EMBO REPORTS
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2022
·Vol. 23
·期 11
·e54569
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IF 9.071
Yueke Lin,Xiaoting Lv,Caiyu Sun,Yanlin Sun,Min Yang,Dapeng Ma,Weiqiang Jing,Yunxue Zhao,Yeping Cheng,Haocheng Xuan,Lihui Han
Tripartite motif protein (TRIM) 50 is a new member of the tripartite motif family, and its biological function and the molecular mechanism it is involved in remain largely unknown. The NOD-like receptor family protein (NLRP)3 inflammasome is actively involved in a wide array of biological processes while mechanisms of its regulation remain to be fully clarified. Here, we demonstrate the role of TRIM50 in NLRP3 inflammasome activation. In contrast to the conventional E3 ligase functions of TRIM proteins, TRIM50 mediates direct oligomerization of NLRP3, thereby suppressing its ubiquitination and promoting inflammasome activation. Mechanistically, TRIM50 directly interacts with NLRP3 through its RING domain and induces NLRP3 oligomerization via its coiled-coil domain. Finally, we show that TRIM50 promotes NLRP3 inflammasome-mediated diseases in mice. We thus reveal a novel regulatory mechanism of NLRP3 via TRIM50 and suggest that modulating TRIM50 might represent a therapeutic strategy for NLRP3-dependent pathologies.
研究领域:
免疫学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
CELL
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2025
·
IF 42.5
Yaozhen Chen,Shouwen Chen,Zhixin Liu,Yafen Wang,Ning An,Yutong Chen,Yihao Peng,Zheng Liu,Qin Liu,Xingbin Hu
The canonical complement-mediated lysis of mature red blood cells (RBCs) leads to severe pathogenesis. However, inhibition strategies targeting complement are not always as efficient as expected, indicating that unknown mechanisms are awaiting elucidation. In this study, we investigate the intracellular events in mature RBCs following complement activation. The collected evidence demonstrates that complement-induced hemolysis is a caspase-8-dependent programmed RBC death. Furthermore, short NLRP3 (miniNLRP3) fragments in RBCs are identified to engage in the assembly of NLRP3-apoptosis-associated speck-like protein containing a CARD (ASC)-caspase-8 complex. Activated caspase-8 directly induces the proteolysis of β-spectrin, thereby disrupting the skeletal network of the RBC membrane, a process we refer to as spectosis. Spectosis signaling is also activated in autoimmune hemolytic anemia or paroxysmal nocturnal hemoglobinuria, and the inhibition of spectosis significantly reduced complement-induced hemolysis. These findings reveal a programmed death cascade in mature RBCs, which may have important implications for the treatment of hemolytic disorders.
研究领域:
免疫学
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血液学
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细胞生物学
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DOI
PubMed
高影响因子
Cell Death Discovery
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2025
·Vol. 11
·期 1
·1-13
·
IF 7
Wei Cheng,Xu Yitian,Zheng Ying,Hong Lizhe,Lyu Chen,Li Haibo,Cao Bin
The mortality associated with influenza A virus (IAV) infection typically results from excessive immune responses, leading to immunopathological lung damage and compromised pulmonary function. Various immunomodulators are seen beneficial when used in conjunction with direct anti-infection treatment. Leukotriene B4 (LTB4) is a derivative of arachidonic acid (AA) and has been shown to be advantageous for numerous infectious diseases, allergies, and autoimmune disorders. Nonetheless, the function of LTB4 in influenza infection remains unclear. This study demonstrates that LTB4 and its primary receptor BLT1, as opposed to the secondary receptor BLT2, act as a protective immune modulator during influenza infection in bone marrow-derived macrophages and mouse models. Mechanistically, LTB4 promotes K27-linked and K48-linked polyubiquitination of the NLRP3 protein at its K886 and K1023 sites via a cAMP/PKA-dependent pathway, which inhibits NLRP3 inflammasome assembly and thereby diminishes subsequent NLRP3 inflammasome activation. The consequent decline in the release of IL-1β and IL-18 leads to a reduction in inflammation caused by viral infection. Furthermore, the administration of a LTB4 treatment in a fatal IAV infection model can mitigate the excessive NLRP3 inflammasome activation and reduce IAV-induced severe pulmonary damage. These findings illustrate the protective function of LTB4 in fatal IAV infection by mitigating the severe inflammation induced by the virus.
研究领域:
免疫学
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病毒学
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药理学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2022
·
IF 5.988
Chai Yuhui,Cai Yawen,Fu Yu,Wang Yingdi,Zhang Yiming,Zhang Xue,Zhu Lingpeng,Miao Mingxing,Yan Tianhua
Depression is a common and serious mental disorder. Data on its pathogenesis remain unclear and the options of drug treatments are limited. Here, we explored the role of pyroptosis, a novel pro-inflammatory programmed cell death process, in depression as well as the anti-depression effects and mechanisms of salidroside (Sal), a bioactive extract from Rhodiola rosea L. We established a corticosterone (CORT)-induced or lipopolysaccharide (LPS)-induced mice in vivo, and CORT, or nigericin (NLRP3 agonist)-induced PC12 cells in vitro. Our findings demonstrated that Sal profoundly mediated CORT or LPS-induced depressive behavior and improved synaptic plasticity by upregulating the expression of brain-derived neurotrophic factor (BDNF) gene. The data showed upregulation of proteins associated with NLRP3-mediated pyroptosis, including NLRP3, cleaved Caspase-1, IL-1β, IL-18, and cleaved GSDMD. The molecular docking simulation predicted that Sal would interact with P2X7 of the P2X7/NF-κB/NLRP3 signaling pathway. In addition, our findings showed that the NLRP3-mediated pyroptosis was regulated by P2X7/NF-κB/NLRP3 signaling pathway. Interestingly, Sal was shown to ameliorate depression via suppression of the P2X7/NF-κB/NLRP3 mediated pyroptosis, and rescued nigericin-induced pyroptosis in the PC12 cells. Besides, knock down of the NLRP3 gene by siRNA markedly increased the inhibitory effects of Sal on pyroptosis and proinflammatory responses. Taken together, our findings demonstrated that pyroptosis plays a crucial role in depression, and Sal ameliorates depression by suppressing the P2X7/NF-κB/NLRP3-mediated pyroptosis. Thus, our study provides new insights into the potential treatment options for depression.
研究领域:
神经科学
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药理学
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分子生物学
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免疫学
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精神病学
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产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
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2023
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IF 8.2
Wang Hao-yu,Lin Xi,Huang Guan-gen,Zhou Rong,Lei Shu-yue,Ren Jing,Zhang Kai-rong,Feng Chun-lan,Wu Yan-wei,Tang Wei
Aberrant NLRP3 activation has been implicated in the pathogenesis of numerous inflammation-associated diseases. However, no small molecular inhibitor that directly targets NLRP3 inflammasome has been approved so far. In this study, we show that Atranorin (C 19 H 18 O 8 ), the secondary metabolites of lichen family, effectively prevents NLRP3 inflammasome activation in macrophages and dendritic cells. Mechanistically, Atranorin inhibits NLRP3 activation induced cytokine secretion and cell pyroptosis through binding to ASC protein directly and therefore restraining ASC oligomerization. The pharmacological effect of Atranorin is evaluated in NLRP3 inflammasome-driven disease models. Atranorin lowers serum IL-1β and IL-18 levels in LPS induced mice acute inflammation model. Also, Atranorin protects against MSU crystal induced mice gouty arthritis model and lowers ankle IL-1β level. Moreover, Atranorin ameliorates intestinal inflammation and epithelial barrier dysfunction in DSS induced mice ulcerative colitis and inhibits NLRP3 inflammasome activation in colon. Altogether, our study identifies Atranorin as a novel NLRP3 inhibitor that targets ASC protein and highlights the potential therapeutic effects of Atranorin in NLRP3 inflammasome-driven diseases including acute inflammation, gouty arthritis and ulcerative colitis.
研究领域:
免疫学
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药理学
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炎症
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疾病模型
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Jiaying Liu,Yuanfan Chen,Jing Zhang,Yun Zheng,Yun An,Chenglai Xia,Yonger Chen,Song Huang,Shaozhen Hou,Dong Deng
Ethnopharmacological relevance The dried fruit of Crataegus pinnatifida Bunge (Hawthorn in Chinese) is a traditional medicine used in China, Japan and Korea for thousands of years. Hawthorn is documented in the Chinese Pharmacopoeia , as a folk medicine that is used to eliminate food, strengthen the stomach, move qi and dissipate blood stasis, treat stagnation of meat and food, gastric distention and fullness, and has anti-inflammatory effects. Vitexin, a flavonoid glycoside, is an important biologically active compound derived from Hawthorn, with significant antioxidant and anti-inflammatory properties. The pharmacological effects of Hawthorn are highly correlated with the antioxidant and anti-inflammatory effects of vitexin. Aim of the study The aim of the present study was to investigate the effect of vitexin on the alleviation of chronic atrophic gastritis (CAG) induced by 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) in a rat model, as well as to elucidate the underlying mechanisms involved. Materials and methods CAG was administered at a concentration of 170 μg/mL MNNG in the drinking water of rats, and the effects of vitexin (30 mg/kg, once daily for 6 weeks) on gastric tissues were subsequently analyzed. Pathological damage was assessed using H&E and AB-PAS staining. Gastrointestinal hormone levels, specifically motilin (MTL) and gastrin (GAS), were quantified using biochemical index determination kits. To evaluate the levels of cytokines, specifically IL-1β and IL-18, in gastric tissue, an enzyme-linked immunosorbent assay (ELISA) was performed. Additionally, to investigate the effects of vitexin on the NLRP3 inflammasome, GES-1 cells were subjected to treatment with lipopolysaccharide (LPS) and adenosine triphosphate (ATP). The targeting of NLRP3 by vitexin was assessed in vitro using CESTA, DARTS, and a synthesized biotin-labeled vitexin probe (biotin-vitexin) in conjunction with dual immunofluorescence. RT-PCR, Western blotting and immunofluorescence were used to evaluate the ameliorative effect of oysterin on LPS + ATP-induced GES-1 cells in vitro. Results Administration of vitexin significantly alleviated the symptoms of chronic atrophic gastritis (CAG) by reducing weight loss and minimizing gastric tissue damage. Treatment with vitexin in CAG rats effectively reduces the production of pro-inflammatory cytokines. Furthermore, vitexin attenuated the activation of the NLRP3 inflammasome in CAG induced by MNNG. Mechanistic experiments showed that NLRP3 is a direct cellular target of vitexin, while vitexin inhibited rat NLRP3 inflammasome. Conclusion Vitexin mitigates MNNG-induced CAG, and its protective effect is linked to the inhibition of NLRP3 inflammasome activation.
研究领域:
药理学
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民族药理学
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胃肠病学
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DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2024
·Vol. 29
·期 6
·1-11
·
IF 3.4
Wenjie Ge,Xian Zhang,Qing Wang,Jianjie Mao,Pengfei Jia,Jianping Cai
Knee osteoarthritis (KOA) is a major cause of disability in elderly individuals. Dicoumarol is a coumarin‑like compound derived from sweet clover [Melilotus officinalis (L.) Pall]. It has been suggested that dicoumarol exhibits various types of pharmacological activities, including anticoagulant, antitumor and antibacterial effects. Due to its various biological activities, dicoumarol has a potential protective effect against OA. Therefore, the present study aimed to assess the effects of dicoumarol on knee osteoarthritis. In the present study, dicoumarol was found to protect rat synoviocytes from lipopolysaccharide (LPS)‑induced cell apoptosis. Western blot analysis showed that dicoumarol significantly reduced the protein expression levels of fibrosis‑related markers and inflammatory cytokines (Tgfb, Timp, Col1a, Il1b and Il18). The inhibitory rates of these proteins were all >50% (P<0.01) compared with those in the LPS and ATP‑induced group. Consistently, the mRNA expression levels of these markers and cytokines were decreased to normal levels by dicoumarol after the treatment of rat synovial fibroblasts with LPS and ATP. Mechanistic studies demonstrated that dicoumarol did not affect NF‑κB signaling, but it did directly interact with NOD‑like receptor protein 3 (NLRP3) to promote its protein degradation, which could be reversed by MG132, but not NH4Cl. The protein half‑life of NLRP3 was accelerated from 26.1 to 4.3 h by dicoumarol. Subsequently, dicoumarol could alleviate KOA in vivo; knee joint diameter was decreased from 11.03 to 9.93 mm. Furthermore, the inflammation and fibrosis of the knee joints were inhibited in rats. In conclusion, the present findings demonstrated that dicoumarol could impede the progression of KOA by inhibiting NLRP3 activation, providing a potential treatment strategy for KOA.
研究领域:
医学
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药理学
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DOI
PubMed
高影响因子
Food & Function
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2025
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IF 5.4
Xiaqing Wu,Huan Chen,Yushan Tian,Hongjuan Wang,Hongwei Hou,Qingyuan Hu,Congyi Wang
Obesity and obesity-related metabolic diseases are causally linked to inflammatory activation. Proinflammatory macrophage infiltration and NLRP3 inflammasome activation contribute to chronic inflammation and insulin resistance. Alleviating inflammatory responses is a reliable method to restore insulin sensitivity and reduce the severity of metabolic syndrome. Solanesol, rich in anti-inflammatory foods (potato, tomato, eggplant, chili peppers), has demonstrated anti-inflammatory properties, but whether it plays a beneficial role in obesity-induced chronic inflammation remains poorly understood. In this study, we investigated the effects of solanesol on the NLRP3 inflammasome and inflammatory responses both in vitro and in high-fat diet (HFD)-fed mice. We found that oral administration of solanesol reduced weight gain, insulin resistance, and inflammation in epididymal white adipose tissue (eWAT) in both HFD-fed obese mice and mice concurrently treated with HFD. This effect was involved with reducing macrophage inflammation and inactivating the NLRP3 inflammasome by reducing K+ efflux and ROS production in macrophages. Solanesol also reprogrammed the phenotype of inflammatory macrophages. Taken together, our study suggests that solanesol may be a promising candidate for treating obesity and obesity-related metabolic diseases.
研究领域:
医学
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免疫学
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代谢研究
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Jian Cui,Meng Yang,Chengli Yu,Haidong Zhang,Yuan Gong,Yang Hu,Yue Wang,Qingxin Yuan,An Pan,Jiepin Li,Yaowen Hu,Zecheng Jin,Xuemei Peng,Anyuan Wu,Junwei Wang,Qian Wang,Yinan Zhang,Lihong Hu
Aberrant activation of the NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome contributes to the pathogenesis of fatal and perplexing pulmonary diseases. Although pharmacological inhibition of the NLRP3 inflammasome brings potent therapeutic effects in clinical trials and preclinical models, the molecular chaperones and transition governing its transformation from an auto-suppressed state to an active oligomer remain controversial. Here, this work shows that sesquiterpene bigelovin inhibited NLRP3 inflammasome activation and downstream pro-inflammatory cytokines release via canonical, noncanonical, and alternative pathways at nanomolar ranges. Chemoproteomic target identification discloses that bigelovin covalently bound to Cys168 of RACK1, disrupting the interaction between RACK1 and NLRP3 monomer and thereby suppressing NLRP3 inflammasome oligomerization in vitro and in vivo. Bigelovin treatment significantly alleviates the severity of NLRP3-related pulmonary disorders in murine models, such as LPS-induced ARDS and silicosis. These results consolidated the intricate role of RACK1 in transiting the NLRP3 state and provided a new anti-inflammatory lead and therapy for NLRP3-driven diseases.
研究领域:
免疫学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
International Journal of Environmental Research and Public Health
·
2019
·Vol. 17
·期 1
·138
·
IF 2.468
Chang Liu,Yaohui Zhu,Zhenxiang Lu,Weina Guo,Bayaer Tumen,Yalan He,Chao Chen,Shanshan Hu,Kangzhi Xu,Yan Wang,Lei Li,Shenghe Li
Acute Cadmium (Cd) exposure usually induces hepatotoxicity. It is well known that oxidative stress and inflammation causes Cd-induced liver injury. However, the effect of nuclear factor erythroid 2-related factor 2 (Nrf2) in Cd-induced liver injury is not completely understood. In this study, we observed Cd-induced liver damage and the potential contribution of Nrf2, nuclear factor-κB (NF-κB), Nod-like receptor 3 (NLRP3), and mitogen-activated protein kinases (MAPKs) signaling pathways. Changes in serum transaminases and proinflammatory cytokines expression showed that Cd could induce acute hepatotoxicity. Moreover, Nrf2 and its downstream heme oxygenase 1 (HO-1) were inhibited by Cd exposure, and Kelch-like ECH-associated protein 1 (Keap1), the inhibitory protein of Nrf2, was increased. Furthermore, NF-κB, NLRP3, and MAPKs signaling pathways were all activated by Cd intoxication. In conclusion, the inhibition of Nrf2, HO-1, and the activation of NF-κB, NLRP3, and MAPKs all contribute to Cd-induced liver injury.Keywords:Cadmium;acute liver injury;Nrf2;NLRP3;NF-κB;MAPKs
研究领域:
毒理学
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分子生物学
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免疫学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2024
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IF 4.2
Liu-Gen Cui,Miao-Miao Zhai,Jian-Jian Yin,Zhi-Mo Wang,Shu-Hui Wang,Yue-Jiao Zhou,Pei-Pei Li,Yang Wang,Li Xia,Pei Wang,Xue-Xiang Cha,Li-Rong Zhang,Sheng-Na Han
Several studies have associated the epitranscriptomic RNA modification of N6-methyladenosine (m 6 A) with cardiovascular diseases; however, how m 6 A modification affects cardiomyocyte pyroptosis after myocardial infarction (MI) remains unknown. Here, we showed that AlkB homolog 5 (ALKBH5), an m 6 A demethylase, is crucial in cardiomyocyte pyroptosis after MI. We used MI rat and mouse models, a cell hypoxia model of rat primary cardiomyocytes (RCMs), and rat embryonic ventricle cell line (H9c2) to explore the functional role of m 6 A modification and ALKBH5 in the heart and cardiomyocytes. Using plasmids and small interfering RNAs, the expressions of ALKBH5 and NOD-like receptor family pyrin domain-containing 3 (NLRP3) were determined to study their functions in regulating cardiomyocyte m 6 A and pyroptosis, respectively. We characterized the role of ALKBH5, which exhibited elevated expression in the ischemic heart tissue of rats and mice and hypoxic cardiomyocytes (RCMs and H9c2 cells). ALKBH5 knockdown alleviated hypoxia-induced H9c2 cell pyroptosis by inhibiting NLRP3 inflammasome activation, whereas ALKBH5 overexpression had the opposite effect. NLRP3 knockdown alleviated hypoxia-induced H9c2 cardiomyocyte pyroptosis by inhibiting ALKBH5 expression, whereas NLRP3 overexpression had the opposite effect. Mechanistically, ALKBH5 mediated m 6 A modification of NLRP3 mRNA in an IGF2BP2-dependent manner, and NLRP3, as a nuclear transcription factor, regulated the ALKBH5 transcription process. Targeting the ALKBH5-NLRP3 loop with the small-molecule inhibitors alleviated cardiomyocyte pyroptosis. Our results highlight that ALKBH5-NLRP3 forms a positive feedback loop that promotes cardiomyocyte pyroptosis after MI. Therefore, inhibiting the ALKBH5-NLRP3 loop is a potential strategy for treating cardiovascular diseases.
研究领域:
心血管疾病
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表观转录组学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Translational Medicine
·
2024
·Vol. 22
·期 1
·1-13
·
IF 6.1
Li Jing,Wang Xiaochen,Bai Jie,Wei Huangzhao,Wang Wenbo,Wang Shuai
Background Hypertension influences the inflammatory pathological changes in the retina. The function of the inflammasomes is significant. To see if Sirtuin 1 (SIRT1) regulates angiotensin II (Ang II)-induced hypertensive retinopathy and inflammation by modulating NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation and the potential protective effects of fucoidan (FO) in mouse retinal vascular endothelial cells (mRECs) and mice retina. Methods The diagnosis of hypertensive retinopathy was made after three weeks of Ang II infusion (3000 ng/kg/min). One day prior to the commencement of Ang II infusion, the mice were treatment with NLRP3 inhibitor MCC950 (10 mg/kg/day, intraperitoneal injections) or FO (300 mg/kg/day, oral gavage). A blood pressure was recorded. Hematoxylin and eosin (H&E) staining was used to conduct pathological alterations, dihydroethidium bromide (DHE) was utilized to assess oxidative stress damage in the retina, and fluorescence angiography was used to identify vascular disorders in the eye. Using immunohistochemical labeling, NLRP3 expression was found. Reactive protein and mRNA expression levels in mouse retina and cells were assessed using Western blot and real-time quantitative polymerase chain reaction (RT-qPCR). Results NLRP3 inflammasome activation and SIRT1 decrease were brought about by Ang II infusion. Retinopathy and dysfunction were lessened by MCC950 target-induced NLRP3 inflammasome activation, while overexpression of SIRT1 had the opposite impact on NLRP3 inflammasome activation, indicating that SIRT1 functions as an upstream regulator of NLRP3 activity. FO may improve SIRT1 expression and decrease NLRP3 activation in retinopathy and dysfunction brought on by Ang II, and the effects were consistent across both in vivo and in vitro models. Conclusions SIRT1 adversely regulates the NLRP3 inflammasome pathway, which in turn increases Ang II-induced inflammation and hypertensive retinopathy. FO may mitigate Ang II-induced retinopathy and dysfunction via modulating the expression of SIRT1/NLRP3. This implies practical approaches to the management of hypertensive retinopathy.
研究领域:
医学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
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