IMMUNITY
·
2023
·
IF 32.4
Yanfei Hou,Zhimeng Wang,Peiyuan Liu,Xubiao Wei,Zhengyin Zhang,Shilong Fan,Lulu Zhang,Fangping Han,Yikang Song,Ling Chu,Conggang Zhang
Lipid metabolism has been associated with the cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) stimulator of interferon genes (STING) DNA-sensing pathway, but our understanding of how these signals are integrated into a cohesive immunometabolic program is lacking. Here, we have identified liver X receptor (LXR) agonists as potent inhibitors of STING signaling. We show that stimulation of lipid metabolism by LXR agonists specifically suppressed cyclic GMP-AMP (cGAMP)-STING signaling. Moreover, we developed cyclic dinucleotide-conjugated beads to biochemically isolate host effectors for cGAMP inhibition, and we found that LXR ligands stimulated the expression of sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A), which is a 2′3′-cGAMP-degrading enzyme. Results of crystal structures suggest that cGAMP analog induces dimerization of SMPDL3A, and the dimerization is critical for cGAMP degradation. Additionally, we have provided evidence that SMPDL3A cleaves cGAMP to restrict STING signaling in cell culture and mouse models. Our results reveal SMPDL3A as a cGAMP-specific nuclease and demonstrate a mechanism for how LXR-associated lipid metabolism modulates STING-mediated innate immunity.
研究领域:
免疫学
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代谢
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分子生物学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Lan Chen,Xi Wu,Dong Li,Shaosheng Jia,Jianan Yu,Bin Li,Jingan Li,Lingchuang Bai,Shaokang Guan
Osteosarcoma is a highly malignant tumor that severely affects the physical and mental health of adolescents. Photothermal synergistic catalytic therapy is regarded as an effective and innovative strategy to eliminate tumor cells and restore bone tissue. Herein, an intelligent and anti-corrosion non-drug-loading platform, based on a dopamine-chelated iron composite coating (FeOOH/PDA-Fe), is constructed on osteogenic magnesium alloys. The prepared films function as an iron “sandwich”, which progressively enhance the corrosion resistance of Mg alloy, and pump iron ions loaded under near-infrared (NIR) irradiation and in the tumor microenvironment, but remain stable in the normal environment. Efficient photothermal therapy-driven tumor apoptosis of modified Mg alloys within the NIR window due to the strong ligand-to-metal charge transfer between intermediates of dopamine and transition metal iron oxidation. In vitro and in vivo studies reveal the synergistic mechanism of photothermal treatment on catalytic therapy for osteosarcoma of the prepared coating, and the mechanism by which the synergistic therapy re-activates the innate immune response by inducing tumor immunogenic death. The modified Mg alloys that combine effective corrosion resistance, highly efficient tumor ablation without drug resistance, and innate immune response re-activation, are likely a point-to-point solution for the comprehensive therapeutic needs of osteosarcoma.
研究领域:
材料科学
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肿瘤学
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生物医学工程
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产品关联
DOI
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2019
·
IF 2.705
Fake Li,Jie Luo,Huan Xu,Yang Wang,Wenbin Jiang,Kai Chang,Shaoli Deng,Ming Chen
Early secreted antigenic target 6-kDa protein (ESAT6) is an essential virulence factor of Mycobacterium tuberculosis (MTb). However, ESAT6 helped fighting MTb infection according to vaccine studies. It's unclear whether ESAT6 confers protection via enhancing the innate immunity of macrophages, which are the first-line defense against MTb. We profiled the global transcriptional changes and characterized the innate immunity of THP-1 macrophages treated with ESAT6. We found ESAT6 promoted the phagocytosis ability, enhanced reactive oxygen species (ROS) generation and accelerated glucose metabolism in macrophages. Meanwhile, ESAT6 induced a distinctive phenotype of macrophages with a concurrence of pro-inflammatory and anti-inflammatory cytokines and chemokines . ESAT6 increased the expression of HIF1α mRNA and protein. Interfering HIF1α with siRNA defected the capacity of phagocytosis and ROS generation as well as glucose metabolism. Thus, ESAT6 enhanced the protective innate immunity of macrophages partially via HIF1α. This study provided clues for developing therapies against tuberculosis by targeting ESAT6.
研究领域:
免疫学
·
微生物学
·
传染病学
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DOI
PubMed
高影响因子
NATURE CELL BIOLOGY
·
2025
·
IF 19.1
Wang Bin,Wang Yongqiang,Pan Ting,Zhou Lili,Ran Yu,Zou Jing,Yan Xiaohua,Wen Zhenke,Lin Shixian,Ren Aiming,Wang Fangwei,Liu Zhuang,Liu Ting,Lu Huasong,Yang Bing,Zhou Fangfang,Zhang Long
Maintaining innate immune homeostasis is critical for preventing infections and autoimmune diseases but effective interventions are lacking. Here we identified C864–C869-mediated intermolecular disulfide-linkage formation as a critical step for human RIG-I activation that can be bidirectionally regulated to control innate immune homeostasis. The viral-stimulated C864–C869 disulfide linkage mediates conjugation of an SDS-resistant RIG-I oligomer, which prevents RIG-I degradation by E3 ubiquitin-ligase MIB2 and is necessary for RIG-I to perform liquid–liquid phase separation to compartmentalize downstream signalsome, thereby stimulating type I interferon signalling. The corresponding C865S ‘knock-in’ caused an oligomerization defect and liquid–liquid phase separation in mouse RIG-I, which inhibited innate immunity, resulting in increased viral load and mortality in mice. Using unnatural amino acids to generate covalent C864–C869 linkage and the development of an interfering peptide to block C864–C869 residues, we bidirectionally regulated RIG-I activities in human diseases. These findings provide in-depth insights on mechanism of RIG-I activation, allowing for the development of methodologies that hold promising implications in clinics.
研究领域:
免疫学
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分子生物学
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病毒学
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产品关联
DOI
PubMed
高影响因子
CHEMOSPHERE
·
2023
·
IF 8.8
Lihui Xuan,Yin Wang,Can Qu,Yuhui Yan,Wensen Yi,Jingjing Yang,Magdalena Skonieczna,Cuimei Chen,Justyna Miszczyk,Dmitry S. Ivanov,Hesham M.H. Zakaly,Vladimir Markovic,Ruixue Huang
Nanoplastics have been widely studied as environmental pollutants, which can accumulate in the human body through the food chain or direct contact. Research has shown that nanoplastics can affect the immune system and mitochondrial function, but the underlying mechanisms are unclear. Lungs and macrophages have important immune and metabolic functions. This study explored the effects of 100 nm PS-NPs on innate immunity, mitochondrial function, and cellular metabolism-related pathways in lung (BEAS-2B) cells and macrophages (RAW264.7). The results had shown that PS-NPs exposure caused a decrease in mitochondrial membrane potential, intracellular ROS accumulation, and Ca 2+ overload, and activated the cGAS-STING signaling pathway related to innate immunity. These changes had been observed at concentrations of PS-NPs as low as 60 μg/mL, which might have been comparable to environmental levels. Non-target metabolomics and Western Blotting results confirmed that PS-NPs regulated prostaglandin B1 and other metabolites to cause cell damage through the cGAS-STING pathway. Supplementation of prostaglandin B1 alleviated the immune activation and metabolic disturbance caused by PS-NPs exposure. This study identified PS-NPs-induced innate immune activation, mitochondrial dysfunction, and metabolic toxicity pathways, providing new insights into the potential for adverse outcomes of NPs in human life.
研究领域:
环境科学
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免疫学
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细胞生物学
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代谢组学
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毒理学
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产品关联
DOI
PubMed
高影响因子
Nano Energy
·
2024
·
IF 16.8
Junkun Feng,Xiaoyi Liu,Kai Li,Weiwei Zhao,Wenjun Wang,Shaohua Ge,Hong Liu,Jianhua Li
Macrophages are the first line of host defense against bacterial infections and mitochondrial reactive oxygen species (mROS) plays an important role in the bactericidal innate response of macrophages. In this work, we propose the concept of engineering macrophages with artificial mROS generation ability to combat bacterial infection, which is enabled by metal phenolic network-mediated lysosomal escape of piezocatalytic nanoparticles (piezoNPs) and piezotronic effect-enhanced intracellular piezocatalysis. By harvesting ultrasound energy, the engineered macrophages can demonstrate pro-inflammatory phenotype, potent phagocytosis and strong bactericidal activity against Staphylococcus aureus ( S. aureus ). By in situ engineering macrophages at the infection site with targeting ligand-modified piezoNPs, the treatment of S. aureus abscess is further demonstrated. This study reveals the potential of intracellular piezotronic nanocatalysis in enhancing innate immune response of macrophages, providing a non-invasive modulation of macrophages-mediated immunotherapy.
研究领域:
生物医学工程
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免疫学
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纳米技术
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微生物学
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产品关联
DOI
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Dongyi Cao,Ruiying Xi,Hongye Li,Zhonghui Zhang,Xiaoke Shi,Shanshan Li,Yujie Jin,Wanli Liu,Guolin Zhang,Xiaohua Liu,Shunxi Dong,Xiaoming Feng,Fei Wang
Caspase-1 plays a central role in innate immunity, as its activation by inflammasomes induces the production of proinflammatory cytokines and pyroptosis. However, specific inhibition of the enzymatic activity of this protease is not effective in suppressing inflammation, owing to its enzyme-independent function. Herein, we identified a cyclohexenyl isothiocyanate compound (CIB-1476) that potently inhibited caspase-1 activity and suppressed the assembly and activation of the NLRP3 inflammasome and gasdermin-D-mediated pyroptosis. Mechanistically, CIB-1476 directly targeted pro-caspase-1 as an irreversible covalent inhibitor by binding to Cys285 and Cys397, resulting in more durable anti-inflammatory effects in the suppression of enzyme-dependent IL-1β production and enzyme-independent nuclear factor κB activation. Chemoproteomic profiling demonstrated the engagement of CIB-1476 with caspase-1. CIB-1476 showed potent therapeutic effects by suppressing inflammasome activation in mice, which was abolished in Casp1–/– mice. These results warrant further development of CIB-1476 along with its analogues as a novel strategy for caspase-1 inhibitors.
研究领域:
免疫学
·
药理学
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生物化学
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分子生物学
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DOI
PubMed
高影响因子
Vaccines
·
2024
·Vol. 12
·期 6
·622
·
IF 5.2
Shufeng Weng,Qingchun Li,Tianran Zhang,Taiyue Lin,Yumo He,Guang Yang,Honghai Wang,Ying Xu
Tuberculosis (TB) is a major global health threat despite its virtual elimination in developed countries. Issues such as drug accessibility, emergence of multidrug-resistant strains, and limitations of the current BCG vaccine highlight the urgent need for more effective TB control measures. This study constructed BCG strains overexpressing Rv1002c and found that the rBCG-Rv1002c strain secreted more glycosylated proteins, significantly enhancing macrophage activation and immune protection againstMycobacterium tuberculosis(M. tb). These results indicate that Rv1002c overexpression promotes elevated levels of O-glycosylation in BCG bacteriophages, enhancing their phagocytic and antigenic presentation functions. Moreover, rBCG-Rv1002c significantly upregulated immune regulatory molecules on the macrophage surface, activated the NF-κB pathway, and facilitated the release of large amounts of NO and H2O2, thereby enhancing bacterial control. In mice, rBCG-Rv1002c immunization induced greater innate and adaptive immune responses, including increased production of multifunctional and long-term memory T cells. Furthermore, rBCG-Rv1002c-immunized mice exhibited reduced lung bacterial load and histological damage uponM. tbinfection. This result shows that it has the potential to be an excellent candidate for a preventive vaccine against TB.
研究领域:
免疫学
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微生物学
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疫苗学
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传染病
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产品关联
DOI
PubMed
高影响因子
PLoS Pathogens
·
2024
·Vol. 20
·期 1
·e1011926
·
IF 5.5
Zihao Wang,Ziming Jiang,Yu Zhang,Congwei Wang,Zhaoyang Liu,Zhankui Jia,Sudhanshu Bhushan,Jinjian Yang,Zhengguo Zhang
Uropathogenic Escherichia coli (UPEC) is the primary causative agent of urinary tract infections (UTIs) in humans. Moreover, as one of the most common bacterial pathogens, UPEC imposes a substantial burden on healthcare systems worldwide. Epithelial cells and macrophages are two major components of the innate immune system, which play critical roles in defending the bladder against UPEC invasion. Yet, the routes of communication between these cells during UTI pathogenesis are still not fully understood. In the present study, we investigated the role of membrane-bound nanovesicles (exosomes) in the communication between bladder epithelial cells and macrophages during UPEC infection, using an array of techniques such as flow cytometry, miRNA profiling, RNA sequencing, and western blotting. Moreover, our in vitro findings were validated in a mouse model of UPEC-induced cystitis. We found that UPEC infection induced the bladder epithelial MB49 cell line to secrete large numbers of exosomes (MB49-U-Exo), which were efficiently absorbed by macrophages both in vivo and in vitro. Assimilation of MB49-U-Exo induced macrophages to produce proinflammatory cytokines, including tumor necrosis factor (TNF)α. Exposure of macrophages to MB49-U-Exo reduced their phagocytic activity (by downregulating the expression of phagocytosis-related genes) and increased their rate of apoptosis. Mechanistically, we showed that MB49-U-Exo were enriched in miR-18a-5p, which induced TNFα expression in macrophages by targeting PTEN and activating the MAPK/JNK signaling pathway. Moreover, administration of the exosome secretion inhibitor GW4869 or a TNFα-neutralizing antibody alleviated UPEC-mediated tissue damage in mice with UPEC-induced cystitis by reducing the bacterial burden of the bladder and dampening the associated inflammatory response. Collectively, these findings suggest that MB49-U-Exo regulate macrophage function in a way that exacerbates UPEC-mediated tissue impairment. Thus, targeting exosomal -release or TNFα signaling during UPEC infection may represent promising non-antibiotic strategies for treating UTIs.
Urinary tract infections, which are typically caused by uropathogenic Escherichia coli (UPEC), affect over 150 million people each year, worldwide. Because the incidence of antibiotic resistance among UPEC strains is on the rise, urinary tract infections are becoming increasingly challenging to treat using this standard treatment method. Moreover, although the host immune response against UPEC has been intensively studied, the mechanism of communication between bladder epithelial cells and macrophages during UPEC infection remains largely unexplored. Here, we characterized the exosomes released from bladder epithelial cells following UPEC infection and evaluated their impact on macrophages. We demonstrated that bladder tissue destruction following excessive innate immune cell activation during UPEC infection may be driven by exosomes secreted from bladder epithelial cells. We further showed that pharmacologically inhibiting exosomal release from epithelial cells limited macrophage-associated inflammation, innate immune cell infiltration, and histopathological injuries in a mouse model of UPEC-induced cystitis. Collectively, our findings suggest that modulating exosome release represents a promising non-antibiotic therapy for UTIs.
研究领域:
微生物学
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免疫学
·
分子生物学
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细胞生物学
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病理学
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产品关联
DOI
PubMed
高影响因子
Nano Today
·
2021
·
IF 20.722
Kai-Ge Chen,An Liu,Cheng-Tao Jiang,Dong-Kun Zhao,Qian-Ni Ye,Yu-Qi Liao,Cong-Fei Xu,Song Shen,Jun Wang
Innate immune cells, including natural killer cells and macrophages, are crucial in tumor surveillance and elimination. In contrast to the relatively complicated process of antigen-specific adaptive immunity, innate immune cells exhibit spontaneous tumoricidal effects by releasing cytolytic granules to adjacent tumor cells or by directly phagocytizing adjacent tumor cells. These effects of innate immune cells highlight the importance and necessity of spatial proximity between activated effector cells and tumor cells in innate antitumor immunity. Here, we describe two dual-functional super bispecific nano-antibodies (S-BsNA) constructed by immobilizing two types of traditional monoclonal antibodies (αKLRG1 and αPDL1, or αCSF1R and αCD47) onto a universal antibody-immobilization platform. The S-BsNA simultaneously regulate the antitumor response of innate immune cells and establish a close physical connection between effector cells and tumor cells. The superiority of S-BsNA over the parental monoclonal antibodies was evaluated in multiple tumor models in vitro and in vivo . S-BsNA can efficiently augment innate antitumor immunity both in vitro and in vivo and can be an alternative modality of immunotherapy, expanding its benefits to a larger patient pool.
研究领域:
免疫学
·
肿瘤学
·
分子生物学
·
细胞生物学
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产品关联
DOI
高影响因子
Probiotics and Antimicrobial Proteins
·
2025
·
IF 4.4
Niu Lingdi,Li Hai,Guo Junjie,Jia Zheng,Chang Qingru,Liu Ning,Zhang Shuhe,Ge Junwei
The gut microbiota plays a complex role in immune system maturation and function. The induction of memory in innate immune cells appears to be part of a co-adaptation between the host and microbiome. As important gut commensals, certain Lactobacillus have been shown to induce innate immune memory. However, the universality, phenotypic characteristics, mechanisms of Lactobacillus -induced innate immune memory, and its potential applications in vaccine immunology remain poorly understood. Here, we discovered that specific strains of the gut commensal Lactobacillus can induce innate immune memory, resulting in a more balanced trained immunity phenotype through SOCS activation. Upon secondary stimulation, macrophages exhibited increased expression of IL-6 , IL-1β , IL-10 , IL-12 , IFN-β , and TGF-β . Peptidoglycan and components in the secretome sensitive to pancreatic enzymes were identified as key elements in inducing trained immunity. Furthermore, mice that underwent training demonstrated rapid resistance to S. aureus infection. Additionally, Lactobacillus -induced trained immunity significantly enhanced the protective efficacy of vaccines against MRSA. Our findings demonstrate that certain Lactobacillus strains can activate non-classical trained immunity, offering potential for enhancing vaccine efficacy. Our study provides new insights into the role of some gut commensals in immune modulation and suggests a novel approach to vaccine enhancement through trained immunity induced by specific gut commensals.
研究领域:
免疫学
·
微生物组研究
·
疫苗学
·
固有免疫
·
分子生物学
·
宿主-微生物相互作用
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产品关联
DOI
PubMed
高影响因子
Advanced Therapeutics
·
2024
·Vol. 7
·期 11
·2400275
·
IF 3.7
Yao Yao,Binqing Xue,Duncan James Lessing,Weihua Chu
Alterations in the intestinal microenvironment, including increased levels of reactive oxygen species (ROS), abnormalities in intestinal mucosal immune regulation, and dysbiosis of the intestinal microbiota, are crucial to the development of inflammatory bowel disease (IBD). Herein, an oral colon-targeting Se-Probiotic@Alginate bead (BLSe) with ROS-scavenging ability and gut immune-microbiota microenvironment remodeling ability is developed using alginate as the primary outer shell encapsulated with probiotics Bacillus licheniformis (BL) and selenium nanoparticles stabilized by yeast glucan (SeNPs). In vitro studies have shown that SeNPs possess antioxidant activity and BLSe exhibits excellent stability in gastric fluids and are released in intestinal fluids. In vivo studies have also shown that BLSe significantly alleviated dextran sulphate sodium (DSS)-induced colitis in mice by inhibiting colon shortening, enhancing antioxidant activity, reducing pro-inflammatory cytokine secretion, and protecting the intestinal mucosal barrier. 16S ribosomal RNA sequencing shows that BLSe can remodel the composition of the gut microbiota by improving bacterial diversity and restoring the relative abundance of beneficial bacteria in the colon. Overall, this study advances a promising probiotic-based nanomedicine for managing IBD.
研究领域:
药学
·
免疫学
·
微生物学
·
胃肠病学
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产品关联
DOI
高影响因子
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