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Fatty acid desaturation by stearoyl-CoA desaturase-1 controls regulatory T cell differentiation and autoimmunity

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Cellular & Molecular Immunology 2023年第6期20卷 666-679页

作者： Elien Grajchen Melanie Loix Paulien Baeten Beatriz F.Côrte-Real Ibrahim Hamad Sam Vanherle Mansour Haidar Jonas Dehairs Jelle Y.Broos James M.Ntambi Robert Zimmermann Rolf Breinbauer Piet Stinissen Niels Hellings Sanne G.S.Verberk Gijs Kooij Martin Giera Johannes V.Swinnen Bieke Broux Markus Kleinewietfeld Jerome J.A.Hendriks Jeroen F.J.Bogie Department of Immunology and Infection Biomedical Research InstituteHasselt UniversityDiepenbeekBelgium University MS Center Hasselt PeltBelgium Neuro-Immune Connections and Repair Lab Department of Immunology and InfectionBiomedical Research InstituteHasselt UniversityDiepenbeekBelgium vib laboratory of translational immunomodulation VIB Center for Inflammation ResearchHasselt UniversityDiepenbeekBelgium Department of Oncology Laboratory of Lipid Metabolism and CancerLKI–Leuven Cancer InstituteKU Leuven-University of LeuvenLeuvenBelgium Department of Molecular Cell Biology and Immunology Amsterdam University Medical CenterVrije Universiteit AmsterdamAmsterdam NeuroscienceMS Center AmsterdamAmsterdamThe Netherlands Center for Proteomics and Metabolomics Leiden University Medical CenterLeidenThe Netherlands Department of Biochemistry Department of Nutritional SciencesUniversity of Wisconsin-MadisonMadisonUSA Institute of Molecular Biosciences University of GrazGrazAustria BioTechMed-Graz GrazAustria Institute of Organic Chemistry Graz University of TechnologyGrazAustria Cardiovascular Research Institute Maastricht Department of Internal MedicineMaastricht UniversityMaastrichtThe Netherlands

The imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis(MS).Emerging evidence indicates that endogenous and dietary-induced changes in fatty acid metabolism have a major impact on both T cell fate and *** date,however,the molecular mechanisms that underlie the impact of fatty acid metabolism on T cell physiology and autoimmunity remain poorly ***,we report that stearoyl-CoA desaturase-1(SCD1),an enzyme essential for the desaturation of fatty acids and highly regulated by dietary factors,acts as an endogenous brake on regulatory T-cell(Treg)differentiation and augments autoimmunity in an animal model of MS in a T cell-dependent *** by RNA sequencing and lipidomics analysis,we found that the absence of Scd1 in T cells promotes the hydrolysis of triglycerides and phosphatidylcholine through adipose triglyceride lipase(ATGL).ATGL-dependent release of docosahexaenoic acid enhanced Treg differentiation by activating the nuclear receptor peroxisome proliferator-activated receptor *** findings identify fatty acid desaturation by SCD1 as an essential determinant of Treg differentiation and autoimmunity,with potentially broad implications for the development of novel therapeutic strategies and dietary interventions for autoimmune disorders such as MS.

关键词： Regulatory T cells Autoimmunity Fatty acid metabolism Stearoyl-CoA desaturase-1 Multiple sclerosis

Insm1 regulates mTEC development and immune tolerance

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Cellular & Molecular Immunology 2023年第12期20卷 1472-1486页

作者： Weihua Tao Zhihuan Ye Yiqiu Wei Jianxue Wang Weixin Yang Guoxing Yu Jieyi Xiong Shiqi Jia The First Affiliated Hospital of Jinan University GuangzhouChina The Guangdong-Hong Kong-Macao Joint University laboratory of Metabolic and Molecular Medicine Jinan UniversityGuangzhouChina The Institute of Clinical Medicine Jinan UniversityGuangzhouChina Key Lab of Guangzhou Basic and translational Research of Pan-Vascular Diseases GuangzhouChina Max Delbrück Center for Molecular Medicine in the Helmholtz Association BerlinGermany vib-KU Leuven Center for Cancer Biology LeuvenBelgium

The expression of self-antigens in medullary thymic epithelial cells(mTECs)is essential for the establishment of immune tolerance,but the regulatory network that controls the generation and maintenance of the multitude of cell populations expressing self-antigens is poorly ***,we show that Insm1,a zinc finger protein with known functions in neuroendocrine and neuronal cells,is broadly coexpressed with an autoimmune regulator(Aire)in ***1 expression is undetectable in most mimetic cell populations derived from mTECs but persists in neuroendocrine mimetic *** of Insm1 in mice downregulated Aire expression,dysregulated the gene expression program of mTECs,and altered mTEC subpopulations and the expression of tissue-restricted *** with these findings,loss of Insm1 resulted in autoimmune responses in multiple peripheral *** found that Insm1 regulates gene expression in mTECs by binding to ***,the majority of the Insm1 binding sites are co-occupied by Aire and enriched in superenhancer ***,our data demonstrate the important role of Insm1 in the regulation of the repertoire of self-antigens needed to establish immune tolerance.

关键词： Medullary thymic epithelial cells(mTECs) Mimetic cells Tissue-restricted antigens(TRAs) Insulinoma-associated protein 1(lnsm1) Autoimmunity Autoimmune regulator(Aire)

Smad1/5/8 are myogenic regulators of murine and human mesoangioblasts

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Journal of Molecular Cell Biology 2016年第1期8卷 73-87页

作者： Domiziana Costamagna Mattia Quattrocelli Florence van Tienen Lieve Umans Irineus FMde Coo An Zwijsen Danny Huylebroeck Maurilio Sampaolesi translational Cardiomyology laboratory Stem Cell Biology and EmbryologyDepartment of Development and RegenerationKU LeuvenLeuvenBelgium laboratory of Experimental Medicine and Clinical Pathology Department of Clinical and Biological SciencesUniversity of TurinTurinItaly Department of Clinical Genetics Maastricht University Medical CenterMaastrichtThe Netherlands laboratory for Developmental Signalling VIB Center for the Biology of DiseaseDepartment of Human GeneticsKU LeuvenLeuvenBelgium laboratory of Molecular Biology(Celgen) Department of Development and RegenerationKU LeuvenLeuvenBelgium Department of Neurology Erasmus MC-Sophia Children’s HospitalRotterdamThe Netherlands Department of Cell Biology Erasmus MCRotterdamThe Netherlands Division of Human Anatomy Department of Public HealthExperimental and Forensic MedicineUniversity of PaviaPaviaItaly

Mesoangioblasts(MABs)are vessel-associated stem cells that express pericyte marker genes and participate in skeletal muscle *** circuits that regulate the myogenic commitment of MABs are still poorly *** critical role of bone morphogenetic protein(BMP)signalling during proliferation and differentiation of adult myogenic precursors,such as satellite cells,has recently been *** whether BMP signalling impacts on the myogenic potential of embryonic and adult MABs both in vitro and in *** of BMP inhibited MAB myogenic differentiation,whereas interference with the interactions between BMPs and receptor complexes induced ***,siRNA-mediated knockdown of Smad8 in Smad1/5-null MABs or inhibition of SMAD1/5/8 phosphorylation with Dorsomorphin(DM)also improved myogenic differentiation,demonstrating a novel role of ***,using a transgenic mouse model of Smad8 deletion,we demonstrated that the absence of SMAD8 protein improved MAB myogenic ***,once injected into a-Sarcoglycan(Sgca)-null muscles,DM-treated MABs were more efficacious to restore a-sarcoglycan(aSG)protein levels and re-establish functional muscle ***,in acute muscle damage,DM-treated MABs displayed a better myogenic potential compared with BMP-treated and untreated ***,SMADs also control the myogenic commitment of human MABs(hMABs).BMP signalling antagonists are therefore novel candidates to improve the therapeutic effects of hMABs.

关键词： BMP signalling mesoangioblast pericytes skeletal muscle regeneration SMAD

A cellular hierarchy in melanoma uncouples growth and metastasis

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四川生理科学杂志 2022年第9期44卷 1633-1633页

作者： Panagiotis Karras laboratory for Molecular Cancer Biology Center for Cancer Biology VIB Leuven Belgium Department of Oncology KU Leuven Leuven Belgium Department of Applied Mathematics and Theoretical Physics Centre for Mathematical Sciences University of Cambridge Cambridge UK The Wellcome Trust/CRUK Gurdon Institute University of Cambridge Cambridge UK Department of General Medical Oncology UZ Leuven Leuven Belgium BGI-Shenzhen Shenzhen China vib BioImaging Core VIB Center for Brain and Disease Research Leuven Belgium vib Bioimaging Core VIB Center for Inflammation Research Ghent Belgium Department of Biomedical Molecular Biology Ghent University Ghent Belgium FACS Expertise Center Center for Cancer Biology VIB Leuven Belgium laboratory of Tumor Microenvironment and Therapeutic Resistance Center for Cancer Biology VIB Leuven Belgium Center for Brain & Disease Research VIB-KU Leuven Leuven Belgium Department of Human Genetics KU Leuven Leuven Belgium Data Mining and Modeling for Biomedicine Group VIB Center for Inflammation Research Ghent Belgium Department of Applied Mathematics Computer Science and Statistics Ghent University Ghent Belgium laboratory for translational Cell and Tissue Research Department of Imaging and Pathology KU Leuven Leuven Belgium laboratory of translational Genetics Center for Cancer Biology VIB Leuven Belgium laboratory of translational Genetics Center for Human Genetics KU Leuven Leuven Belgium Herbert Irving Comprehensive Center Columbia University Irving Medical Center New York USA laboratory of Stem Cells and Cancer Université Libre de Bruxelles (ULB) Brussels Belgium Wellcome Trust-MRC Stem Cell Institute University of Cambridge Cambridge UK

Although melanoma is notorious for its high degree of heterogeneity and plasticity1,2,the origin and magnitude of cell-state diversity remains poorly ***,it is unclear whether growth and metastatic dissemination are supported by overlapping or distinct melanoma ***,by combining mouse genetics,single-cell and spatial transcriptomics,lineage tracing and quantitative modelling,we provide evidence of a hierarchical model of tumour growth that mirrors the cellular and molecular logic underlying the cell-fate specification and differentiation of the embryonic neural *** show that tumorigenic competence is associated with a spatially localized perivascular niche,a phenotype acquired through an intercellular communication pathway established by endothelial *** with a model in which only a fraction of cells are fated to fuel growth,temporal single-cell tracing of a population of melanoma cells with a mesenchymal-like state revealed that these cells do not contribute to primary tumour growth but,instead,constitute a pool of metastatic initiating cells that switch cell identity while disseminating to secondary *** data provide a spatially and temporally resolved map of the diversity and trajectories of melanoma cell states and suggest that the ability to support growth and metastasis are limited to distinct pools of *** observation that these phenotypic competencies can be dynamically acquired after exposure to specific niche signals warrant the development of therapeutic strategies that interfere with the cancer cell reprogramming activity of such microenvironmental cues.

关键词： melanoma metastasis organs

BCL9 regulates CD226 and CD96 checkpoints in CD8^(+)T cells to improve PD-1 response in cancer

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Signal Transduction and Targeted Therapy 2021年第9期6卷 2883-2896页

作者： Mei Feng Zhongen Wu Yan Zhou Zhuang Wei Enming Tian Shenglin Mei Yuanyuan Zhu Chenglong Liu Fenglian He Huiyu Li Cao Xie Joy Jin Jibin Dong Dehua Yang Ker Yu Junbin Qian Diether Lambrechts Ming-Wei Wang Di Zhu Department of Pharmacology School of Basic Medical Sciences and School of PharmacyFudan UniversityShanghaiChina School of Pharmacy Fudan UniversityShanghaiChina Key laboratory of Systems Biology Innovation Center for Cell Signaling NetworkCAS Center for Excellence in Molecular Cell ScienceInstitute of Biochemistry and Cell BiologyShanghai Institutes for Biological SciencesChinese Academy of SciencesShanghaiChina Clinical translational Research Center Shanghai Pulmonary HospitalSchool of Life Science and TechnologyTongji UniversityShanghaiChina School of Medicine University of California at San FranciscoSan FranciscoCAUSA Department of Gynecologic Oncology Women's HospitalZhejiang University School of MedicineHangzhouChina vib Center for Cancer Biology and laboratory for translational Genetics Department of Human GeneticsKU LeuvenLeuvenBelgium School of Life Science and Technology ShanghaiTech UniversityShanghaiChina The National Center for Drug Screening and the CAS Key laboratory of Receptor Research Shanghai Institute of Materia MedicaChinese Academy of Sciences(CAS)ShanghaiChina Shanghai Engineering Research Center of Immune Therapy and Key laboratory of Smart Drug Delivery Fudan UniversityShanghaiChina

To date,the overall response rate of PD-1 blockade remains unsatisfactory,partially due to limited understanding of tumor immune microenvironment(TIME).B-cell lymphoma 9(BCL9),a key transcription co-activator of the Wnt pathway,is highly expressed in *** genetic depletion and pharmacological inhibition of BCL9 in tumors,we found that BCL9 suppression reduced tumor growth.

关键词： BCL tumor CD226

Impact of radiotherapy on the immune landscape in oesophageal adenocarcinoma

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World Journal of Gastroenterology 2022年第21期28卷 2302-2319页

作者： Noel E Donlon Maria Davern Fiona O'Connell Andrew Sheppard Aisling Heeran Anshul Bhardwaj Christine Butler Ravi Narayanasamy Claire Donohoe James J Phelan Niamh Lynam-Lennon Margaret R Dunne Stephen Maher Jacintha O'Sullivan John V Reynolds Joanne Lysaght Department of Surgery Trinity Translational Medicine InstituteSt James HospitalDublin D08Ireland

BACKGROUND In the contemporary era of cancer immunotherapy,an abundance of clinical and translational studies have reported radiotherapy(RT)and immunotherapies as a viable option for immunomodulation of many cancer subtypes,with many related clinical trials *** locally advanced disease,chemotherapy or chemoradiotherapy followed by surgical excision of the tumour remain the principal treatment strategy in oesophageal adenocarcinoma(OAC),however,the use of the host immune system to improve anti-tumour immunity is rapidly garnering increased support in the curative *** To immunophenotype OAC patients’immune checkpoint(IC)expression with and without radiation and evaluate the effects of checkpoint blockade on cell *** In the contemporary era of cancer immunotherapy,an abundance of studies have demonstrated that combination RT and IC inhibitors(ICIs)are effective in the immunomodulation of many cancer subtypes,with many related clinical trials *** surgical excision and elimination of tumour cells by chemotherapy or chemoradiotherapy remains the gold standard approach in OAC,the propagation of anti-tumour immune responses is rapidly garnering increased support in the curative *** aim of this body of work was to immunophenotype OAC patients’IC expression with and without radiation and to establish the impact of checkpoint blockade on cell *** study was a hybrid combination of in vitro and ex vivo *** of serum immune proteins was performed by enzyme-linked immunosorbent *** cytometry staining was performed to evaluate IC expression for in vitro OAC cell lines and ex vivo OAC *** viability in the presence of radiation with and without IC blockade was assessed by a cell counting kit-8 *** We identified that conventional dosing and hypofractionated approaches resulted in increased IC expression(PD-1,PD-L1,TIM3,TIGIT)in vitro and ex vivo in *** were two distinct subco

关键词： Oesophageal Cancer Radiotherapy Immunotherapy Immunology Surgery Oncology

Decrease of Peripheral Blood CD8+/CD28- Suppressor T Cell Followed by Dentritic Cells immunomodulation among Metastatic Breast Cancer Patients

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Chinese Journal of Cancer Research 2010年第4期22卷 310-315页

作者： Guo-hong Song Jun Ren Lijun Di Jing Yu Jie Zhang Bin Shao Jun Jia Wei Sun Key laboratory of Carcinogenesis and translational Research（Ministry of Education） Department of Medical Oncology Peking University Cancer Hospital ＆ Institute Beijing 100142 China

Objective： To explore the effects of dentritic cells on the peripheral blood lymphocyte subpopulations of metastatic breast cancer patients treated with chemotherapy. Methods： The current study involved 44 metastatic breast cancer patients treated with docetaxel-based chemotherapy. Among them, 25 cases were treated with dendritic cells derived from CD34＋ hematopoietic stem cells enriched autologous peripheral mononuclear cells after chemotherapy, and 19 cases received chemotherapy alone. Peripheral blood samples were collected from each patient before and after treatment, and lymphocyte subpopulations including CD3＋, CD3＋/CD4＋, CD3＋/CD8＋, CD3-/CD16＋56＋, CD3＋/CD16＋56＋, CD4＋/CD25＋, CD8＋/CD28-, CD8＋/CD28＋, CD4/CD8, DC1, DC2 and DC1/DC2 were analysed by a 3-color flow cytometric analysis. Results： The two treatment groups were well matched with regard to demographic and baseline disease characteristics. Comparing the changes of lymphocyte subpopulations between the two groups, it showed that the difference of the change of CD8＋/CD28-lymphocyte had statistic significance. The percentage of CD8＋/CD28-lymphocyte was lower in the chemotherapy＋DC group, but higher in the chemotherapy-alone group. Conclusion： As CD8＋/CD28-lymphocyte represent a kind of suppressive T lymphocyte, we conclude that dentritic cell therapy can relieve immunosuppression to some extent.

关键词： Metastatic breast cancer Dentritic cell Lymphocyte subpopulations Regulatory T cell

Quercetin-solid lipid nanoparticle-embedded hyaluronic acid functionalized hydrogel for immunomodulation to promote bone reconstruction

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Regenerative Biomaterials 2023年第1期10卷 713-728页

作者： Pinghui Zhou Bomin Yan Bangguo Wei Liangmin Fu Ying Wang Wenrui Wang Li Zhang Yingji Mao Department of Orthopaedics The First Affiliated Hospital of Bengbu Medical CollegeBengbu 233004China School of Life Science Bengbu Medical CollegeBengbu 233030China Anhui Province Key laboratory of Tissue Transplantation Bengbu Medical CollegeBengbu 233030China Department of Plastic Surgery The First Affiliated Hospital of Bengbu Medical CollegeBengbu 233004China Anhui Province Key laboratory of translational Cancer Research Bengbu Medical UniversityAnhui 233030China

Bone defects are a persistent challenge in clinical *** repair therapies based on tissue-engineered materials,which are known to have a crucial role in defective bone regeneration,have gathered increased attention,the current treatments for massive bone defects have several *** the present study,based on the immunomodulatory inflammatory microenvironment properties of quercetin,we encapsulated quercetin-solid lipid nanoparticles(SLNs)in a ***-responsive poly(ε-caprolactone-co-lactide)-b-poly(ethylene glycol)-b-poly(ε-caprolactone-co-lactide)modifications were coupled to the main chain of hyaluronic acid hydrogel,constructing a novel,injectable bone immunomodulatory hydrogel *** in vitro and in vivo data showed that this bone immunomodulatory scaffold forms an anti-inflammatory microenvironment by decreasing M1 polarization,while elevating the M2 *** effects on angiogenesis and anti-osteoclastic differentiation were *** findings further proved that administering quercetin SLNs encapsulated in a hydrogel can aid bone defect reconstruction in rats,providing new insights for large-scale bone defect repair.

关键词： quercetin hydrogels macrophages inflammatory microenvironments bone tissue engineering

NAD^(+) salvage governs the immunosuppressive capacity of mesenchymal stem cells

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Cellular & Molecular Immunology 2023年第10期20卷 1171-1185页

作者： Jiankai Fang Pengbo Hou Shisong Liu Muqiu Zuo Zhanhong Liu Wangwang Chen Yuyi Han Yanan Li Tingting Wang Chao Feng Peishan Li Changshun Shao Yufang Shi The Third Affiliated Hospital of Soochow University Institutes for Translational MedicineState Key Laboratory of Radiation Medicine and ProtectionSuzhou Medical College of Soochow UniversitySuzhouChina Department of Experimental Medicine and Biochemical Sciences TORUniversity of Rome“Tor Vergata”RomeItaly laboratory Animal Center Suzhou Medical College of Soochow UniversitySuzhouChina Shanghai Institute of Nutrition and Health Chinese Academy of SciencesShanghaiChina

Mesenchymal stem/stromal cells(MSCs)possess robust immunoregulatory functions and are promising therapeutics for inflammatory *** capacity is not innate but is activated or‘licensed’by inflammatory *** licensing mechanism remains ***,we examined whether inflammatory cytokines metabolically reprogrammed MSCs to confer this immunoregulatory *** response to stimulation by inflammatory cytokines,MSCs exhibited a dramatic increase in the consumption of glucose,which was accompanied by an enhanced use of nicotinamide adenine dinucleotide(NAD^(+))and increased expression of nicotinamide phosphoribosyltransferase(NAMPT),a central enzyme in the salvage pathway for NAD^(+) *** NAD^(+) synthesis was blocked by inhibiting or depleting NAMPT,the immunosuppressive function of MSCs induced by inflammatory cytokines was greatly ***,when NAD^(+) metabolism in MSCs was perturbed,their therapeutic benefit was decreased in mice suffering from inflammatory bowel disease and acute liver *** analysis revealed that NAMPT-driven production of NAD^(+) was critical for the inflammatory cytokine-induced increase in glycolysis in ***,the increase in glycolysis led to succinate accumulation in the tricarboxylic acid cycle,which led to hypoxia-inducible factor 1α(HIF-1α)stabilization and subsequently increased the transcription of key glycolytic genes,thereby persistently maintaining glycolytic *** study demonstrated that unlike its proinflammatory role in immune cells,NAD^(+) metabolism governs the anti-inflammatory function of MSCs during inflammation.

关键词： Mesenchymal stem/stromal cells NAD^(+)metabolism immunomodulation Glycolysis HIF-1a Succinate