune diseases. The volume-regulated anion channels (VRACs) have been recently demonstrated to permeate cGAMP, thus making the channel essential for the activation of the cGAS-cGAMP-STING axis. DCPIB, a prominent inhibitor of VRAC channel, has been recently reported to also significantly activate TREK1 channel. Herein, in this study, we have designed and synthesized a series of novel DCPIB derivatives and investigated their potential regulatory effects on VRAC/TREK1 channels. Our results manifested that compound 6u was a dual inhibitor of VRAC/TREK1 channels with IC 50 s of 7.11 ± 0.94 μM and 4.43 ± 0.90 μM, respectively. On top of that, our data demonstrated that 6u impaired interferon production in a concentration-dependently manner by dampening cGAS-cGAMP-STING pathway without any cytotoxicity when it comes to herpes simplex virus type 1 (HSV1) infection. To sum up, our study not only discovered a novel DCPIB analog with dual inhibitory effects on VRAC/TREK1 channels but also provided a new strategy for the design and development of newly potent VRAC inhibitors, which benefits the treatment of cGAS-STING related autoimmune and inflammatory diseases .
研究领域:
药理学
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免疫学
·
分子生物学
·
化学
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DOI
PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2020
·Vol. 25
·期 2
·1140-1150
·
IF 4.486
Jie Xu,Dazhi Chen,Lanling Jin,Zhengkang Chen,Yulu Tu,Xiaozhe Huang,Feiben Xue,Jialu Xu,Mingzhuan Chen,Xiaodong Wang,Yongping Chen
Inflammation and fibrosis are major consequences of autoimmune hepatitis, however, the therapeutic mechanism remains to be investigated. USP4 is a deubiquitinating enzyme and plays an important role in tissue fibrosis and immune disease. Vialinin A is an extract from mushroom and is a specific USP4 inhibitor. However, there is lack of evidences that Vialinin A plays a role in autoimmune hepatitis. By employing S100-induced autoimmune hepatitis in mice and AML12 cell line, therapeutic mechanism of Vialinin A was examined. Inflammation was documented by liver histological staining and inflammatory cytokines. Fibrosis was demonstrated by Masson, Sirius red staining and fibrotic cytokines with western blot and real-time RT-PCR. In experimental animal, there were increases in inflammation and fibrosis as well as USP4, and which were reduced after treatment of Vialinin A. Vialinin A also reduced Rheb and phosphorylated mTOR. Moreover, in LPS-treated AML12 cells, LPS-induced USP4, inflammatory and fibrotic cytokines, phosphorylated mTOR and Rheb. Specific inhibitory siRNA of USP4 reduced USP4 level and the parameters mentioned above. In conclusion, USP4 was significantly elevated in autoimmune hepatitis mice and Vialinin A reduced USP4 level and attenuate inflammation and fibrosis in the liver. The mechanism may be related to regulation of Rheb/mTOR signalling.
研究领域:
药理学
·
免疫学
·
肝病学
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产品关联
DOI
PubMed
高影响因子
CLINICAL IMMUNOLOGY
·
2025
·
IF 3.8
Shuang Pan,Mengshu Yu,Bowei Fan,Bin Wang,Xinrui Yang,Jiawen Zhang,Xiaoqi Liu,Xiaojian Hong,Wei Yang
Autoimmune myocarditis refers to the inflammation of myocardial tissue caused by innate and adaptive immune responses, characterized by elevated levels of tumour necrosis factor-α (TNF-α), a classic pro-inflammatory factor. Although hydrogen exhibits anti-inflammatory and antioxidant properties, its therapeutic effects in autoimmune myocarditis have not been evaluated. Therefore, the present study aimed to explore whether hydrogen can alleviate autoimmune myocarditis via TNF-α. An experimental autoimmune myocarditis (EAM) model was established in BALB/c mice via subcutaneous injection of pig-derived myocardial myoglobin emulsified with complete Freund's adjuvant. The treatment group received 2 % hydrogen inhalation twice a day (3 h each time) for 21 days. CD4+ T cell expression was higher in the EAM group than in the Control group, and this increase was attenuated following treatment with hydrogen. Additionally, the levels of TNF-α and related inflammatory factors were substantially higher in the EAM group than in the Control group, and these changes were reversed following hydrogen treatment. Echocardiography assessments demonstrated a significant improvement in heart function following treatment with hydrogen compared to that in the EAM group. Pathological results revealed significant inflammatory cell infiltration and fibrosis in the hearts of the untreated EAM group. Tissue immunofluorescence and protein immunoblotting indicated elevated necroptosis markers in the EAM group, which were downregulated after treatment with hydrogen. This study demonstrates that hydrogen effectively ameliorated autoimmune myocarditis by modulating necroptosis via the TNF/TNFR1 signalling pathway, making it a promising novel therapeutic strategy for myocarditis.
研究领域:
免疫学
·
心脏病学
·
分子生物学
·
炎症研究
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产品关联
DOI
PubMed
高影响因子
IMMUNITY
·
2023
·
IF 32.4
Qiong Luo,Yijun Liu,Ke Shi,Xuecheng Shen,Yaqi Yang,Xuejiao Liang,Liangliang Lu,Wenxuan Qiao,Airu Chen,Dongmei Hong,Yang Sun,Qiang Xu
Anti-interleukin-17 (IL-17) therapy has been used in various autoimmune diseases. However, the efficacy is unexpectedly limited in several IL-17-associated diseases, and the mechanism of limited efficacy remains unclear. Here, we show that a molecular complex containing the adaptor molecule Act1 and tyrosine phosphatase SHP2 mediated autonomous IL-17R signaling that accelerated and sustained inflammation. SHP2, aberrantly augmented in various autoimmune diseases, was induced by IL-17A itself in astrocytes and keratinocytes, sustaining chemokine production even upon anti-IL-17 therapies. Mechanistically, SHP2 directly interacted with and dephosphorylated Act1, which replaced Act1-TRAF5 complexes and induced IL-17-independent activation of IL-17R signaling. Genetic or pharmacologic inactivation of SHP2, or blocking Act1-SHP2 interaction, paralyzed both IL-17-induced and IL-17-independent signaling and attenuated primary or relapsing experimental autoimmune encephalomyelitis. Therefore, Act1-SHP2 complexes mediate an alternative pathway for autonomous activation of IL-17R signaling, targeting which could be a therapeutic option for IL-17-related diseases in addition to current antibody therapies.
研究领域:
免疫学
·
分子生物学
·
自身免疫疾病
·
药理学
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产品关联
DOI
PubMed
高影响因子
INFLAMMATION
·
2019
·Vol. 42
·期 4
·1179-1189
·
IF 2.939
Xue Yu-Long,Zhang Sheng-Xiao,Zheng Chao-Feng,Li Yu-Feng,Zhang Li-Hui,Hao Yu-Fei,Wang Shu,Li Xue-Wen
Signal transducer and activator of transcription 4 (STAT4) has been implicated in the progression of myocarditis. The aim of the current study was to investigate the role by which STAT4 influences autoimmune myocarditis in an attempt to identify a theoretical therapeutic perspective for the condition. After successful establishment of an autoimmune myocarditis rat model, the expression patterns of STAT4, NF-κB pathway–related genes, Th1 inflammatory cytokines (IFN-γ and IL-2), and Th2 inflammatory cytokines (IL-6 and IL-10) were subsequently determined. The rats with autoimmune myocarditis were treated with oe-STAT4 or sh-STAT4 lentiviral vectors to evaluate the role of STAT4 in autoimmune myocarditis, or administrated with 1 mL 10 μmol/L of BAY11-7082 (the NF-κB pathway inhibitor) via tail vein to investigate the effect of the NF-κB pathway on autoimmune myocarditis. Finally, cell apoptosis was evaluated. The serum levels of IFN-γ and IL-2, extent of IκBα and P65 phosphorylation, and the expression of STAT4 were elevated, while the serum levels of IL-6 and IL-10 as well as the expression of IκBα were reduced among the rats with autoimmune myocarditis, which was accompanied by an increase in the apoptotic cells. More importantly, the silencing of STAT4 or the inhibition of the NF-κB pathway was detected to result in a decrease in the serum levels of IFN-γ and IL-2 and an elevation of the serum levels of IL-6 and IL-10, and inhibited myocardial cell apoptosis in rats with autoimmune myocarditis. Moreover, STAT4 silencing was also observed to decrease the extent of IκBα and P65 phosphorylation while acting to elevate the expression of IκBα. Taken together, silencing of STAT4 could hinder the progression of autoimmune myocarditis by balancing the expression of Th1/Th2 inflammatory cytokines via the NF-κB pathway, which may provide a novel target for experimental autoimmune myocarditis (EAM) treatment.
研究领域:
免疫学
·
心脏病学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Jiaxing Huang,Xiaotang Wang,Na Li,Wei Fan,Xingran Li,Qian Zhou,Jiangyi Liu,Wanqian Li,Zhi Zhang,Xiaoyan Liu,Shuhao Zeng,Hui Yang,Meng Tian,Peizeng Yang,Shengping Hou
Activated microglia in the retina are essential for the development of autoimmune uveitis. Yin-Yang 1 (YY1) is an important transcription factor that participates in multiple inflammatory and immune-mediated diseases. Here, an increased YY1 lactylation in retinal microglia within in the experimental autoimmune uveitis (EAU) group is observed. YY1 lactylation contributed to boosting microglial activation and promoting their proliferation and migration abilities. Inhibition of lactylation suppressed microglial activation and attenuated inflammation in EAU. Mechanistically, cleavage under targets & tagmentation （CUT&Tag） analysis revealed that YY1 lactylation promoted microglial activation by regulating the transcription of a set of inflammatory genes, including STAT3, CCL5, IRF1, IDO1 , and SEMA4D . In addition, p300 is identified as the writer of YY1 lactylation. Inhibition of p300 decreased YY1 lactylation and suppressed microglial inflammation in vivo and in vitro. Collectively, the results showed that YY1 lactylation promoted microglial dysfunction in autoimmune uveitis by upregulating inflammatory cytokine secretion and boosting cell migration and proliferation. Therapeutic effects can be achieved by targeting the lactate/p300/YY1 lactylation/inflammatory genes axis.
研究领域:
免疫学
·
神经科学
·
分子生物学
·
眼科学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）