Th17/Treg imbalance mediates hepatic intolerance to exogenous lipopolysaccharide and exacerbates liver injury in triptolide induced excessive immune response

Zhang, Haoran; Yuan, Ziqiao; Zhu, Ying; Yuan, Zihang; Wang, Jie; Cheng, Nong; Zhou, Shaoyun; Tang, Qianhui; Zhang, Luyong; Jiang, Zhenzhou; Yu, Qihong

doi:10.1016/j.jep.2022.115422

Cited by 18 publications

(10 citation statements)

References 31 publications

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“…29,30 Studies have indicated that the imbalance of Th17/Treg is associated with different inflammation and autoimmune diseases. [31][32][33] Predecessors' research has demonstrated that the imbalance between Th17/Treg is an essential reason for rheumatoid arthritis (RA). 34 In this study, psoriasis modeling significantly increased the ratio of Th17/Treg in CD + T cells of mice.…”

Section: Discussionmentioning

confidence: 99%

“…Regulatory T cells could suppress or release cytokines to play an anti‐inflammatory role, which is essential for maintaining immunological self‐tolerance and immune homeostasis 29,30 . Studies have indicated that the imbalance of Th17/Treg is associated with different inflammation and autoimmune diseases 31–33 . Predecessors' research has demonstrated that the imbalance between Th17/Treg is an essential reason for rheumatoid arthritis (RA) 34 .…”

Section: Discussionmentioning

confidence: 99%

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Etanercept alleviates psoriasis by reducing the Th17/Treg ratio and promoting M2 polarization of macrophages

Jiang

Chen

et al. 2022

Immunity Inflam & Disease

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Introduction: This study aimed to investigate the effect of etanercept in psoriasis and its underlying mechanism.Methods: Female mice were treated with imiquimod (IMQ) to induce psoriasis, and intraperitoneally administered etanercept (0.1-0.4 mg/ml). The RAW264.7 cells were treated with LPS and IFN-γ to polarize to M1, and were treated with IL-13 and IL-4 to polarize to M2. Results: In our study, Etanercept markedly reduced the psoriasis area and severity index scores, and epidermal thickness of mice induced by IMQ. In addition, etanercept reduced the levels of TNF-α and IL-6/12/23, and enhanced the levels of IL-4/10, reduced Th17/Treg ratio and facilitated the polarization of macrophages to M2 in psoriasis model mice. Furthermore, etanercept inhibited the JAK/STAT3 pathway and increased the protein levels of SOCS1 and SOCS3. Conclusions: In conclusion, our findings indicated that etanercept could inhibit the JAK/STAT3 pathway to reduce Th17/Treg ratio and promote M2 polarization, thereby alleviating psoriasis of mice.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Etanercept alleviates psoriasis by reducing the Th17/Treg ratio and promoting M2 polarization of macrophages

Jiang

Chen

et al. 2022

Immunity Inflam & Disease

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“…Animal treatment was described in our previous research ( Yuan et al, 2019b ; Yuan et al, 2020 ; Zhang et al, 2022 ). C57BL/6 mice used in this experiment were purchased from SPF (Beijing) Biotechnology Co., Ltd.…”

Section: Methodsmentioning

confidence: 99%

Macrophage malfunction in Triptolide-induced indirect hepatotoxicity

et al. 2022

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Background and Objective: Indirect hepatotoxicity is a new type of drug-induced hepatotoxicity in which the character of a drug that may induce its occurrence and the underlying mechanism remains elusive. Previously, we proved that Triptolide (TP) induced indirect hepatotoxicity upon LPS stimulation resulting from the deficiency of cytoprotective protein of hepatocyte. However, whether immune cells participated in TP-induced indirect hepatotoxicity and the way immune cells change the liver hypersensitivity to LPS still need to be deeply investigated. In this study, we tried to explore whether and how macrophages are involved in TP-induced indirect hepatotoxicity.Method: Firstly, TP (500 μg/kg) and LPS (0.1 mg/kg) were administrated into female C57BL/6 mice as previously reported. Serum biochemical indicators, morphological changes, hepatic macrophage markers, as well as macrophage M1/M2 markers were detected. Secondly, macrophage scavenger clodronate liposomes were injected to prove whether macrophages participated in TP-induced indirect hepatotoxicity. Also, the ability of macrophages to secrete inflammatory factors and macrophage phagocytosis were detected. Lastly, reverse docking was used to find the target of TP on macrophage and the possible target was verified in vivo and in RAW264.7 cells.Results: TP pretreatment increased the liver hypersensitization to LPS accompanied by the recruitment of macrophages to the liver and promoted the transformation of macrophages to M1 type. Depletion of hepatic macrophages almost completely alleviated the liver injury induced by TP/LPS. TP pretreatment increased the secretion of pro-inflammatory factors and weakened the phagocytic function of macrophages upon LPS exposure. Reverse docking results revealed that MerTK might be the real target of TP.Conclusion: TP disrupts inflammatory cytokines profile and phagocytic function of hepatic macrophages, resulting in the production of massive inflammatory factors and the accumulation of endotoxin in the liver, ultimately leading to the indirect hepatotoxicity of TP. MerTK might be the target of TP on the macrophage, while the binding of TP to MerTK should be investigated in vivo and in vitro.

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“…f. Triptolide has a broad range of pharmacological effects on autoimmune diseases, including rheumatoid arthritis ( Li et al, 2022a ), systemic lupus erythematosus ( Zhang et al, 2022a ), ankylosing spondylitis ( Ji et al, 2022 ), and so on. Due to poor water solubility (0.017 mg/ml) and severe toxicity including excessive immune responses, its clinical application is greatly limited ( Ding et al, 2017 ), and several strategies has been applied to reduce its toxicity and to improve its solubility ( Kang et al, 2022a ; Zhang et al, 2022b ; Rao et al, 2022 ).…”

Section: Natural Products Undergoing Clinical Evaluation In Pancreati...mentioning

confidence: 99%

The therapeutic potential of natural products for treating pancreatic cancer

Wang

Zhang

et al. 2022

Front. Pharmacol.

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Pancreatic cancer is one of the most malignant tumors of the digestive tract, with the poor prognosis and low 5-year survival rate less than 10%. Although surgical resection and chemotherapy as gemcitabine (first-line treatment) has been applied to the pancreatic cancer patients, the overall survival rates of pancreatic cancer are quite low due to drug resistance. Therefore, it is of urgent need to develop alternative strategies for its treatment. In this review, we summarized the major herbal drugs and metabolites, including curcumin, triptolide, Panax Notoginseng Saponins and their metabolites etc. These compounds with antioxidant, anti-angiogenic and anti-metastatic activities can inhibit the progression and metastasis of pancreatic cancer. Expecting to provide comprehensive information of potential natural products, our review provides valuable information and strategies for pancreatic cancer treatment.

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Th17/Treg imbalance mediates hepatic intolerance to exogenous lipopolysaccharide and exacerbates liver injury in triptolide induced excessive immune response

Cited by 18 publications

References 31 publications

Etanercept alleviates psoriasis by reducing the Th17/Treg ratio and promoting M2 polarization of macrophages

Etanercept alleviates psoriasis by reducing the Th17/Treg ratio and promoting M2 polarization of macrophages

Macrophage malfunction in Triptolide-induced indirect hepatotoxicity

The therapeutic potential of natural products for treating pancreatic cancer

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