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Neddylation is a novel therapeutic target for lupus by regulating double negative T cell homeostasis

Signal Transduction and Targeted Therapy 2024年第2期9卷 738-750页

作者： Yun Zhang Lijun Du Chenxi Wang Zhangsheng Jiang Qingchi Duan Yiping Li Zhijun Xie Zhixing He Yi Sun Lin Huang Liwei Lu Chengping Wen Key Laboratory of Chinese medicine rheumatology of Zhejiang Province Research Institute of Chinese Medical Clinical Foundation and ImmunologyCollege of Basic Medical ScienceZhejiang Chinese Medical UniversityHangzhou 310053China Department of General Surgery Sir Run Run Shaw HospitalZhejiang University School of MedicineHangzhou 310016China Cancer institute(Key Laboratory of Cancer Prevention and Intervention China National Ministry of Education)of the Second Affiliated Hospital and Institute of Translational MedicineZhejiang University School of MedicineHangzhou 310029China Cancer Center of Zhejiang University Hangzhou 310029China Department of Pathology and Shenzhen institute of Research and Innovation The University of Hong KongHong KongChina Chongqing International institute for Immunology Chongqing 400038China

Systemic lupus erythematosus(SLE),a severe autoimmune disorder,is characterized by systemic inflammatory response,autoantibody accumulation and damage to organs.The dysregulation of double-negative(DN)T cells is considered as a crucial commander during SLE.Neddylation,a significant type of protein post-translational modification(PTM),has been well-proved to regulate T cell-mediated immune response.However,the function of neddylation in SLE is still unknown.Here,we reported that neddylation inactivation with MLN4924,a specific inhibitor of NEDD8-activating enzyme E1(NAE1),or genetic abrogation of Ube2m in T cells decreased DN T cell accumulation and attenuated murine lupus development.Further investigations revealed that inactivation of neddylation blocked Bim ubiquitination degradation and maintained Bim level in DN T cells,contributing to the apoptosis of the accumulated DN T cells in lupus mice.Then double knockout(KO)lupus-prone mice(Ube2m-/-Bim-/-lpr)were generated and results showed that loss of Bim reduced Ube2m deficiency-induced apoptosis in DN T cells and reversed the alleviated lupus progression.Our findings identified that neddylation inactivation promoted Bim-mediated DN T cell apoptosis and attenuated lupus progression.Clinically,we also found that in SLE patients,the proportion of DN T cells was raised and their apoptosis was reduced.Moreover,compared to healthy groups,SLE patients exhibited decreased Bim levels and elevated Cullin1 neddylation levels.Meantime,the inhibition of neddylation induced Bim-dependent apoptosis of DN T cells isolated from SLE patients.Altogether,our findings provide the direct evidence about the function of neddylation during lupus,suggesting a promising therapeutic approach for this disease.

关键词： inactivation double finding

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Development and Validation of Diagnostic Criteria for Elderly Atopic Dermatitis

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International Journal of Dermatology And Venereology 2024年第1期07卷 1-5页

作者： Wang Shang-Shang Li Zheng Gu Chao-Ying Yin Hui-Bin Wu Yue-Meng Yao Xu Li Wei Chinese Academy of Medical Sciences and Peking Union Medical College Nanjing Jiangsu 210042 Department of Dermatology Shanghai institute of Dermatology Huashan Hospital Fudan University Shanghai 200040 China Department of Allergy and rheumatology Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs Hospital for Skin Diseases (institute of Dermatology)

Objective: Elderly atopic dermatitis (AD) is a newly identified subtype of AD. Whether specific diagnostic criteria are needed for elderly AD has been debated. This study aimed to propose diagnostic criteria for elderly AD and evaluate the sensitivity.Methods: A hospital-based study was conducted. We screened the clinical features of 1,312 patients with AD of different ages in 1 cohort and proposed a set of diagnostic criteria for elderly AD. The criteria were then validated in another cohort of 223 patients clinically diagnosed with elderly AD by dermatologists specialized in AD to examine the diagnostic sensitivity compared with other criteria by chi-square test.Results: Based on the patients’ clinical features, a set of diagnostic criteria for elderly AD were proposed. The new diagnostic criteria showed significantly higher sensitivity than the classical diagnostic criteria (P < 0.001), especially for mild and moderate AD (P < 0.001). Of all 223 patients with elderly AD, 93.3% fulfilled our criteria, while only 43.5%, 65.5%, and 52.0% fulfilled the Hanifin and Rajka criteria, the Japanese Dermatology Academy criteria, and the United Kingdom Working Party criteria, respectively.Conclusion: The newly proposed criteria for elderly AD yielded high diagnostic sensitivity, particularly for mild and moderate AD.

关键词： atopic dermatitis elderly diagnostic criteria sensitivity clinical features atypical

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Potential risk genes for primary Sjogren's syndrome from a meta-analysis by linear regression and random forest classification

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Genes & Diseases 2024年第3期11卷 128-131页

作者： Tomas Cerdo Teresa Torres Moral Maimonides Biomedical Research institute of Cordoba(IMIBIC) Reina Sofia University HospitalUniversity of CordobaCordoba 14004Spain Centre for rheumatology Research Division of MedicineUniversity College LondonLondon W1T 4JFUK Faculty of Computer Sciences Multimedia and TelecommunicationUniversitat Oberta de CatalunyaBarcelona 08018Spain Dermatology Department Melanoma UnitAugust Pi i Sunyer Biomedical Research Institute(IDIBAPS)and Hospital ClinicBarcelona 08036Spain Center for Networked Biomedical Research on Rare Diseases(CIBERER) Carlos II Health InstituteMadrid 28029Spain

Primary Sjogren's syndrome(psS)is one of the most widespread autoimmune diseases with unknown origin,characterized by a lymphocytic infiltrate of the exocrine glands and the production of anti-SSA/Ro and anti-SSB/La antibodies that cause dysfunction and destruction mainly of salivary and lachrymal glands,leading to dry eyes and dry mouth.In the absence of a standardized evidence-based screening tool to decide which patients with dry eye must be referred for study of this pathology.

关键词： Sjogren lymphocytic salivary

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Comparison of clinical features and outcomes of proliferative,fibrotic,and mixed subtypes of IgG4-related disease:A retrospective cohort study

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Chinese Medical Journal 2024年第3期137卷 303-311页

作者： Linyi Peng Xinlu Zhang Jiaxin Zhou Jieqiong Li Zheng Liu Hui Lu Yu Peng Yunyun Fei Yan Zhao Xiaofeng Zeng Wen Zhang Department of rheumatology and Clinical Immunology Peking Union Medical College HospitalNational Clinical Research Center for Dermatologic and Immunologic DiseasesState Key Laboratory of Complex Severe and Rare DiseasesThe Ministry of Education Key LaboratoryBeijing 100730China institute of Clinical Medicine Peking Union Medical College Hospital(PUMCH)Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China

Background:Immunoglobulin G4-related disease(IgG4-RD)is a recently recognized immune-mediated disorder that can affect almost any organ in the human body.IgG4-RD can be categorized into proliferative and fibrotic subtypes based on patients’clinicopathological characteristics.This study aimed to compare the clinical manifestations,laboratory findings,and treatment outcomes of IgG4-RD among different subtypes.Methods:We prospectively enrolled 622 patients with newly diagnosed IgG4-RD at Peking Union Medical College Hospital from March 2011 to August 2021.The patients were divided into three groups according to their clinicopathological characteristics:proliferative,fibrotic,and mixed subtypes.We compared demographic features,clinical manifestations,organ involvement,laboratory tests,and treatment agents across three subtypes.We then assessed the differences in treatment outcomes among 448 patients receiving glucocorticoids alone or in combination with immunosuppressants.Moreover,risk factors of relapse were revealed by applying the univariate and multivariate Cox regression analysis.Results:We classified the 622 patients into three groups consisting of 470 proliferative patients,55 fibrotic patients,and 97 mixed patients,respectively.We found that gender distribution,age,disease duration,and frequency of allergy history were significantly different among subgroups.In terms of organ involvement,submandibular and lacrimal glands were frequently involved in the proliferative subtype,while retroperitoneum was the most commonly involved site in both fibrotic subtype and mixed subtype.The comparison of laboratory tests revealed that eosinophils(P=0.010),total IgE(P=0.006),high-sensitivity C-reactive protein(P<0.001),erythrocyte sedimentation rate(P<0.001),complement C4(P<0.001),IgG(P=0.001),IgG1(P<0.001),IgG4(P<0.001),and IgA(P<0.001),at baseline were significantly different among three subtypes.Compared with proliferative and mixed subtypes,the fibrotic subtype showed the lowest rate of relapse(log-rank P=0.014).Conclus

关键词： IgG4-related disease Proliferative subtype Fibrotic subtype Clinical features Treatment outcome

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Rapid and sensitive detection of Epstein-Barr virus antibodies in nasopharyngeal carcinoma by chemiluminescence strips based on iron-porphyrin single atom nanozyme

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Nano Research 2024年第3期17卷 1827-1836页

作者： Daji Wang Jie Wang Dan Liu Jiuyang He Meiying Wang Haibing Huang Guohui Nie Hui Ding Xiyun Yan Nanozyme Synthesis Center Shenzhen Institute of Synthetic BiologyShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China Center for Drug Evaluation National Medical Products AdministrationBeijing 100022China Shenzhen Key Laboratory of nanozymes and Translational Cancer Research Department of Otolaryngologyand Shenzhen Institute of Translational MedicineShenzhen Second People’s Hospital/the First Affiliated Hospital of Shenzhen University Health Science CenterShenzhen 518035China CAS Engineering Laboratory for Nanozyme Key Laboratory of Protein and Peptide PharmaceuticalInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China Department of rheumatology and Immunology Shenzhen Second People’s HospitalThe First Affiliated Hospital of Shenzhen UniversityShenzhen 518055China

The correlation between Epstein-Barr virus(EBV)infection and nasopharyngeal carcinoma(NPC)risk has been extensively researched.The continual monitoring of EBV-IgAs provides a promising approach of NPC screening in its early stage.In this study,we successfully synthesized a single-atom nanozyme(SANzyme)through the application of iron-porphyrin based metal organic framework(MOF-FeP).The MOF-FeP possesses precisely-defined electronic and geometric structures that accurately mimic highly-evolved catalytic site of natural peroxidase.The peroxidase-like activity of MOF-FeP enables it to catalyze the chemiluminescence of luminol substrate.By integrating MOF-FeP into a traditional strip,we created a rapid and highly-sensitive evaluation tool for detecting EBV-IgAs.Importantly,the MOF-FeP strip enables the simultaneous detection of three EBV-IgAs,greatly improving the accuracy of EBV-associated NPC screening.The sensitivities of the MOF-FeP strip(75.56%–93.30%)surpass those of current enzyme-linked immunosorbent assay(ELISA)methods(64.44%–82.22%).This test takes only 16 min to perform as opposed to the customary 1–2 h required for standard ELISA.Additionally,the MOF-FeP strip is suitable for whole blood samples,thereby significantly simplifying the sample preparation and detection process.In conclusion,the MOF-FeP strip combines the simplicity of traditional strip with the high catalytic activity of SANzyme.Our innovative MOF-FeP strip offers a new point-of-care strategy for EBV-IgAs detection,which is expected to markedly facilitate early screening for EBV-associated diseases.

关键词： iron-porphyrin single-atom nanozyme(SANzyme) chemiluminescence strips Epstein-Barr virus(EBV) nasopharyngeal carcinoma(NPC) antibody detection

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Living Chinese Herbal Scaffolds from Microfluidic Bioprinting for Wound Healing

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Research 2024年第1期2023卷 107-118页

作者： Xiaocheng Wang Jinxuan Jia Mengying Niu Wenzhao Li Yuanjin Zhao Department of rheumatology and Immunology Nanjing Drum Tower HospitalSchool of Biological Science and Medical EngineeringSoutheast UniversityNanjing 210096China Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)Wenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouZhejiang 325001China State Key Laboratory of Bioelectronics School of Biological Science and Medical EngineeringSoutheast UniversityNanjing 210096China Chemistry and Biomedicine Innovation Center Nanjing UniversityNanjing 210023China

Biological scaffolds have been widely employed in wound healing applications,while their practical efficiency is compromised by insufficient oxygen delivery to the 3-dimensional constructs and inadequate nutrient supply for the long-term healing process.Here,we present an innovative living Chinese herbal scaffold to provide a sustainable oxygen and nutrient supply for promoting wound healing.Through a facile microfluidic bioprinting strategy,a traditional Chinese herbal medicine(Panax notoginseng saponins[PNS])and a living autotrophic microorganism(microalgae Chlorella pyrenoidosa[MA])were successfully encapsulated into the scaffolds.The encapsulated PNS could be gradually released from the scaffolds,which promoted cell adhesion,proliferation,migration,and tube formation in vitro.In addition,benefiting from the photosynthetic oxygenation of the alive MA,the obtained scaffolds would produce sustainable oxygen under light illumination,exerting a protective effect against hypoxia-induced cell death.Based on these features,we have demonstrated through in vivo experiments that these living Chinese herbal scaffolds could efficiently alleviate local hypoxia,enhance angiogenesis,and thereby accelerate wound closure in diabetic mice,indicating their great potential in wound healing and other tissue repair applications.

关键词： healing wound protective

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Etanercept-synthesizing adipose-derived stem cell secretome:A promising therapeutic option for inflammatory bowel disease

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World Journal of Gastrointestinal Surgery 2024年第3期16卷 882-892页

作者： Say-June Kim Ok-Hee Kim Ha-Eun Hong Ji Hyeon Ju Do Sang Lee Department of Surgery Seoul St.Mary’s HospitalCollege of Medicinethe Catholic University of KoreaSeoul 06591South Korea Catholic Central Laboratory of Surgery Institute of Biomedical IndustryCollege of Medicinethe Catholic University of KoreaSeoul 06591South Korea Division of rheumatology Department of Internal MedicineSeoul St.Mary’s HospitalCollege of MedicineThe Catholic University of KoreaSeoul 06591South Korea

BACKGROUND Inflammatory bowel disease(IBD)is a chronic inflammatory condition of the gastrointestinal tract,with tumor necrosis factor(TNF)-αplaying a key role in its pathogenesis.Etanercept,a decoy receptor for TNF,is used to treat inflammatory conditions.The secretome derived from adipose-derived stem cells(ASCs)has anti-inflammatory effects,making it a promising therapeutic option for IBD.AIM To investigate the anti-inflammatory effects of the secretome obtained from ASCs synthesizing etanercept on colon cells and in a dextran sulfate sodium(DSS)-induced IBD mouse model.METHODS ASCs were transfected with etanercept-encoding mini-circle plasmids to create etanercept-producing cells.The secretory material from these cells was then tested for anti-inflammatory effects both in vitro and in a DSS-induced IBD mouse model.RESULTS This study revealed promising results indicating that the group treated with the secretome derived from etanercept-synthesizing ASCs[Etanercept-Secretome(Et-Sec)group]had significantly lower expression levels of inflammatory mediators,such as interleukin-6,Monocyte Chemoattractant Protein-1,and TNF-α,when compared to the control secretome(Ct-Sec).Moreover,the Et-Sec group exhibited a marked therapeutic effect in terms of preserving the architecture of intestinal tissue compared to the Ct-Sec.CONCLUSION These results suggest that the secretome derived from ASCs that synthesize etanercept has potential as a therapeutic agent for the treatment of IBD,potentially enhancing treatment efficacy by merging the anti-inflam-matory qualities of the ASC secretome with etanercept's targeted approach to better address the multifaceted pathophysiology of IBD.

关键词： Adipose-derived stem cells Etanercept Inflammatory bowel disease Secretome Tumor necrosis factor-α

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Nuclear receptor coactivator 6 is a critical regulator of NLRP3 inflammasome activation and gouty arthritis

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Cellular & Molecular Immunology 2024年第3期21卷 227-244页

作者： Kang-Gu Lee Bong-Ki Hong Saseong Lee Naeun Lee Seung-Whan Kim Donghyun Kim Wan-Uk Kim Center for Integrative Rheumatoid Transcriptomics and Dynamics The Catholic University of KoreaSeoul 06591Republic of Korea Department of Biomedicine&Health Sciences The Catholic University of KoreaSeoul 06591Republic of Korea Department of Pharmacology Asan Medical CenterUniversity of Ulsan College of MedicineSeoul 05505Republic of Korea Bio-Medical institute of Technology University of UlsanSeoul 05505Republic of Korea Department of Microbiology and Immunology Seoul National University College of MedicineSeoul 03080Republic of Korea institute of Infectious Diseases Seoul National University College of MedicineSeoul 03080Republic of Korea Division of rheumatology Department of Internal MedicineThe Catholic University of KoreaSeoul 06591Republic of Korea

Transcriptional coactivators regulate the rate of gene expression in the nucleus.Nuclear receptor coactivator 6(NCOA6),a coactivator,has been implicated in embryonic development,metabolism,and cancer pathogenesis,but its role in innate immunity and inflammatory diseases remains unclear.Here,we demonstrated that NCOA6 was expressed in monocytes and macrophages and that its level was increased under proinflammatory conditions.Unexpectedly,nuclear NCOA6 was found to translocate to the cytoplasm in activated monocytes and then become incorporated into the inflammasome with NLRP3 and ASC,forming cytoplasmic specks.Mechanistically,NCOA6 associated with the ATP hydrolysis motifs in the NACHT domain of NLRP3,promoting the oligomerization of NLRP3 and ASC and thereby instigating the production of IL-1βand active caspase-1.Of note,Ncoa6 deficiency markedly inhibited NLRP3 hyperactivation caused by the Nlrp3^(R258W) gain-of-function mutation in macrophages.Genetic ablation of Ncoa6 substantially attenuated the severity of two NLRP3-dependent diseases,folic-induced acute tubular necrosis and crystal-induced arthritis,in mice.Consistent with these findings,NCOA6 was highly expressed in macrophages derived from gout patients,and NCOA6-positive macrophages were significantly enriched in gout macrophages according to the transcriptome profiling results.Conclusively,NCOA6 is a critical regulator of NLRP3 inflammasome activation and is therefore a promising target for NLRP3-dependent diseases,including gout.

关键词： Nuclear receptor coactivator 6 Nuclear-to-cytoplasmic translocation NLRP3 inflammasome NACHT domain Gouty arthritis

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Dysfunction of the adhesion G protein-coupled receptor latrophilin 1(ADGRL1/LPHN1)increases the risk of obesity

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2298-2311页

作者： Heba ZabriTorsten Schöneberg AndréNguyen Dietzsch Hadi Al-Hasani Joachim Altschmied Katharina Bottermann Jana Brendler Judith Haendeler Susanne Horn Isabell Kaczmarek Antje Körner Kerstin Krause Kathrin Landgraf Diana Le Duc Laura Lehmann Stefan Lehr Stephanie Pick Albert Ricken Rene Schnorr Angela Schulz Martina Strnadová Akhil Velluva Heba Zabri Torsten Schöneberg Doreen Thor Simone Prömel Rudolf Schönheimer institute of Biochemistry Medical FacultyLeipzig UniversityLeipzigGermany institute for Clinical Biochemistry and Pathobiochemistry Medical FacultyGerman Diabetes CenterLeibniz Center for Diabetes Research at Heinrich Heine University DüsseldorfDüsseldorfGermany German Center for Diabetes Research(DZD e.V.) Munich-NeuherbergGermany Cardiovascular Degeneration Clinical Chemistry and Laboratory DiagnosticsMedical FacultyUniversity Hospital and Heinrich Heine University DüsseldorfDüsseldorfGermany Cardiovascular Research institute(CARID) Medical FacultyUniversity Hospital and Heinrich Heine University DüsseldorfDüsseldorfGermany institute of Pharmacology Medical FacultyUniversity Hospital and Heinrich Heine University DüsseldorfDüsseldorfGermany institute of Anatomy Medical FacultyLeipzig UniversityLeipzigGermany Center for Pediatric Research Hospital for Children and AdolescentsMedical FacultyLeipzig UniversityLeipzigGermany Helmholtz institute for Metabolic Obesity and Vascular Research(HI-MAG)of the Helmholtz Zentrum München at the University of Leipzig and University Hospital LeipzigLeipzigGermany Department of Endocrinology NephrologyRheumatologyLeipzig University Medical CenterLeipzigGermany institute of Human Genetics Leipzig University Medical CenterLeipzigGermany institute of Cell Biology Department of BiologyHeinrich Heine University DüsseldorfDüsseldorfGermany School of Medicine University of Global Health EquityKigaliRwanda

Obesity is one of the diseases with severe health consequences and rapidly increasing worldwide prevalence.Understanding the complex network of food intake and energy balance regulation is an essential prerequisite for pharmacological intervention with obesity.G protein-coupled receptors(GPCRs)are among the main modulators of metabolism and energy balance.They,for instance,regulate appetite and satiety in certain hypothalamic neurons,as well as glucose and lipid metabolism and hormone secretion from adipocytes.Mutations in some GPCRs,such as the melanocortin receptor type 4(MC4R),have been associated with early-onset obesity.Here,we identified the adhesion GPCR latrophilin 1(ADGRL1/LPHN1)as a member of the regulating network governing food intake and the maintenance of energy balance.Deficiency of the highly conserved receptor in mice results in increased food consumption and severe obesity,accompanied by dysregulation of glucose homeostasis.Consistently,we identified a partially inactivating mutation in human ADGRL1/LPHN1 in a patient suffering from obesity.Therefore,we propose that LPHN1 dysfunction is a risk factor for obesity development.

关键词： obesity metabolism intake

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A comprehensive look at the psychoneuroimmunoendocrinology of spinal cord injury and its progression: mechanisms and clinical opportunities

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Military Medical Research 2024年第2期11卷 228-267页

作者： Miguel A.Ortega Oscar Fraile-Martinez Cielo García-Montero Sergio Haro Miguel Ángel Álvarez-Mon Diego De Leon-Oliva Ana M.Gomez-Lahoz Jorge Monserrat Mar Atienza-Pérez David Díaz Elisa Lopez-Dolado Melchor Álvarez-Mon Department of Medicine and Medical Specialities University of Alcala28801 Alcala de HenaresSpain Ramón y Cajal institute of Sanitary Research(IRYCIS) 28034 MadridSpain Department of Psychiatry and Mental Health Hospital Universitario Infanta Leonor28031 MadridSpain Service of Rehabilitation National Hospital for Paraplegic PatientsCarr.de la PeraledaS/N45004 ToledoSpain Immune System Diseases‑rheumatology Service and Internal Medicine University Hospital Príncipe de Asturias(CIBEREHD)28806 Alcala de HenaresSpain

Spinal cord injury(SCI)is a devastating and disabling medical condition generally caused by a traumatic event(primary injury).This initial trauma is accompanied by a set of biological mechanisms directed to ameliorate neural damage but also exacerbate initial damage(secondary injury).The alterations that occur in the spinal cord have not only local but also systemic consequences and virtually all organs and tissues of the body incur important changes after SCI,explaining the progression and detrimental consequences related to this condition.Psychoneuroimmunoendocrinology(PNIE)is a growing area of research aiming to integrate and explore the interactions among the different systems that compose the human organism,considering the mind and the body as a whole.The initial traumatic event and the consequent neurological disruption trigger immune,endocrine,and multisystem dysfunction,which in turn affect the patient's psyche and well-being.In the present review,we will explore the most important local and systemic consequences of SCI from a PNIE perspective,defining the changes occurring in each system and how all these mechanisms are interconnected.Finally,potential clinical approaches derived from this knowledge will also be collectively presented with the aim to develop integrative therapies to maximize the clinical management of these patients.

关键词： Spinal cord injury(SCI) Psychoneuroimmunoendocrinology(PNIE) Secondary injury Immunoinflammatory dysfunction Gut microbiota Translational opportunities

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