Small
·
2020
·Vol. 16
·期 46
·2004240
·
IF 11.459
Ya-Ru Zhang,Jia-Qi Luo,Jing-Yang Zhang,Wei-Min Miao,Jia-Si Wu,Hua Huang,Qi-Song Tong,Song Shen,Kam W. Leong,Jin-Zhi Du,Jun Wang
Activation of the phagocytosis of macrophages to tumor cells is an attractive strategy for cancer immunotherapy, but the effectiveness is limited by the fact that many tumor cells express an increased level of anti-phagocytic signals (e.g., CD47 molecules) on their surface. To promote phagocytosis of macrophages, a pro-phagocytic nanoparticle (SNPA CALR&aCD47 ) that concurrently carries CD47 antibody (aCD47) and a pro-phagocytic molecule calreticulin (CALR) is constructed to simultaneously modulate the phagocytic signals of macrophages. SNPA CALR&aCD47 can achieve targeted delivery to tumor cells by specifically binding to the cell-surface CD47 and block the CD47-SIRPα pathway to inhibit the “don't eat me” signal. Tumor cell-targeted delivery increases the exposure of recombinant CALR on the cell surface and stimulates an “eat me” signal. Simultaneous modulation of the two signals enhances the phagocytosis of 4T1 tumor cells by macrophages, which leads to significantly improved anti-tumor efficacy in vivo. The findings demonstrate that the concurrent blockade of anti-phagocytic signals and activation of pro-phagocytic signals can be effective in macrophage-mediated cancer immunotherapy.
研究领域:
癌症免疫学
·
纳米技术
·
免疫疗法
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR BIOLOGY
·
2024
·
IF 1.5
Yang S. J.,Ying J. L.,Xie W. J.
Abstract Microglia phagocytosis plays an important role in the pathogenesis of neurodegeneration. Defects or dysfunction of microglia phagocytosis were observed in neurodegenerative diseases, with different targets and associated receptors influencing the microglia response. Moreover, non-canonical LC3-associated (microtubule-associated protein 1 light chain 3) phagocytosis was extensively studied recently as a novel form of phagocytosis on macrophages, but little on microglia. Here, we investigated changes in phagocytic function of microglia activated by lipopolysaccharide (LPS) as well as rapamycin-regulated phagocytosis. Phagocytosis in mouse BV2 cells and primary microglia was analyzed by flow cytometry and immunofluorescence. Phagocytosis-related mechanisms in BV2 cells were analyzed using Western blotting and real-time polymerase chain reaction. Rapamycin was shown to reduce LPS-induced phagocytosis of microglia and at the same time stimulate LС3-dependent phagocytosis by regulating Atg3 , Atg4 and Atg7 expression. In addition, in BV2 cells, the PI3K/AKT/mTOR pathway may be involved in phagocytosis. These results suggest that phagocytosis of microglia is a complex process, and the increase in phagocytosis should not be considered as a maturation of phagocytic function. The data will provide new insights into the mechanisms of phagocytosis and neuroimmunity.
研究领域:
神经科学
·
免疫学
·
细胞生物学
·
药理学
✓ 已验证
产品关联
DOI
高影响因子
Autophagy
·
2025
·
IF 14.3
Xue Yang,Linyue Lv,Yuelan Zhang,Zhuyou Zhang,Shaowei Zeng,Xinyi Zhang,Qinyang Wang,Martin Dorf,Shitao Li,Bishi Fu
STING1/MITA not only induces innate immune responses but also triggers macroautophagy/autophagy to selectively degrade signaling molecules. However, the molecular mechanisms regulating STING1-mediated selective autophagy remain unclear. Here, we first report that ATP2A2 directly interacts with STING1, regulating STING1-mediated innate immune response by modulating its polymerization and trafficking, thereby inhibiting DNA virus infection. Notably, while screening for reticulophagy receptors involved in STING1-mediated selective autophagy, we identified SEC62 as an important receptor protein in STING1-mediated reticulophagy. Mechanistically, SEC62 strengthens its interaction with STING1 upon activation and concurrently facilitates STING1-mediated reticulophagy upon starvation, which are dependent on ATP2A2. Furthermore, knocking down SEC62 in WT cells inhibits STING1-mediated MAP1LC3B/LC3B lipidation and autophagosome formation, an effect that is lost in ATP2A2 knockout cells, suggesting that SEC62’s role in STING1-mediated selective autophagy is ATP2A2 dependent. Thus, our findings identify the reticulophagy receptor SEC62 as a novel receptor protein regulating STING1-mediated selective autophagy, providing new insight into the mechanism regarding a reticulophagy receptor in the process of STING1-induced selective autophagy.Abbrevations: aa: amino acids; AP-MS: affinity tag purification-mass spectrometry; ATP2A1: ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 1; ATP2A2: ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2; ATP2A3: ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 3; CANX: calnexin; CCPG1: cell cycle progression 1; CGAS: cyclic GMP-AMP synthase; ctDNA: calf thymus DNA; dsRNA: double-stranded RNA; diABZI: diamidobenzimidazole; ER: endoplasmic reticulum; ERGIC: ER-Golgi intermediate compartment; EBSS: Earle’s Balanced Salt Solution; EV: empty vector; FL: full length; GOLGA2/GM130: golgin A2; HSV-1: herpes simplex virus type 1; IRF3: interferon regulatory factor 3; IFNs: type I interferons; ISD: interferon stimulatory DNA; KO: knockout; MAVS: mitochondrial antiviral signaling protein; MOI: multiplicity of infection; poly(I:C): polyinosinic-polycytidylic acid; NBR1: NBR1 autophagy cargo receptor; PRR: pattern recognition receptor; reticulophagy: selective autophagic degradation of the ER; RETREG1/FAM134B: reticulophagy regulator 1; RIGI: RNA sensor RIG-I; RTN3L: reticulon 3; SEC62: SEC62 homolog, preprotein translocation factor; SeV: Sendai virus; STIM1: stromal interaction molecule 1; STING1/MITA: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TEX264: testis expressed 264, ER-phagy receptor; TMX1: thioredoxin related transmembrane protein 1; VSV: vesicular stomatitis virus; VACV: vaccinia virus; ZMPSTE24: zinc metallopeptidase STE24.
研究领域:
免疫学
·
细胞生物学
·
病毒学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Pharmaceutical Analysis
·
2024
·
IF 6.1
Caiyi Yang,Kehan Chen,Yunliang Chen,Xuting Xie,Pengcheng Li,Meng Zhao,Junjie Liang,Xueqian Xie,Xiaoyun Chen,Yanping Cai,Bo Xu,Qing Wang,Lian Zhou,Xia Luo
The incomplete degradation of tumour cells by macrophages (Mφ) is a contributing factor to tumour progression and metastasis, and the degradation function of Mφ is mediated through phagosomes and lysosomes. In our preliminary experiments, we found that overactivation of NADPH oxidase 2 (NOX2) reduced the ability of Mφ to degrade engulfed tumour cells. Above this, we screened out liquiritin from Glycyrrhiza uralensis Fisch , which can significantly inhibit NOX2 activity and inhibit tumours, to elucidate that suppressing NOX2 can enhance the ability of Mφ to degrade tumour cells. We found that the tumour environment could activate the NOX2 activity in Mφ phagosomes, causing Mφ to produce excessive reactive oxygen species (ROS), thus prohibiting the formation of phagolysosomes before degradation. Conversely, inhibiting NOX2 in Mφ by liquiritin can reduce ROS and promote phagosome-lysosome fusion, therefore improving the enzymatic degradation of tumour cells after phagocytosis, and subsequently promote T cell activity by presenting antigens. We further confirmed that liquiritin down-regulated the expression of the NOX2 specific membrane component protein gp91 phox, blocking its binding to the NOX2 cytoplasmic component proteins p67 phox and p47 phox, thereby inhibiting the activity of NOX2. This study elucidates the specific mechanism by which Mφ cannot degrade tumour cells after phagocytosis, and indicates that liquiritin can promote the ability of Mφ to degrade tumour cells by suppressing NOX2.
研究领域:
免疫学
·
癌症生物学
·
细胞生物学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
DEVELOPMENTAL CELL
·
2023
·Vol. 58
·期 23
·2746-2760
·
IF 11.8
Puri C,Gratian MJ,Rubinsztein DC
The sequence of morphological intermediates that leads to mammalian autophagosome formation and closure is a crucial yet poorly understood issue. Previous studies have shown that yeast autophagosomes evolve from cup-shaped phagophores with only one closure point, and mammalian studies have inferred that mammalian phagophores also have single openings. Our superresolution microscopy studies in different human cell lines in conditions of basal and nutrient-deprivation-induced autophagy identified autophagosome precursors with multifocal origins that evolved into unexpected finger-like phagophores with multiple openings before becoming more spherical structures. Compatible phagophore structures were observed with whole-mount and conventional electron microscopy. This sequence of events was visualized using advanced SIM 2 superresolution live microscopy. The finger-shaped phagophore apertures remained open when ESCRT function was compromised. The efficient closure of autophagic structures is important for their release from the recycling endosome. This has important implications for understanding how autophagosomes form and capture various cargoes.
研究领域:
细胞生物学
·
分子生物学
·
显微镜技术
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Immunology
·
2019
·
IF 4.716
Wu Liting,Kong Linghe,Yang Yanjian,Bian Xia,Wu Siwei,Li Bingxi,Yin Xiaoxue,Mu Liangliang,Li Jun,Ye Jianmin
Teleost B cells have phagocytic activities for ingesting particulate antigens, such as bacteria, in addition to the functional secretion of immunoglobulins (Igs). In the present study, the phagocytic activities of IgM+ B cells under various differentiational conditions residing in peripheral blood leukocytes were investigated in a teleost fish Nile tilapia (Oreochromis niloticus). The IgM+ B cells were recognized as IgMlo or IgMhi subsets based on their membrane IgM (mIgM) levels. The mIgM, secreted IgM (sIgM), major histocompatibility complex class II and reactive oxygen species were detected. Expressions of transcription factors (Pax5 and Blimp-1) and B cell signaling molecules (CD79a, CD79b, BLNK, and LYN) suggested that IgMlo B cells were resembling as plasma-like cells and IgMhi resembling as naïve/mature B cells, respectively. Analysis of phagocytic activities demonstrated that both IgMlo and IgMhi B cells have a similar phagocytic ability (phagocytosis percentage); however, the phagocytic capacity [phagocytic index and the mean fluorescence intensity (MFI)] of IgMhi B cells was significantly higher than that of IgMlo B cells. Taken together, the results indicated that B cell differentiation may cause the decrease of phagocytic capacity but not phagocytic ability of phagocytic IgM+ B cells in teleost. The finding may provide an evolutionary evidence for understanding the greater specialization of the B cell in more sophisticated adaptive humoral immunity, by decreasing phagocytic activity in order to contribute its function more specifically into antibody-secreting.
研究领域:
免疫学
·
海洋生物学
·
细胞生物学
·
进化生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2022
·Vol. 13
·期 1
·1-22
·
IF 17.694
Zhou Tian,Li Yuxin,Li Xiaoyu,Zeng Fanzhuo,Rao Yanxia,He Yang,Wang Yafei,Liu Meizhen,Li Dali,Xu Zhen,Zhou Xin,Du Siling,Niu Fugui,Peng Jiyun,Mei Xifan,Ji Sheng-Jian,Shu Yousheng,Lu Wei,Guo Feifan,Wu Tianzhun,Yuan Ti-Fei,Mao Ying,Peng Bo
Microglia are important immune cells in the central nervous system (CNS) that undergo turnover throughout the lifespan. If microglial debris is not removed in a timely manner, accumulated debris may influence CNS function. Clearance of microglial debris is crucial for CNS homeostasis. However, underlying mechanisms remain obscure. We here investigate how dead microglia are removed. We find that although microglia can phagocytose microglial debris in vitro, the territory-dependent competition hinders the microglia-to-microglial debris engulfment in vivo. In contrast, microglial debris is mainly phagocytosed by astrocytes in the brain, facilitated by C4b opsonization. The engulfed microglial fragments are then degraded in astrocytes via RUBICON-dependent LC3-associated phagocytosis (LAP), a form of noncanonical autophagy. Interference with C4b-mediated engulfment and subsequent LAP disrupt the removal and degradation of microglial debris, respectively. Together, we elucidate the cellular and molecular mechanisms of microglial debris removal in mice, extending the knowledge on the maintenance of CNS homeostasis.
研究领域:
神经科学
·
免疫学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small
·
2023
·Vol. 19
·期 23
·2207360
·
IF 13.3
Weiwei Zhang,Yuguo Deng,Jinhao Zhao,Tao Zhang,Xiang Zhang,Wenping Song,Lin Wang,Tianlong Li
Nature provides a successful evolutionary direction for single-celled organisms to solve complex problems and complete survival tasks – pseudopodium. Amoeba, a unicellular protozoan, can produce temporary pseudopods in any direction by controlling the directional flow of protoplasm to perform important life activities such as environmental sensing, motility, predation, and excretion. However, creating robotic systems with pseudopodia to emulate environmental adaptability and tasking capabilities of natural amoeba or amoeboid cells remains challenging. Here, this work presents a strategy that uses alternating magnetic fields to reconfigure magnetic droplet into Amoeba-like microrobot, and the mechanisms of pseudopodia generation and locomotion are analyzed. By simply adjusting the field direction, microrobots switch in monopodia, bipodia, and locomotion modes, performing all pseudopod operations such as active contraction, extension, bending, and amoeboid movement. The pseudopodia endow droplet robots with excellent maneuverability to adapt to environmental variations, including spanning 3D terrains and swimming in bulk liquids. Inspired by the “Venom,” the phagocytosis and parasitic behaviors have also been investigated. Parasitic droplets inherit all the capabilities of amoeboid robot, expanding their applicable scenarios such as reagent analysis, microchemical reactions, calculi removal, and drug-mediated thrombolysis. This microrobot may provide fundamental understanding of single-celled livings, and potential applications in biotechnology and biomedicine.
研究领域:
生物医学工程
·
仿生学
·
微纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2022
·
IF 8.039
Wen Song,Fan Yang,Hang Yang,Yi Xu,Shu-Jun Song,Yan Meng,Si-Tian Wei,Tao Wan,Ying Zhou,Bin Zhou,Jing Kuang,Tao Yu,Wen-Xiu Qiu
Compared to the activation of acquired immunity by the immune checkpoint blockade, the activation of innate immunity via anti-phagocytosis checkpoint blockade could significantly increase the beneficiary population of immunotherapy. However, the activation of innate immunity and the occurrence of phagocytosis are only accomplished when the interaction between pro-phagocytosis signals and anti-phagocytosis signals is realized. Herein, a versatile nanoplatform (DHMR) based on mesoporous silicon nanoparticles (MSNPs) has been constructed. Two drugs, doxorubicin, a chemotherapeutic drug which could initiate tumor cells to release pro-phagocytosis signals, and RRx-001, an immunoadjuvant that could effectively implement the anti-phagocytosis checkpoint blockade, were loaded in MSNPs. Further decoration of hyaluronic acid encapsulation endows DHMR with the function of tumor targeting and long circulation. Ultimately, the DHMR system could efficiently and accurately target tumor tissue, release the drugs in the tumor microenvironment, achieve the activation of innate immunity, and finally dramatically inhibit the growth and metastasis of tumor cells.
研究领域:
肿瘤学
·
免疫疗法
·
纳米技术
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2025
·
IF 26.8
Hua Huang,Qi-Song Tong,Jing-Yang Zhang,Wei-Min Miao,Hui-Han Yu,Jun Wang,Song Shen,Jin-Zhi Du
The phagocytosis of macrophages to tumor cells represents an alluring strategy for cancer immunotherapy; however, its effectiveness is largely hindered by the detrimental upregulation of anti-phagocytic signals and insufficient expression of pro-phagocytic signals of tumor cells. Here, a pro-phagocytic polymer-based nanocomplex is designed to promote the macrophage engulfment of tumor cells through concurrent modulation of both the “eat me” and “don't eat me” signals. The nanocomplex MNC CD47i-CALRt is formed by complexing a synthetic PAMAM derivative (G4P–C7A) that is capable of intrinsically inducing the exposure of calreticulin (CALR, a crucial pro-phagocytic protein) and a small inference RNA that can inhibit the expression of CD47 (a primary anti-phagocytic protein). MNC CD47i-CALRt can significantly delay tumor growth and prolong the survival of tumor-bearing mice with negligible hematopoietic toxicity in multiple murine colorectal cancer models. Furthermore, the pro-phagocytic capacity of MNC CD47i-CALRt is validated in the patient-derived tumor organoid model. Collectively, the phagocytosis-promoting nanocomplex provides a simple and potent strategy for boosting macrophage-mediated cancer immunotherapy.
研究领域:
肿瘤学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
American Journal of Translational Research
·
2017
·
IF 2.829
Yuanfeng Zhu,Shijun Fan,Ning Wang,Xiaoli Chen,Yongjun Yang,Yongling Lu,Qian Chen,Jiang Zheng,Xin Liu
Activation of NADPH oxidase 2 (NOX2) triggers reactive oxygen species (ROS) generation, both of which are essential for robust microbial clearance by phagocytes. However, it is unknown whether inhibition of NOX2 activation or ROS generation affects cellular phagocytosis. Here, we found that the classic NOX2 inhibitor diphenyleneiodonium (DPI) induced uptake of E. coli by murine peritoneal macrophages through enhancing phagocytosis, and this effect was temperature-sensitive and attenuated by cytochalasin D as well as chemical inhibition of Syk and PLCγ, two downstream kinases involved in actin polymerization during phagocytosis. DPI also decreased the production of TNF-α and IL-6 resulting from E. coli stimulation. The DPI-induced enhancement of phagocytosis was independent of NOX2 inhibition or ROS generation but depended on increased intracellular calcium and activation of the p38 MAPK signaling pathway. Furthermore, DPI enhanced bacterial elimination and ameliorated inflammation in E. coli -infected mice, leading to improved survival. Our results demonstrate that DPI facilitates ROS-independent bacterial phagocytosis by macrophages through activation of calcium and p38 MAPK signaling pathways.
研究领域:
免疫学
·
分子生物学
·
医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2021
·
IF 6.953
Can Song,Feihong Huang,Linyu Liu,Quan Zhou,Dan Zhang,Qi Fang,Hui Lei,Hong Niu
Pectins have proven to be advantageous for human health as they regulate beneficial microbial communities and enhance immunity. The fruit of Clausena lansium (Lour.) Skeels (Wampee), also referred to as “treasure in fruit”, is rich in pectin polysaccharides . In this study, a homogalacturonan-type pectin (CCP2) with a molecular weight of 8.9 × 10 4 Da and degree of esterification of 42.86% was isolated from Wampee fruit. The gut microbiota regulation and phagocytosis-enhancing properties of CCP2 were examined in vivo and in vitro, respectively. Oral administration of CCP2 dramatically decreased the abundance of Bacteroidetes and increased the abundance of Firmicutes in intestinal bacteria in mice. The content of short-chain fatty acids in the feces also significantly improved. Moreover, CCP2 exhibited excellent phagocytosis-enhancing activities on RAW 264.7 macrophages. These results suggested that CCP2 could be a potential gut microbiota regulator and phagocytosis-enhancer, which could be used in food products to promote health through beneficial manipulation of gut microbiota.
研究领域:
食品科学
·
微生物学
·
营养学
✓ 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）