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TREM-2 Drives Development of Multiple Sclerosis by Promoting Pathogenic Th17 Polarization

Neuroscience Bulletin 2024年第1期40卷 17-34页

作者： Siying Qu Shengfeng Hu Huiting Xu Yongjian Wu siqi ming Xiaoxia Zhan Cheng Wang Xi Huang Center for Infection and Immunity and Guangdong Provincial Engineering Research Center of Molecular Imaging The Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhai 519000China The State Key Laboratory of Respiratory Disease Guangdong Provincial Key Laboratory of Allergy and Clinical ImmunologyThe Second Affiliated HospitalGuangzhou Medical UniversityGuangzhou 510260China Department of Laboratory Medicine The First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510080China Division of Nephrology Department of Medicinethe Fifth Affliated Hospital of Sun Yat-sen UniversityZhuhai 519000China

Multiple sclerosis(MS)is a neuroinflammatory demyelinating disease,mediated by pathogenic T helper 17(Th17)***,the therapeutic effect is accompa-nied by the fluctuation of the proportion and function of Th17 cells,which prompted us to find the key regulator of Th17 differentiation in ***,we demonstrated that the triggering receptor expressed on myeloid cells 2(TREM-2),a modulator of pattern recognition receptors on innate immune cells,was highly expressed on pathogenic CD4-positive T lymphocyte(CD4^(+)T)cells in both patients with MS and experimental autoimmune encephalomyelitis(EAE)mouse *** knockout of Trem-2 in CD4^(+)T cells significantly alleviated the disease activity and reduced Th17 cell infiltration,activation,differentiation,and inflammatory cytokine production and secretion in EAE ***,with Trem-2 knockout in vivo experiments and in vitro inhibitor assays,the TREM-2/zeta-chain associated protein kinase 70(ZAP70)/signal transducer and activator of transcription 3(STAT3)signal axis was essential for Th17 activation and differentiation in EAE *** conclusion,TREM-2 is a key regulator of pathogenic Th17 in EAE mice,and this sheds new light on the potential of this therapeutic target for MS.

关键词： Multiple sclerosis Experimental autoimmune encephalomyelitis T helper 17 Triggering receptor expressed on myeloid cells 2

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GITR exacerbates lysophosphatidylcholine-induced macrophage pyroptosis in sepsis via posttranslational regulation of NLRP3

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Cellular & Molecular Immunology 2024年第7期21卷 674-688页

作者： Siping Liang Jinyu Zhou Can Cao Yiting Liu siqi ming Xi Liu Yuqi Shang Juanfeng Lao Qin Peng Jiahui Yang Minhao Wu Zhongshan School of Medicine Sun Yat-sen UniversityGuangzhouChina Key Laboratory of Tropical Disease Control(Sun Yat-sen University) Ministry of EducationGuangzhouChina Department of Infectious Diseases The Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhaiChina

The NLRP3 inflammasome functions as an inflammatory driver,but its relationship with lipid metabolic changes in early sepsis remains ***,we found that GITR expression in monocytes/macrophages was induced by lysophosphatidylcholine(LPC)and was positively correlated with the severity of *** is a costimulatory molecule that is mainly expressed on T cells,but its function in macrophages is largely *** in vitro data showed that GITR enhanced LPC uptake by macrophages and specifically enhanced NLRP3 inflammasome-mediated macrophage ***,in vivo studies using either cecal ligation and puncture(CLP)or LPS-induced sepsis models demonstrated that LPC exacerbated sepsis severity/lethality,while conditional knockout of GITR in myeloid cells or NLRP3/caspase-1/IL-1βdeficiency attenuated sepsis severity/***,GITR specifically enhanced inflammasome activation by regulating the posttranslational modification(PTM)of *** competes with NLRP3 for binding to the E3 ligase MARCH7 and recruits MARCH7 to induce deacetylase SIRT2 degradation,leading to decreasing ubiquitination but increasing acetylation of ***,these findings revealed a novel role of macrophage-derived GITR in regulating the PTM of NLRP3 and systemic inflammatory injury,suggesting that GITR may be a potential therapeutic target for sepsis and other inflammatory diseases.

关键词： GITR Macrophage NLRP3 inflammasome Sepsis Posttranslational modification

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Tetrahedral DNA nanostructures synergize with MnO_(2) to enhance antitumor immunity via promoting STING activation and M1 polarization

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2494-2505页

作者： Siping Liang Jiaying Li Zhengyu Zou Miao Mao siqi ming Fan Lin Ziyan Zhang Can Cao Jinyu Zhou Yuanqing Zhang Jiaping Li Minhao Wu Zhongshan School of Medicine Sun Yat-sen UniversityGuangzhou 510080China Department of Laboratory Medicine Guangdong Second Provincial General HospitalGuangzhou 510317China Guangdong Key Laboratory of Chiral Molecule and Drug Discovery School of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China Department of Interventional Oncology The First Afﬁliated HospitalSun Yat-sen UniversityGuangzhou 510080China

Stimulator of interferon genes(STING) is a cytosolic DNA sensor which is regarded as a potential target for antitumor immunotherapy. However, clinical trials of STING agonists display limited anti-tumor effects and dose-dependent side-effects like inflammatory damage and cell toxicity. Here,we showed that tetrahedral DNA nanostructures(TDNs) actively enter macrophages to promote STING activation and M1 polarization in a size-dependent manner, and synergized with Mn^(2+) to enhance the expressions of IFN-β and iNOS, as well as the co-stimulatory molecules for antigen presentation. Moreover, to reduce the cytotoxicity of Mn^(2+),we constructed a TDN-MnO_(2) complex and found that it displayed a much higher efficacy than TDN plus Mn^(2+) to initiate macrophage activation and anti-tumor response both in vitro and in vivo. Together, our studies explored a novel immune activation effect of TDN in cancer therapy and its synergistic therapeutic outcomes with MnO_(2).These findings provide new therapeutic opportunities for cancer therapy.

关键词： Tetrahedral DNA nanostructure Manganese MnO_(2) STING M1 polarization Antigen presentation Anti-tumor immunity Cancer therapy

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L-citrulline and L-glutamine combination based on the plasma metabolomic of COVID-19 asymptomatic patients protects from coronavirus infection

L-citrulline and L-glutamine combination based on the plasma...

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第十四届全国免疫学学术大会

作者： siqi ming Siying Qu Yongjian Wu Jiayou Wei Hong Shan Xi Huang The Fifth Affiliated Hospital of Sun Yat-sen University

The outbreak of coronavirus disease 2019(COVID-19) has caused a worldwide pandemic since *** disorder is a contributing factor to deaths from COVID-1 ***,the underlying mechanism of metabolic dysfunction in COVID-1 9 patients and the potential interventions are not *** we performed targeted plasma metabolomic and compared the metabolite profiles among healthy controls,asymptomatic,moderate and severe COVID-19 *** the altered metabolites,arachidonic acid and linolenic acid pathway metabolites were profoundly up-regulated in COVID-1 9 *** biosynthesis,alanine,asparate and glutamate metabolism pathways were significantly disturbed in asymptomatic *** the comparison of metabolite variances among the groups,higher levels of L-citrulline and L-glutamine were found in asymptomatic carriers and moderate or severe patients at remission ***,the effectively protective effect of L-citrulline and L-glutamine combination was confirmed in coronavirus-infected mice and endotoxin-induced septic ***,our data reveals the metabolite profile of asymptomatic patients and proposes a potential strategy for COVID-19 treatment via the combined supplementation of L-citrulline and L-glutamine.

关键词： COVID-19 metabolomic asymptomatic patients L-citrulline L-glutamine

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SLAMF7 Regulates Inflammatory Response In Macrophage During Polymicrobial Sepsis

SLAMF7 Regulates Inflammatory Response In Macrophage During ...

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第十四届全国免疫学学术大会

作者： Yongjian Wu Juanfeng Lao Miao Li Minhao Wu siqi ming Lei Liu Sitang Gong Haibo Zhou Xi Huang Center for Infection and Immunity and Guangdong Provincial Key Laboratory of Biomedical Imaging the Fifth Affiliated Hospital of Sun Yat-sen University National Clinical Research Center for Infectious Disease Shenzhen Third People's Hospital Guangzhou Women and Children's Medical Center Guangzhou Institute of Pediatrics Guangzhou Medical University The Sixth Affiliated Hospital of Guangzhou Medical University Qingyuan People's Hospital

Uncontrolled microbe-triggered inflammation Results in multiple organ injury and shock in sepsis. However, the regulatory mechanisms that restrict cytokine storm are still elusive. Using gene screening, we identified an immunoglobulin-like receptor called Signaling Lymphocyte Activation Molecular Family-7(SLAMF7), as a key regulator of inflammation during sepsis. We found that the expression of SLAMF7 on monocytes and macrophages was significantly elevated in sepsis subjects and septic mice. SLAMF7 attenuated TLR dependent MAPKs and NF-κB signaling activation by co-operating with Src homology 2-containing inositol-5’-phosphatase1(SHIP1). Furthermore, SLAMF7 interacted with SHIP1 and TNF receptor associated factor 6(TRAF6) to inhibited K63 ubiquitination of TRAF6. In addition, we found that intracellular domain tyrosine phosphorylation sites of SLAMF7 and phosphatase domain of SHIP1 were indispensable for the interaction of SLAMF7/SHIP1/TRAF6 and the modulation of cytokines production. Finally, recombinant murine SLAMF7 peptide agonist or genetic knockout of SLAMF7 in mice demonstrated that SLAMF7 conferred protection against lethal sepsis and endotoxemia by suppressing inflammatory cytokines. Taken together, our findings reveal a critical negative regulatory role of SLAMF7 on cytokine storm in macrophages during polymicrobial sepsis, and therefore provide new sights into a novel diagnostic marker and therapeutic target for sepsis.

关键词： Sepsis SLAMF7 Inflammatory cytokines SHIP1 TRAF6

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TREM-2 is a sensor and activator of T cell response in SARS-CoV-2 infection

TREM-2 is a sensor and activator of T cell response in SARS-...

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第十四届全国免疫学学术大会

作者： Yongjian Wu Manni Wang Huan Yin siqi ming Xingyu Li Guangmin Jiang Ye Liu Peihui Wang Guangde Zhou Sitang Gong Haibo Zhou Hong Shan Xi Huang The Fifth Affiliated Hospital of Sun Yat-sen University Cheeloo College of Medicine Shandong University Shenzhen Third People's Hospital the Second Affiliated Hospital of Southern University of Science and Technology Guangzhou Women and Children's Medical Center Guangzhou Medical University The Sixth Affiliated Hospital of Guangzhou Medical University Qingyuan People's Hospital

The lack of understanding of T cell responses against SARS-CoV-2, largely impedes the vaccine development and drug discovery of coronavirus disease 2019(COVID-19). Here we identified that triggering receptor expressed on myeloid cells 2(TREM-2) was induced on blood and lung infiltrating T cells of COVID-19 patients. Importantly, TREM-2 bound to SARS-CoV-2 membrane(M) protein through immunoglobulin domain. Subsequently, TREM-2 interacted and activated CD3ζ/ZAP70 complex, leading to STAT1 phosphorylation and T-bet transcription. In vitro stimulation with M protein reconstituted pseudovirus, TREM-2 promoted Th1 cytokines IFN-γ and TNF produced by T cells. In vivo infection of TREM-2-CD4 conditional knockout mice with murine coronavirus mouse hepatitis virus A-59 showed that intrinsic TREM-2 in T cells enhanced Th1 response and viral clearance, thus aggravating the destruction of lung. Taken together, these findings identified a novel role of TREM-2 in SARS-CoV-2 infection, which may provide potential strategies for drug discovery and clinical management of COVID-19.

关键词： SARS-CoV-2 TREM-2 T cell

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One-pot photoreduction to prepare NIR-absorbing plasmonic gold nanoparticles tethered by amphiphilic polypeptide copolymer for synergistic photothermal-chemotherapy

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Chinese Chemical Letters 2019年第1期30卷 187-191页

作者： siqi Yang Linzhu Zhou Yue Su Rong Zhang Chang-ming Dong School of Chemistry and Chemical Engineering Shanghai Key Laboratory of Electrical Insulation and Thermal Aging Shanghai Jiao Tong University Joint Research Center for Precision Medicine Shanghai Jiao Tong University Affiliated Sixth People's Hospital South Campus Shanghai Fengxian Central Hospital

We developed one-pot photoreduction strategy to prepare near infrared light(NIR)-absorbing plasmonic gold nanoparticles(Au NPs) tethered by amphiphilic polypeptide copolymer poly(L-cysteine)-b-poly(ethylene oxide)(PLC-b-PEO). The PLC-b-PEO@Au NPs possessed strong NIR absorption at 700–1100 nm and ultrahigh photothermal conversion efficiency of 62.1%. Upon the NIR irradiation(808nm,2 W/cm^2,5 min), the PLC-b-PEO@Au NPs(1mg/mL) sharply attained an elevation of 30.8℃ and the hyperthermia effect could efficiently kill cancer cells in vitro. As for the PT-CT treatment, the doxorubicin(DOX)-loaded nanoparticles of DOX-PLC-b-PEO@Au NPs gave a combination index of 0.9 compared to single chemotherapy(CT) or photothermal therapy(PT), demonstrating a synergistic effect.

关键词： Near infrared Plasmonic gold nanoparticles Polypeptide Photothermal therapy Combination therapy

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Residual Stress Removal Under Pulsed Electric Current

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Acta Metallurgica Sinica(English Letters) 2020年第2期33卷 281-289页

作者： siqi Xiang Xinfang Zhang State Key Laboratory of Advanced Metallurgy School of Metallurgical and Ecological EngineeringUniversity of Science and Technology BeijingBeijing 100083China

The effect of a pulsed electric current on the residual stress evolution of metal materials has been *** was found that the surface and internal residual stresses in the as-quenched samples were reduced dramatically by electropulsing.A large number of experimental data show that the residual stress reduction is proportional to the initial residual stress and related to the material properties and electropulsing *** the combined actions of drift electrons,Joule heating,and residual stress,the dislocation mobility was enhanced,resulting in plastic strain and the decrease in residual *** electrons played a unique role in the electropulsing treatment,acting as an additional force pushing dislocations *** dislocations ultimately accumulated at a grain boundary,forming a parallel ***,the phenomenological equation of the residual stress evolution under electropulsing was derived from the experimental data.

关键词： Electroplastic Residual stress Dislocation movement Phenomenological equation

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Metasurface for highly-efficient on-chip classical and quantum all-optical modulation

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Light(Science & Applications) 2022年第9期11卷 1952-1953页

作者： siqi yan Jianji Dong Wuhan National Laboratory for Optoelectronics School of Optical and Electronic InformationHuazhong University of Science and TechnologyWuhanChina

Metasurface made of artificially two-dimensional structured subwavelength-scaled nanostructures gives rise to unprecedented efficient way to realize on-chip all-optical modulation,in both classical regime and quantum ... 详细信息

关键词： quantum surface classical

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Wide Area Analytics for Geographically Distributed Datacenters

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Tsinghua Science and Technology 2016年第2期21卷 125-135页

作者： siqi Ji Baochun Li the Department of Electrical and Computer Engineering University of TorontoToronto M5S 3G4Canada.

Big data analytics, the process of organizing and analyzing data to get useful information, is one of the primary uses of cloud services today. Traditionally, collections of data are stored and processed in a single datacenter. As the volume of data grows at a tremendous rate, it is less efficient for only one datacenter to handle such large volumes of data from a performance point of view. Large cloud service providers are deploying datacenters geographically around the world for better performance and availability. A widely used approach for analytics of gee-distributed data is the centralized approach, which aggregates all the raw data from local datacenters to a central datacenter. However, it has been observed that this approach consumes a significant amount of bandwidth, leading to worse performance. A number of mechanisms have been proposed to achieve optimal performance when data analytics are performed over geo-distributed datacenters. In this paper, we present a survey on the representative mechanisms proposed in the literature for wide area analytics. We discuss basic ideas, present proposed architectures and mechanisms, and discuss several examples to illustrate existing work. We point out the limitations of these mechanisms, give comparisons, and conclude with our thoughts on future research directions.

关键词： big data analytics geo-distributed datacenters

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