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CCR2 enhances CD25 expression by FoxP3^(+) regulatory T cells and regulates their abundance independently of chemotaxis and CCR2^(+) myeloid cells

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Cellular & molecular Immunology 2020年第2期17卷 123-132页

作者： Yifan Zhan Nancy Wang Ajithkumar Vasanthakumar Yuxia Zhang michael Chopin Stephen L.Nutt Axel Kallies andrew m.lew The Walter&Eliza Hall Institute of medical Research ParkvilleVIC 3052Australia Department of medical Biology University of MelbourneParkvilleVIC 3010Australia Guangzhou Institute of Paediatrics Guangzhou Women and Children’s Medical CentreGuangzhou Medical University510623 GuangzhouGuangdongChina Department of microbiology and Immunology Peter Doherty Institute for Infection and ImmunityUniversity of MelbourneParkvilleVIC 3010Australia

A wide array of chemokine receptors,including CCR2,are known to control Treg migration.Here,we report that CCR2 regulates Tregs beyond chemotaxis.We found that CCR2 deficiency reduced CD25 expression by FoxP3^(+) Treg cells.Such a change was also consistently present in irradiation chimeras reconstituted with mixed bone marrow from wild-type(WT)and CCR2−/−strains.Thus,CCR2 deficiency resulted in profound loss of CD25 ^(hi) FoxP3^(+) Tregs in secondary lymphoid organs as well as in peripheral tissues.CCR2−/−Treg cells were also functionally inferior to WT cells.Interestingly,these changes to Treg cells did not depend on CCR2+monocytes/moDCs(the cells where CCR2 receptors are most abundant).Rather,we demonstrated that CCR2 was required for TLR-stimulated,but not TCR-or IL-2-stimulated,CD25 upregulation on Treg cells.Thus,we propose that CCR2 signaling can increase the fitness of FoxP3^(+) Treg cells and provide negative feedback to counter the proinflammatory effects of CCR2 on myeloid cells.

关键词： CCR2 CD25 organs

CIS controls the functional polarization of Gm-CSF-derived macrophages

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Cellular & molecular Immunology 2023年第1期20卷 65-79页

作者： Shengbo Zhang Jai Rautela Naiara G.Bediaga Tatiana B.Kolesnik Yue You Junli Nie Laura F.Dagley Justin Bedo Hanqing Wang Li Sun Robyn Sutherland Elliot Surgenor Nadia Iannarella Rhys Allan Fernando Souza-Fonseca-Guimaraes Yi Xie Qike Wang Yuxia Zhang Yuekang Xu Stephen L.Nutt andrew m.lew Nicholas D.Huntington Sandra E.Nicholson michaël Chopin Yifan Zhan Walter and Eliza Hall Institute of medical Research ParkvilleVICAustralia Department of medical Biology University of MelbourneParkvilleVICAustralia Department of Biochemistry and molecular Biology Biomedicine Discovery InstituteMonash UniversityClaytonVICAustralia oNKo-Innate Pty Ltd Moonee PondsVICAustralia Department of Computing and Information Systems University of MelbourneParkvilleVICAustralia Department of Respiratory medicine Guangzhou Institute of PediatricsGuangzhou Women and Children’s Medical CentreState Key Laboratory of Respiratory DiseasesGuangzhou Medical UniversityGuangzhouGuangdongChina College of Biological Science Anhui Normal UniversityHefeiChina University of Queensland Diamantina Institute University of QueenslandTranslational Research InstituteBrisbaneQLDAustralia Program in Cardiovascular and metabolic Disorders Duke-NUS Medical SchoolDukeSingapore Drug Discovery Shanghai Huaota BiopharmShanghaiChina

The cytokine granulocyte-macrophage-colony stimulating factor (Gm-CSF) possesses the capacity to differentiate monocytes into macrophages (mØs) with opposing functions, namely, proinflammatory m1-like mØs and immunosuppressive m2-like mØs. Despite the importance of these opposing biological outcomes, the intrinsic mechanism that regulates the functional polarization of mØs under Gm-CSF signaling remains elusive. Here, we showed that Gm-CSF-induced mØ polarization resulted in the expression of cytokine-inducible SH2-containing protein (CIS) and that CIS deficiency skewed the differentiation of monocytes toward immunosuppressive m2-like mØs. CIS deficiency resulted in hyperactivation of the JAK-STAT5 signaling pathway, consequently promoting downregulation of the transcription factor Interferon Regulatory Factor 8 (IRF8). Loss- and gain-of-function approaches highlighted IRF8 as a critical regulator of the m1-like polarization program. In vivo, CIS deficiency induced the differentiation of m2-like macrophages, which promoted strong Th2 immune responses characterized by the development of severe experimental asthma. Collectively, our results reveal a CIS-modulated mechanism that clarifies the opposing actions of Gm-CSF in mØ differentiation and uncovers the role of Gm-CSF in controlling allergic inflammation.

关键词： CIS Gm-CSF macrophage m2 m1

Rational Schur Superalgebras

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Algebra Colloquium 2024年第2期31卷 209-220页

作者： andrew Riesen Shun-Jen Cheng Department of mathematical and Statistical Sciences University of Alberta 1132489 Ave NWEdmontonAlbertaCanada 不详

We develop and study the generalization of rational Schur algebras to the super setting.Similar to the classical case,this provides a new method for studying rational supermodules of the general linear supergroup GL(m|n).Furthermore,we establish a Schur-Weyl duality result for rational Schur superalgebras and conclude that under certain conditions these objects will be semisimple.

关键词： Schur algebra supermathematics general linear supergroup

mesenchymal stem cell-based TRAIL delivery inhibits the metastatic state of clinical therapy-resistant progressive neuroblastoma

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World Journal of Pediatrics 2024年第3期20卷 287-293页

作者： Dinesh Babu Somasundaram andrew maher Sheeja Aravindan Zhongxin Yu Brian mBesch Natarajan Aravindan Department of Radiation Oncology University of Oklahoma Health Sciences CenterOklahoma CityOKUSA Stephenson Cancer Center Oklahoma CityOKUSA Department of Pathology University of Oklahoma Health Sciences CenterOklahoma CityOKUSA Radiation Biology Laboratory University of Oklahoma Health Sciences CenterBSEB 302F941 Stanton L.Young BoulevardOklahoma CityOK 73104USA

Progressive neuroblastomas(pNBs)that defy current intensive multimodal clinical therapy(ImCT)are a significant contributor to overall childhood cancer deaths[l].Neuroblastomas(NBs)that survive first-line ImCT actively evolve to acquire genetic and molecular rearrangements and display unparalleled plasticity and evolution,which causes frequent relapses in a rapidly accelerating timeline[2-4].

关键词： neuroblastoma clinical evolve

Evaluating implicit gender bias at Canadian otolaryngology meetings through use of professional title

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World Journal of Otorhinolaryngology-Head and Neck Surgery 2024年第1期10卷 12-17页

作者： Kylen Van Osch Agnieszka Dzioba Khadija Ahmed andrew macDonald Jamila Skinner Harley Williams Julie E.Strychowsky m.Elise Graham Department of Otolaryngology-Head&Neck Surgery Schulich School of Medicine&DentistryWestern UniversityLondonOntarioCanada Department of Otolaryngology London Health Sciences Centre Children's HospitalLondonOntarioCanada Faculty of medicine Schulich School of Medicine&DentistryWestern UniversityLondonOntarioCanada

Objectives:Increasing numbers of women enter medical school annually.The number of female physicians in leadership positions has been much slower to equalize.There are also well‐documented differences in the treatment of women as compared to men in professional settings.Female presenters are less likely to be introduced by their professional title(“Doctor”)for grand rounds and conferences,especially with a man performing the introduction.This study reviewed the Canadian Society of Otolaryngology–Head and Neck Surgery(CSOHNS)meetings from 2017 to 2020 to determine the proportion of presenters introduced by their professional title and whether this varied by gender.methods:Recordings from CSOHNS meetings were reviewed and coded for introducer and presenter demographics,including leadership positions and gender.Chi‐squared tests of proportion and multivariate logistic regression was used to compare genders and identify factors associated with professional versus unprofessional forms of address.Results:No significant association was found between professional title use and introducer or presenter gender.Female presenters were introduced with professional title 69.6%of the time,while male presenters were introduced with professional title 67.6%of the time(P=0.69).Residents were introduced with a professional title with the most frequency(75.8%),while attending staff were introduced with a professional title with the least frequency(63.0%)(P=0.02).Conclusions:The lack of gender bias in speaker introductions at recent CSOHNS meetings demonstrates progress in achieving gender equity in medicine.Research efforts should continue to define additional forms of unconscious bias that may be contributing to gender inequity in leadership positions.

关键词： attitude of health personnel gender identity Otolaryngology women

Biofabrication of nanocomposite-based scaffolds containing human bone extracellularmatrix for the differentiation of skeletal stem and progenitor cells

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Bio-Design and manufacturing 2024年第2期7卷 121-136页

作者： Yang-Hee Kim Janos m.Kanczler Stuart Lanham andrew Rawlings marta Roldo Gianluca Tozzi Jonathan I.Dawson Gianluca Cidonio Richard O.C.Oreffo Faculty of medicine Bone and Joint Research GroupCentre for Human DevelopmentStem Cells and RegenerationInstitute of Developmental SciencesUniversity of SouthamptonSouthampton SO166YDUK School of Pharmacy and Biomedical Science University of PortsmouthPortsmouth PO12DTUK School of Engineering Faculty of Engineering and ScienceUniversity of GreenwichGreenwich ME44TBUK Center for Life Nano-and Neuro-Science(CLN2S) Italian Institute of Technology00161 RomeItaly

Autograft or metal implants are routinely used in skeletal repair.However,they fail to provide long-term clinical resolution,necessitating a functional biomimetic tissue engineering alternative.The use of native human bone tissue for synthesizing a biomimeticmaterial inkfor three-dimensional(3D)bioprintingof skeletal tissueis anattractivestrategyfor tissueregeneration.Thus,human bone extracellular matrix(bone-ECm)offers an exciting potential for the development of an appropriate microenvironment for human bone marrow stromal cells(HBmSCs)to proliferate and differentiate along the osteogenic lineage.In this study,we engineered a novel material ink(LAB)by blending human bone-ECm(B)with nanoclay(L,Laponite®)and alginate(A)polymers using extrusion-based deposition.The inclusion of the nanoﬁller and polymeric material increased the rheology,printability,and drug retention properties and,critically,the preservation of HBmSCs viability upon printing.The composite of human bone-ECm-based 3D constructs containing vascular endothelial growth factor(VEGF)enhanced vascularization after implantation in an ex vivo chick chorioallantoic membrane(CAm)model.The inclusion of bone morphogenetic protein-2(BmP-2)with the HBmSCs further enhanced vascularization and mineralization after only seven days.This study demonstrates the synergistic combination of nanoclay with biomimetic materials(alginate and bone-ECm)to support the formation of osteogenic tissue both in vitro and ex vivo and offers a promising novel 3D bioprinting approach to personalized skeletal tissue repair.

关键词： Extracellular matrix Nanoclay Bone 3D bioprinting

Early anticoagulation in patients with stroke and atrial fibrillation is associated with fewer ischaemic lesions at 1 month: the ATTUNE study

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Stroke & Vascular Neurology 2024年第1期9卷 30-37,I0034页

作者： Angelos Sharobeam Longting Lin Christina Lam Carlos Garcia-Esperon Yash Gawarikar Ronak Patel matthew Lee-Archer andrew Wong michael Roizman Amanda Gilligan andrew Lee Kee meng Tan Susan Day Christopher Levi Stephen m Davis mark Parsons Bernard Yan melbourne Brain Centre at Royal melbourne Hospital ParkvilleVictoriaAustralia University of New South Wales South Western Sydney Clinical School LiverpoolNew South WalesAustralia Department of Neurology John Hunter HospitalNewcastleNew South WalesAustralia Department of Neurology Calvary Public HospitalCanberraAustralian Capital TerritoryAustralia Department of Neurology Northern Hospital EppingEppingVictoriaAustralia Department of Neurology Royal Brisbane and Women's HospitalHerstonQueenslandAustralia The University of Queensland School of medicine HerstonQueenslandAustralia Neurosciences Clinical Institute Epworth HealthcareRichmondVirginiaAustralia Department of Neurology Austin HealthUniversity of MelbourneHeidelbergVictoriaAustralia Flinders University College of medicine and Public Health AdelaideSouth AustraliaAustralia Department of Neurology Gold Coast University HospitalSouthportQueenslandAustralia The University of Sydney Northern Clinical School St LeonardsNew South WalesAustralia Department of Neurology and Neurophysiology Liverpool HospitalLiverpoolNew South WalesAustralia

Background The optimal time to commence anticoagulation in patients with atrial fibrillation(AF)after ischaemic stroke or transient ischaemic attack(TIA)is unclear,with guidelines differing in recommendations.A limitation of previous studies is the focus on clinically overt stroke,rather than radiologically obvious diffusion-weighted imaging ischaemic lesions.We aimed to quantify silent ischaemic lesions and haemorrhages on mRI at 1month in patients commenced on early(mic lesions and more haemorrhages in the early anticoagulant group at 1-month mRI.methods A prospective multicentre,observational cohort study was performed at 11 Australian stroke centres.Clinical and mRI data were collected at baseline and follow-up,with blinded imaging assessment performed by two authors.Timing of commencement of anticoagulation was at the discretion of the treating stroke physician.Results We recruited 276 patients of whom 208 met the eligibility criteria.The average age was 74.2 years(SD±10.63),and 79(38%)patients were female.median National Institute of Health Stroke Scale score was 5(IQR 1–12).median baseline ischaemic lesion volume was 5mL(IQR 2–17).There were a greater number of new ischaemic lesions on follow-up mRI in patients commenced on anticoagulation≥4days after index event(17%vs 8%,p=0.04),but no difference in haemorrhage rates(22%vs 32%,p=0.10).Baseline ischaemic lesion volume of≤5mL was less likely to have a new haemorrhage at 1month(p=0.02).There was no difference in haemorrhage rates in patients with an initial ischaemic lesion volume of>5mL,regardless of anticoagulation timing.Conclusion Commencing anticoagulationmic lesions at 1month in AF patients.There is no increased rate of haemorrhage with early anticoagulation.These results suggest that early anticoagulation after mild-to-moderate acute ischaemic stroke associated with AF might be safe,but randomised controlled s

关键词： patients lesions ischaemic

CD8+T cell metabolic flexibility elicited by CD28-ARS2 axisdriven alternative splicing of PKm supports antitumor immunity

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Cellular & molecular Immunology 2024年第3期21卷 260-274页

作者： G.Aaron Holling Colin A.Chavel Anand P.Sharda mackenzie m.Lieberman Caitlin m.James Shivana m.Lightman Jason H.Tong Guanxi Qiao Tiffany R.Emmons Thejaswini Giridharan Shengqi Hou andrew m.Intlekofer Richard m.Higashi Teresa W.m.Fan andrew N.Lane Kevin H.Eng Brahm H.Segal Elizabeth A.Repasky Kelvin P.Lee Scott H.Olejniczak Department of Immunology Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Department of medicine Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer CenterNew YorkNY 10065USA Center for Environmental Systems Biochemistry Department of Toxicology and Cancer Biology and Markey Cancer CenterLexingtonKY 40536USA Department of Cancer Genetics and Genomics Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Present address:University of Colorado Boulder BoulderCO 80309USA Present address:Dana Farber Cancer Institute BostonMA 02215USA Present address:massachusetts Institute of Technology BostonMA 02139USA Present address:melvin and Bren Simon Comprehensive Cancer Center Indiana University School of MedicineIndianapolisIN 46202USA

metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been determined.In this study,we investigated the influence of the nuclear cap-binding complex(CBC)adaptor protein ARS2 on mature T cells.In doing so,we discovered a novel signaling axis that endows activated CD8+T cells with flexibility of glucose catabolism.ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events.Among these effects,the CD28-ARS2 axis suppressed the expression of the m1 isoform of pyruvate kinase in favor of PKm2,a key determinant of CD8+T-cell glucose utilization,interferon gamma production,and antitumor effector function.Importantly,PKm alternative splicing occurred independently of CD28-driven PI3K pathway activation,revealing a novel means by which costimulation reprograms glucose metabolism in CD8+T cells.

关键词： Immunometabolism mRNA splicing CD8 T cells ARS2 PKm2

Thirteen years to get from b to a:one of the neglected isoforms of IL-37 enters the stage

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Cellular & molecular Immunology 2024年第2期21卷 201-202页

作者： Steven X.Cho Ina Rudloff andrew m.Ellisdon Claudia A.Nold-Petry marcel F.Nold Ritchie Centre Hudson Institute of Medical ResearchMelbourneVICAustralia Department of Pediatrics Monash UniversityMelbourneVICAustralia Cancer Program Biomedicine Discovery InstituteMonash UniversityMelbourneVICAustralia monash Newborn Monash Children’s HospitalMelbourneVICAustralia

Interleukin(IL)-37 is one of the few anti-inflammatory members of the predominantly pro-inflammatory IL-1 cytokine family.IL-37 possesses alarmin-like properties[1]and exerts its activities via intracellular[2]as well as cell surface receptor-dependent mechanisms,and the latter involves IL-1R8 and IL-18Rα[3].Because of its powerful and broad-spectrum“peacemaking”[4]functions,considerable efforts have been invested in developing IL-37-based anti-inflammatory therapeutics[5,6].

关键词： Interleukin neglected cytokine