Cell Communication and Signaling
·
2024
·Vol. 22
·期 1
·1-17
·
IF 8.2
Zhang Yu,Wu Rong,Zhan Xi,Wang Xuan-Yi,Xiang Lin-Wei,Duan Ya-Qian,You Yan,Zhang Jian-Bo,Wu Rui,Zhang Yun-Yuan,Duan Liang
Background Absent in melanoma 2 (AIM2) inflammasome-dependent pyroptosis and neutrophil extracellular traps (NETs) have been implicated in chronic liver disease (CLD). However, the specific intrahepatic cell type that undergoes AIM2 inflammasome-dependent pyroptosis and how their interaction augments hepatic inflammation/fibrosis remains unclear.Methods The expression and correlation of AIM2 inflammasome-dependent pyroptosis-related indicators and NETs were analyzed in biopsy tissue and blood specimens from chronic hepatitis patients (CHs). Cell-based experiments were conducted to investigate their interaction. In vitro and in vivo experiments were used to analyze their effects on the progression of hepatic inflammation/fibrosis as well as their clinical importance.Results Elevated levels of AIM2 inflammasome-dependent pyroptosis indicators and NETs were detected in biopsy tissue and blood specimens. Circulating NETs were positively correlated with pyroptosis-related indicators, and both were related with disease severity. Confocal imaging revealed that AIM2 was mainly localized to hepatic macrophages, indicating that hepatic macrophages were the major cell type that underwent pyroptosis. NETs were directly engulfed by macrophages and then stimulated AIM2 inflammasome-dependent macrophage pyroptosis in vitro, which amplified the activation of hepatic stellate cells (HSCs) and increased collagen deposition. Administration of the NETs degradation agent DNase I or the AIM2 inflammasome activation inhibitor ODN A151 effectively alleviated chronic liver inflammation/fibrosis progression in vivo.Conclusion sNETs-induced AIM2 inflammasome-dependent pyroptosis in macrophages facilitates liver inflammation/fibrosis progression. The identified NET–AIM2 inflammasome cascade could serve as a novel therapeutic target for hepatic inflammation/fibrosis progression.
研究领域:
免疫学
·
肝病学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Communication and Signaling
·
2025
·Vol. 23
·期 1
·1-21
·
IF 8.9
Li Lei,Peng Ruilong,Wang Cong,Chen Xin,Gheyret Dilmurat,Guan Siyu,Chen Bo,Liu Yafan,Liu Xilei,Cao Yiyao,Han Cha,Xiong Jianhua,Li Fanjian,Lu Taoyuan,Jia Haoran,Li Kaiji,Wang Jinchao,Zhang Xu,Xu Jianye,Wang Yajuan,Xu Xin,Li Tuo,Zhang Jianning,Zhang Shu
Neutrophils are the first responders among peripheral immune cells to infiltrate the central nervous system following a traumatic brain injury (TBI), triggering neuroinflammation that can exacerbate secondary tissue damage. The precise molecular controls that dictate the inflammatory behavior of neutrophils post-TBI, however, remain largely elusive. Our comprehensive analysis of the molecular landscape surrounding the trauma in TBI mice has revealed a significant alteration in the abundance of β2 integrin (ITGB2), predominantly expressed by neutrophils and closely associated with immune responses. Using the fluid percussion injury (FPI) mouse model, we investigated the therapeutic efficacy of Rovelizumab, an agent that blocks ITGB2. The treatment has demonstrated significant improvements in neurologic function in TBI mice, attenuating blood–brain barrier permeability, mitigating oxidative stress and inflammatory mediator release, and enhancing cerebral perfusion. Moreover, ITGB2 blockade has effectively limited the adherence, migration, and infiltration of neutrophils, and has impeded the formation of neutrophil extracellular traps (NETs) upon their activation. Finally, it was demonstrated that ITGB2 mediates these effects mainly through its interaction with intercellular adhesion molecule-1 (ICAM 1) of endotheliocyte. These findings collectively illuminate ITGB2 as a crucial molecular switch that governs the adverse effects of neutrophils post-TBI and could be targeted to improve clinical outcome in patients.
研究领域:
神经科学
·
免疫学
·
创伤医学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INFLAMMATION
·
2024
·
IF 4.5
Liu Qi,Zhao Yubo,Dong Shuai,Bai Xingyuan,Chen Bin,Liu Xijuan,Shen Jing,Zhu Dan
Deciphering the complex and redundant process of acute inflammation remains challenging. The failure of numerous clinical trials assessing anti-inflammation agents which had promising preclinical effects inevitably questions the validity of current animal models of inflammation. This study aimed to better understand the process of immune inflammatory response and to select more suitable models to evaluate the effect of potential anti-inflammatory drugs. Zymosan and λ-carrageenan are the most used representatives of particulate and soluble irritants that trigger acute inflammation in the air pouch inflammation model. When zymosan was used, the number of exudate cells first increased at 4 h-8 h, followed by a drop at 12 h-24 h. While, the changes in number of leukocytes in peripheral blood and proportion of neutrophils in bone marrow have the opposite trend. Meanwhile, neutrophils released neutrophil extracellular traps (NETs) to clean zymosan particles. In contrast, the cell migration response to carrageenan increased during 4 h to 24 h, no obvious NETs were observed, and the number of leukocytes in peripheral blood increased and the proportion of neutrophils in bone marrow decreased slightly. This study indicated that although both zymosan and carrageenan are sterile irritants, the characteristics of the inflammatory response induced by each other were different. In the acute phase of inflammation, zymosan-stimulated neutrophils were mobilized, recruited, and engulfed, and then died by NETs. Carrageenan stimulated the production of cytokines/chemokines by neutrophils or macrophages, but did not lead to an obvious death by releasing NETs. Graphical Abstract
研究领域:
免疫学
·
药理学
·
炎症研究
·
动物模型
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ANNALS OF MEDICINE
·
2025
·
IF 4.3
Yun Yang,Lengqiu Guo,Jinghua Yu,Wei Peng,Qi Wang,Lan Wei,Xihua Chen,Chunyan Min,Xiaogang Jiang,Song Zhu,Haixin Zhao,Zhenyu Xuan,Jianzhong Yu,Jian Zhang
Background Da-Yuan-Yin Decoction (DYY), used since the early Qing Dynasty in China for damp-heat syndrome, was evaluated for its comprehensive protective effects.Materials and methods Rats received a high-fat/high-sugar diet for 14 days, then daily exposure to high temperature/humidity (31.0 ± 0.5°C, 85%-95%) for 10 hours over 14 days. Damp-heat syndrome was induced on day 29 via intraperitoneal lipopolysaccharide (LPS) injections (1 mg/kg and 0.5 mg/kg after 4 hours). Two hours post-modeling, rats received DYY (400 or 800 mg/kg/day) orally for 5 days. Symptoms were scored. On day 33, kidney, spleen, tongue, lung, liver, stomach, and colon tissues underwent histopathological and immunochemical/immunofluorescence analysis. Serum levels of inflammation factors, C-reactive protein (CRP), cell-free DNA (cfDNA), myeloperoxidase (MPO), and superoxide dismutase (SOD) were quantified. Complete blood count (CBC), blood biochemistry, short-chain fatty acids (SCFAs), gut microbiota composition in the colon, and metabolites in the cecum were analyzed.Results DYY significantly reduced symptom scores and decreased CRP level, while also regulating parameters in CBC and biochemical profiles. The treatment ameliorated tissue damage in the kidney, spleen, tongue, lung, liver, stomach, and colon. DYY downregulated citrullinated histone H3 (Cit H3), polyclonal peptidylarginine deiminase 4 (PADI4), and MPO expressions in the lung, stomach, and colon. Furthermore, it modulated inflammatory responses, suppressed the interleukin-23 (IL-23)/janus kinase-2 (JAK2)/signal transduction and transcription activator-3 (STAT3) signaling pathway and enhanced antioxidant activity. DYY administration significantly increased total SCFA content. The intervention restored gut microbiota diversity and abundance, while ameliorating metabolic dysregulation.Conclusion Systemic pathophysiological alterations were observed in rats with damp-heat syndrome. The comprehensive protective effects of DYY involved suppression of neutrophil extracellular traps (NETs) formation through downregulation of PADI4 expression, modulation of inflammatory responses, inhibition of the IL-23/JAK2/STAT3 signaling pathway, restoration of intestinal microecological balance and metabolic homeostasis, and enhancement of antioxidant.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Translational Medicine
·
2024
·Vol. 22
·期 1
·1-19
·
IF 6.1
Sun Xingzi,Ding Hanxi,Li Xingyu,Wu Yongjian,Huang Xi
Background Traditional methods for treating diabetic wounds are limited in effectiveness because of their long healing times, the risk of immune rejection, and susceptibility to infection. Suppressing neutrophil extracellular traps (NETs) is an effective strategy for reducing persistent inflammation in diabetic wounds. Although disulfiram (DSF) can inhibit the significant increase of NETs in diabetic wounds, oral DSF suffers from rapid and harmful metabolism in the liver. To address these challenges, we developed a nanomedicine formulation in which DSF was incorporated into the hydrogel.Methods In this study, we developed a DSF-laden sodium alginate hydrogel wound dressing, DEP@SA, and characterized its composition, properties, and performance. We examined the effects of DEP@SA on inflammatory phase-related markers such as NETs and their pathway proteins, inflammatory factors, and macrophage phenotypes in a high-glucose environment in vivo and in vitro. In addition, the effects of DEP@SA on tissue regenerative capacity such as epidermal proliferative migration and angiogenesis, were also assessed.Results The results showed that by utilizing extracellular vesicles as a drug delivery system, we effectively mitigated the degradation of DSF via direct contact with aqueous solutions and ensured the stability of DSF@SA, which could then be applied to diabetic wounds. The inflammatory phase-related indicators revealed that DSF@SA effectively reduced inflammation levels, decreased NETs formation, suppressed the Caspase-1/GSDMD pathway in neutrophils, and promoted the polarization of M2 macrophages. Moreover, the hydrogel accelerated wound healing by promoting angiogenesis and re-epithelialization, thereby shortening the diabetic wound healing time.Conclusion sThis study confirmed that the DSF@SA composite dressing has the potential to enhance diabetic wound repair and offers a novel approach for drug reutilization.Graphical Abstract
研究领域:
药学
·
生物医学工程
·
伤口愈合
·
免疫学
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
·
2022
·
IF 3.973
Lu Peng,Xiangyu Zhu,Zongming Qin,Jing Liu,Erqun Song,Yang Song
Polychlorinated biphenyls (PCBs) are a group of persistent organic environmental pollutants with various toxic effects. Our previous research found that a highly reactive quinone metabolite of PCBs, namely, PCB29-pQ, causes excessive reactive oxygen species (ROS) production and different toxic actions. Neutrophil extracellular traps (NETs), the product of NETosis, are one of the newly discovered programmed cell deaths. Recent studies have suggested the association of NET formation with excess ROS. The objective of this study was to investigate the influence of PCB29-pQ exposure on NETs and its possible molecular mechanisms. Using scanning electron microscopy, immunofluorescence microscopy, and the quantitative analysis of extracellular DNA, we found that PCB29-pQ exposure induces the formation of NETs in mouse bone marrow. Mechanistically, our results suggested that PCB29-pQ induces histone citrullination and chromatin decondensation, which are necessary processes for NET formation. Moreover, PCB29-pQ exposure increases ROS and autophagy levels, while ROS and autophagy inhibitors significantly reverse NET formation. These results indicated that PCB29-pQ-induced NET formation was mediated by the intracellular ROS level and autophagy signaling. In general, our research uncovered a toxicity mechanism of PCB29-pQ, which suggested the necessity of evaluating its immunotoxicity during the risk assessment of PCB exposure.
研究领域:
毒理学
·
免疫学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2023
·
IF 10
Xiaoqing Han,Xingbo Wang,Jiao Yan,Panpan Song,Yanjing Wang,Chao Shang,Yunyun Wu,Hua Zhang,Zhenxin Wang,Haiyuan Zhang,Xi Li
Premetastatic niche (PMN) is a prerequisite for tumor metastasis. Destruction of PMN can significantly suppress the tumor metastasis. Bone marrow-derived cells are usually recruited into the premetastatic organs to support PMN formation, which can be orchestrated by tumor-derived secreted factors. Neutrophils can chemotactically migrate towards the inflammatory sites and consume tumor-derived secreted factors, capable of acting as therapeutic agents for a broad-spectrum suppression of PMN formation and metastasis. However, neutrophils in response to inflammatory signals can release neutrophil extracellular traps (NETs), promoting the tumor metastasis. Herein, live neutrophils are converted into dead neutrophils ( C NE) through a quick-frozen process to maintain PMN-targeting and tumor-derived secreted factor-consuming abilities but eliminate NET-releasing shortcomings. Considering macrophages-regulated remodeling of the extracellular matrix in PMN, bacterial magnetosomes (Mag) are further hitchhiked on the surface of C NE to form C NE Mag , which can repolarize macrophages from M2 to M1 phenotype for further disruption of PMN formation. A series of in vitro and in vivo assessments have been applied to confirm the effectiveness of C NE Mag in suppression of PMN formation and metastasis. This study presents a promising strategy for targeted anti-metastatic therapy in clinics.
研究领域:
肿瘤学
·
免疫学
·
细胞生物学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2023
·
IF 8.9
Dongxu Wang,Kai Yin,Yue Zhang,Hongmin Lu,Lulu Hou,Hongjing Zhao,Mingwei Xing
Endemic fluorosis (EF) has been listed as one of the serious public health problems in many countries. Long-term exposure to high fluoride can lead to severe neuropathological damage to the brain. Although long-term research has revealed the mechanism of some brain inflammation caused by excessive fluoride, the role of intercellular interactions, especially immune cells, in brain damage is still unclear. Fluoride can induce ferroptosis and inflammation in the brain in our study. A co-culture system of neutrophil extranets and primary neuronal cells showed that fluoride can aggravate neuronal cell inflammation by causing neutrophil extranets (NETs). In terms of the mechanism of action, we found that fluoride leads to the opening of calcium ion channels by causing neutrophil calcium imbalance, which in turn leads to the opening of L-type calcium ion channels (LTCC). Extracellular free iron enters the cell from the open LTCC, leading to neutrophil ferroptosis, which releases NETs. Blocking LTCC (nifedipine) rescued neutrophil ferroptosis and reduced the generation of NETs. Inhibition of ferroptosis (Fer-1) did not block cellular calcium imbalance. In summary, our study explores the role of NETs in fluoride-induced brain inflammation and suggests that blocking calcium channels may be one of the possibilities to rescue fluoride-induced ferroptosis.
研究领域:
神经科学
·
免疫学
·
毒理学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
INORGANIC CHEMISTRY COMMUNICATIONS
·
2024
·
IF 4.4
Jie Wang,Ya-Nan Yu,Rou Huang,Ce Wang,Zheng Yin
Mix-ligands strategy is highly efficient for the rational construction of MOFs with particular structure motifs and high porosity, yet challenging and requiring matching in hierarchical coordination assembly and synergetic crystallization. The solvothermal reactions of 1,3,5-tris[4-carboxyphenyl]benzene (H 3 btb) and 1,4-benzenedicarboxylic acid (H 2 bdc) with different 3d metal ions , generated highly porous mixed-ligands MOFs of [(CH 3 ) 2 NH 2 ] 2 [Mn 3 (btb) 2 (bdc)]·12DMF·3MeOH ( Mn-btb-bdc ) having anionic 3D frameworks constructed from linear [Mn 3 (COO) 8 ] nodes, [Co 4 (btb) 2 (bdc)(H 2 O) 3 ]·15DMF·7H 2 O ( Co-btb-bdc ) processing neutral frameworks constituted by linear [Co 3 (COO) 6 (H 2 O) 4 ] and paddle-wheel [Co 2 (COO) 4 (H 2 O) 2 ] nodes, as well as one single-ligand MOFs of [(CH 3 ) 2 NH 2 ][Cd(btb)(H 2 O)]·8DMF ( Cd-btb-2fold ) exhibiting 2-fold interpenetrated ths net frameworks due to the unsuccessful introduce of the coexisted bdc ligand. Two new topology net of 2,3,8-connected net with point symbol of (4 2 ·6) 2 (4 4 ·6 6 ·8 12 ·10 5 ·12)(6) and 2,3,4,6-connected net with Point Symbol of (4·8 2 ) 4 (4 2 ·8 11 ·10 2 ) 2 (8 4 ·12 2 )(8 2 ) were found for Mn-btb-bdc and Co-btb-bdc . All these three MOFs are highly porous with void fractions of 60.9%, 52.2% and 61.4%, stemming from 3D-penetrated, 3D-penetrated and 1D channels, respectively. Such structural differentiations are attributed to the diversified electronic structure and coordination preference of different 3d metal ions, as well as the solvent template and temperature effects. Two-steps gate-opening behaviour in gas sorption isotherms was found in the flexible Mn-btb-bdc MOFs.
研究领域:
材料科学
·
化学
✓ 已验证
产品关联
DOI
高影响因子
Nano Today
·
2024
·
IF 13.2
Qiaoxuan Wang,Qi Cheng,Guangshuai Yao,Zhaolong Wang,Lingjiang Zhu,Zhiru Zeng,Lingyun Jia,Yan Du,Jing Xue,Changyou Gao
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease primarily driven by inappropriate infiltration and activation of immune cells and pro-inflammatory cytokines. Among them, neutrophils with high plasticity play a pathogenic role in RA by abnormal neutrophil immune activities. As anti-IL-17A therapies failed to achieve long-term ideal therapeutic outcomes in clinical trials, we speculated that the underlying cause may be associated with the abnormal activity of neutrophils that have a direct link to IL-17A. Herein, we created a cationic hydrogel loaded with anti-IL-17A nanobodies (Nbs) capable of synergistically weakening the inflammatory activities of neutrophils and relieving inflammation in RA. Based on the host-guest interaction, the hydrogel was comprised of β-cyclodextrin-modified hyperbranched polylysine (HBPL-CD) and adamantane-modified hyaluronic acid (HA-Ad). The physical properties were adjusted to match the mechanical environment of joints and enable injection. The hydrogel with Nbs could adsorb cell-free DNA (cfDNA) persistently and slowly release anti-IL-17A Nbs, which synergistically alleviated the inflammatory activities of neutrophils via inhibiting the IL-17A stimulated neutrophil extracellular traps (NETs) of neutrophils from RA patients and mice with collagen-induced arthritis (CIA), reducing the level of pro-inflammatory cytokines, and suppressing the inflammatory phenotype of neutrophils in vitro . The ankle injection of the hydrogel with Nbs into a mouse model of CIA could alleviate the RA symptoms in vivo . This novel platform is believed to provide a guideline for treating IL-17A-related diseases by combining Nbs with the immunoregulation of neutrophils.
研究领域:
生物医学工程
·
免疫学
·
药学
·
风湿病学
✓ 已验证
DOI
高影响因子
Nano Today
·
2022
·
IF 18.962
Jiao Liu,Xiao Zhang,Pengfei Zou,Jiahui Yao,Lingling Liu,Yun Cai,Tongyi Sun,Yuanyuan Gao,Li-Li Li
Antibiotic-resistance is a growing threat since it endangers the antibiotic treatments such as surgery, transplants and skin damage, which may cause the top-risk of death to public in 2050. Here, we fabricated nano-antibiotic transformers ( NATs ) that co-assembled with two lipopeptides and loaded with antibiotics. Once specifically bonding onto the bacterial membrane through multi-targeting of Lipo-20 , our NATs activated the in-situ nanofiber deformation, which enhanced membrane disruption and antibiotic penetration resulting in antibiotic adjuvant effect (FICI=0.3, 8-fold reduced the MIC of antibiotic). Meanwhile, the transformed nanofiber further trapped the bacteria similar as the neutrophil extracellular traps (NETs) to enhance the clearance of bacteria in vivo . Additionally, the optimized ratios of two components of lipopeptides maintained the high antibiotic adjuvant activity and more significantly reduced hemolysis. Our NATs significantly prolong the life-time of antibiotic without resistance appear over one month. Finally, the clinical isolated antibiotic-resistance Klebsiella pneumoniae induced pneumonia can be cured based on the synergistic interactions of antibiotic adjuvant activity and targeted antibiotic delivery. We believed such nanotranformers will offer us a broadly applicable drug-delivery system for antibiotic-resistance infection in vivo .
研究领域:
纳米技术
·
药学
·
微生物学
·
传染病学
✓ 已验证
DOI
高影响因子
Journal of the American Heart Association
·
2022
·
IF 6.106
Xin‐Lin Zhang,Ting‐Yu Wang,Zheng Chen,Hong‐Wei Wang,Yong Yin,Lian Wang,Yong Wang,Biao Xu,Wei Xu
BackgroundHeart failure with preserved ejection fraction (HFpEF) remains an increasing public health problem with substantial morbidity and mortality but with few effective treatments. A novel inflammatory mechanism has been proposed, but the inflammatory signals promoting the development of HFpEF remain greatly unknown.Methods and ResultsSerum of patients with HFpEF was collected for measurement of circulating neutrophils and markers of neutrophil extracellular traps (NETs). To induce HFpEF phenotype, male C57BL/6 mice underwent uninephrectomy, received a continuous infusion of d‐aldosterone for 4 weeks, and maintained on 1.0% sodium chloride drinking water. Heart tissues were harvested, immune cell types determined by flow cytometry, NETs formation by immunofluorescence, and western blotting. Differentiated neutrophils were cultured to investigate the effect of HMGB1 (high mobility group protein B1) and SGLT2 (sodium‐glucose cotransporter‐2) inhibitor on NETs formation in vitro. Circulating neutrophils and NETs markers are elevated in patients with HFpEF, as are cardiac neutrophils and NETs formation in HFpEF mice. NETs inhibition with deoxyribonuclease 1 in experimental HFpEF mice reduces heart macrophages infiltration and inflammation and ameliorates cardiac fibrosis and diastolic function. Damage‐associated molecular pattern HMGB1 expression is elevated in cardiac tissue of HFpEF mice, and HMGB1 inhibition reduces heart neutrophil infiltration and NETs formation and ameliorates diastolic function. Lastly, SGLT2 inhibitor empagliflozin down‐regulates heart HMGB1 expression, attenuates NETs formation and cardiac fibrosis, and improves diastolic function in HFpEF mice.ConclusionsNETs contribute to the pathogenesis of HFpEF, which can be ameliorated by HMGB1 inhibition and SGLT2 inhibitors. Thus, HMGB1 and NETs may represent novel therapeutic targets for the treatment of HFpEF.
研究领域:
心脏病学
·
免疫学
·
药理学
✓ 已验证
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）