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Plant cell wall-mediated disease resistance:Current understanding and future perspectives

Molecular Plant 2024年第5期17卷 699-724页

作者： Antonio Molina Lucıa Jorda Miguel Angel Torres Marina Martın-Dacal Diego Jose Berlanga Patricia Fernandez-Calvo Elena Gomez-Rubio Sonsoles Martın-Santamarıa Centro de Biotecnología y Genómica de Plantas Universidad Politécnica de Madrid(UPM)-Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria(INIA/CSIC)Campus de Montegancedo UPMPozuelo de Alarcon(Madrid)Spain Departamento de Biotecnologıa-Biología Vegetal Escuela Técnica Superior de Ingenierıa AgronomicaAlimentarıa y de BiosistemasUPMMadridSpain Centro de Investigaciones Biologicas Margarita Salas Consejo Superior de Investigaciones Científicas(CSIC)Ramiro de Maeztu 928040 MadridSpain Misión Biológica de Galicia Consejo Superior de Investigaciones Científicas(CSIC)Campus de Montegancedo UPMPozuelo de Alarcón(Madrid)Spain

Beyond their function as structural barriers,plant cell walls are essential elements for the adaptation of plants to environmental conditions.Cell walls are dynamic structures whose composition and integrity can be altered in response to environmental challenges and developmental cues.These wall changes are perceived by plant sensors/receptors to trigger adaptative responses during development and upon stress perception.Plant cell wall damage caused by pathogen infection,wounding,or other stresses leads to the release of wall molecules,such as carbohydrates(glycans),that function as damage-associated molecular patterns(damps).damps are perceived by the extracellular ectodomains(ECDs)of pattern recognition receptors(PRRs)to activate pattern-triggered immunity(PTI)and disease resistance.Similarly,glycans released from the walls and extracellular layers of microorganisms interacting with plants are recognized as microbe-associated molecular patterns(MAMPs)by specific ECD-PRRs triggering PTI responses.The number of oligosaccharides damps/MAMPs identified that are perceived by plants has increased in recent years.However,the structural mechanisms underlying glycan recognition by plant PRRs remain limited.Currently,this knowledge is mainly focused on receptors of the LysM-PRR family,which are involved in the perception of various molecules,such as chitooligosaccharides from fungi and lipo-chitooligosaccharides(i.e.,Nod/MYC factors from bacteria and mycorrhiza,respectively)that trigger differential physiological responses.Nevertheless,additional families of plant PRRs have recently been implicated in oligosaccharide/polysaccharide recognition.These include receptor kinases(RKs)with leucine-rich repeat and Malectin domains in their ECDs(LRR-MAL RKs),Catharanthus roseus RECEPTOR-LIKE KINASE 1-LIKE group(CrRLK1L)with Malectin-like domains in their ECDs,as well as wall-associated kinases,lectin-RKs,and LRR-extensins.The characterization of structural basis of glycans recognition by these new plant receptors will shed light

关键词： Arabidopsis thaliana cell wall damage-associated molecular patterns damps disease resistance glycans oligosaccharides pattern-triggered immunity PTl pattern recognition receptor PRRs

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damps’role in inflammatory bowel disease:a paradoxical player of mtDNA-STING signaling pathway in gut homeostasis

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Science Bulletin 2019年第19期64卷 1396-1398页

作者： Qiongyuan Hu Yanhan Ren Dominic ASlade Quan Zhou Xiuwen Wu Jinjian Huang Guosheng Gu Gefei Wang Jianan Ren Jieshou Li Research Institute of General Surgery Jinling HospitalSchool of MedicineNanjing UniversityNanjing210093China Chicago Medical School Rosalind Franklin UniversityNorth ChicagoIL60064-3095USA Department of Surgery Salford Royal NHS Foundation TrustStott LaneSalfordUK School of Medicine Nanjing UniversityNanjing210029China

The inflammatory bowel disease(IBD),including Crohn’s disease(CD)and ulcerative colitis,are chronic,relapsing immune mediated disorders of the gastrointestinal homeostasis and intestinal inflammation[1].Failure to resolve mucosal inflammation and maintain gut barrier are notable shared clinical challenges in IBD,in particular when they activate immune cells within the gut lamia propria.Clinical trials and animal model studies aiming towards damps have demonstrated that they can be effective therapeutic targets in mucosal inflammation of IBD.

关键词： pro IBD damps mtDNA

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TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by damps released from chemically stressed cancer cells

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Cellular & Molecular Immunology 2014年第2期11卷 150-159页

作者： Hongliang Fang Bing Ang Xinyun Xu Xiaohui Huang Yanfeng Wu Yanping Sun Wenying Wang Nan Li Xuetao Cao Tao Wan Institute of Immunology Zhejiang University School of Medicine Hangzhou 310058 China National Key Laboratory of Medical Immunology and Instituteof Immunology Seconci Military I~edical University Shanghai 260433~ China Department of General Surgery Changzheng Hospital Second MilitaryMedical University Shanghai 200003 China These authors contributed equally to this work.

The combination of immunotherapy and chemotherapy is regarded as a promising approach for the treatment of certain types of cancer. However, the underlying mechanisms need to be fully investigated to guide the design of more efficient protocols for cancer chemoimmunotherapy. It is well known that danger-associated molecular patterns （damps） can activate immune cells, including dendritic cells （DCs）, via Toll-like receptors （TLRs）; however, the role of damps released from chemical drug-treated tumor cells in the activation of the immune response needs to be further elucidated. Here, we found that colorectal cancer （CRC） cells treated with oxaliplatin （OXA） and/or 5-fluorouracil （5-Fu） released high levels of high-mobility group box 1 （HMGB1） and heat shock protein 70 （HSP70）. After OXA/5-Fu therapy, the sera of CRC patients also exhibited increased levels of HMGB1 and HSP70, both of which are well-known damps. The supernatants of dying CRC cells treated with OXA/5-Fu promoted mouse and human DC maturation, with upregulation of HLA-DR, CD80 and CD86 expression and enhancement of IL-lp, TNF-a, MIP-la, MIP-lp, RANTES and IP-IO production. Vaccines composed of DCs pulsed with the supernatants of chemically stressed CRC cells induced a more significant IFN-y-producing Thl response both in vitroand in vivo. However, the supernatants of chemically stressed CRC cells failed to induce phenotypic maturation and cytokine production in TLR4-deficient DCs, indicating an essential role of TLR4 in DAMP-induced DC maturation and activation. Furthermore, pulsing with the supernatants of chemically stressed CRC cells did not efficiently induce an IFN-y-producing Thl response in TLR4-deficient DCs. Collectively, these results demonstrate that damps released from chemically stressed cancer cells can activate DCs viaTLR4 and enhance the induction of an anti-tumor T-cell immune response, delineating a clinically relevant immuno-adjuvant pathway triggered by damps.

关键词： damps dendritic cells chemotherapy immunotherapy TLR4

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Targeting whole body metabolism and mitochondrial bioenergetics in the drug development for Alzheimer’s disease

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Acta Pharmaceutica Sinica B 2022年第2期12卷 511-531页

作者： Steven N.Austad Scott Ballinger Thomas W.Buford Christy S.Carter Daniel L.Smith Jr Victor Darley-Usmar Jianhua Zhang Department of Biology University of Alabama at BirminghamBirminghamAL 35294USA Department of Pathology University of Alabama at BirminghamBirminghamAL 35294USA Department of Medicine University of Alabama at BirminghamBirminghamAL 35294USA Department of Nutrition Sciences University of Alabama at BirminghamBirminghamAL 35294USA

Aging is by far the most prominent risk factor for Alzheimer’s disease(AD),and both aging and AD are associated with apparent metabolic alterations.As developing effective therapeutic interventions to treat AD is clearly in urgent need,the impact of modulating whole-body and intracellular metabolism in preclinical models and in human patients,on disease pathogenesis,have been explored.There is also an increasing awareness of differential risk and potential targeting strategies related to biological sex,microbiome,and circadian regulation.As a major part of intracellular metabolism,mitochondrial bioenergetics,mitochondrial quality-control mechanisms,and mitochondria-linked inflammatory responses have been considered for AD therapeutic interventions.This review summarizes and highlights these efforts.

关键词： Mitochondrial DNA Mitochondrial electron transport chain Mitochondrial quality control Reactive species damps Hexokinase biosynthesis pathway Diabetes Circadian regulation Microbiome

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damps对人肝癌HepG2细胞增殖能力影响的机制研究

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武汉大学学报（医学版） 2013年第5期34卷 665-669页

作者：邬善敏柯文杰袁方均张小霞武汉大学人民医院肝胆腔镜外科湖北武汉430060 湖北医药学院附属东风医院肝胆外科湖北十堰442001 武汉大学人民医院消化内科湖北武汉430060

目的:探讨在损伤相关模式分子(damps)诱导下人肝癌HepG2细胞增殖能力变化的发生机制。方法:将HepG2细胞分为对照组,damps组,IL-6 siRNA组,IL-6 siRNA+damps组;MTT比色法检测HepG2细胞增殖能力的变化;实时荧光定量PCR法检测IL-6及STAT3 m... 详细信息

目的:探讨在损伤相关模式分子(damps)诱导下人肝癌HepG2细胞增殖能力变化的发生机制。方法:将HepG2细胞分为对照组,damps组,IL-6 siRNA组,IL-6 siRNA+damps组;MTT比色法检测HepG2细胞增殖能力的变化;实时荧光定量PCR法检测IL-6及STAT3 mRNA的表达;Western blot法测定HepG2细胞STAT3蛋白和磷酸化STAT3蛋白的表达。结果:damps组细胞增殖能力较对照组显著增强,IL-6 mRNA及STAT3 mRNA的表达较对照组显著上调,差异均有统计学意义(Pdamps组磷酸化STAT3蛋白的表达高于对照组,差异有统计学意义(Pdamps可能通过IL-6/STAT3信号通路促进人肝癌HepG2细胞的增殖。

关键词： damps IL-6 STAT3信号通路 HepG2细胞

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damps和肾脏疾病

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肾脏病与透析肾移植杂志 2014年第2期23卷 163-167页

作者：何静施少林南京军区南京总医院国家肾脏疾病临床医学研究中心全军肾脏病研究所南京210016

damps是机体受到损伤后释放的内源性预警信号,可激活固有免疫系统,联系适应性免疫,介导无菌性炎症。近年来,damps在肾脏疾病领域日益受到关注。为此,本文将对常见damps、damps受体、damps与肾脏疾病的关系等作一综述。

关键词：肾脏疾病 damps 模式识别受体

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Regulation of neuroimmune processes by damage-and resolution-associated molecular patterns

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Neural Regeneration Research 2021年第3期16卷 423-429页

作者： Andis Klegeris Department of Biology University of British Columbia Okanagan CampusKelownaBCCanada

Sterile inflammatory processes are essential for the maintenance of central nervous system homeostasis,but they also contribute to various neurological disorders,including neurotrauma,stroke,and demyelinating or neurodegenerative diseases.Immune mechanisms in the central nervous system and periphery are regulated by a diverse group of endogenous proteins,which can be broadly divided into the pro-inflammatory damageassociated molecular patterns(damps)and anti-inflammatory resolution-associated molecular patterns(RAMPs),even though there is notable overlap between the DAMPand RAMP-like activities for some of these molecules.Both groups of molecular patterns were initially described in peripheral immune processes and pathologies;however,it is now evident that at least some,if not all,of these immunomodulators also regulate neuroimmune processes and contribute to neuroinflammation in diverse central nervous system disorders.The review of recent literature demonstrates that studies on damps and RAMPs of the central nervous system still lag behind the much broader research effort focused on their peripheral counterparts.Nevertheless,this review also reveals that over the last five years,significant advances have been made in our understanding of the neuroimmune functions of several well-established damps,including high-mobility group box 1 protein and interleukin 33.Novel neuroimmune functions have been demonstrated for other damps that previously were considered almost exclusively as peripheral immune regulators;they include mitochondrial transcription factor A and cytochrome C.RAMPs of the central nervous system are an emerging area of neuroimmunology with very high translational potential since some of these molecules have already been used in preclinical and clinical studies as candidate therapeutic agents for inflammatory conditions,such as multiple sclerosis and rheumatoid arthritis.The therapeutic potential of DAMP antagonists and neutralizing antibodies in central nervous system neuroinflammatory diseases is al

关键词： Alzheimer's disease astrocytes damps HMGB1 microglia neurodegeneration neuroimmune responses neuroinflammation neurotrauma oligodendrocytes pattern-recognition receptors RAMPs

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damps和PAMPs在特纳牙形成中的作用探讨及30例特纳牙病例的临床研究

DAMPs和PAMPs在特纳牙形成中的作用探讨及30例特纳牙病例的临床研...

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作者：刘鑫郑州大学

学位级别：硕士

目的:建立特纳牙动物模型,包括乳牙根尖周炎及乳牙挫入伤实验犬模型。分析损伤相关模式分子（damps）及受体在乳牙挫入伤和病原体相关分式分子（PAMPs）的受体（TLR4）在乳牙根尖炎对继承恒牙异常中的作用,并进一步探讨特纳牙的发生机... 详细信息

目的:建立特纳牙动物模型,包括乳牙根尖周炎及乳牙挫入伤实验犬模型。分析损伤相关模式分子（damps）及受体在乳牙挫入伤和病原体相关分式分子（PAMPs）的受体（TLR4）在乳牙根尖炎对继承恒牙异常中的作用,并进一步探讨特纳牙的发生机制。明确在治疗乳牙外伤时及早拔除受伤乳牙的正确性,为临床治疗乳牙挫入性损伤提供新思路。通过对特纳牙临床病例的分析,研究特纳牙的病因及临床表现。方法:1.选取35天龄本地杂交犬9只,建立乳牙根尖周炎模型。9只犬随机分为3组,每组3只,同一只犬的左侧上下切牙及尖牙为空白对照组,不做处理,右侧上下切牙及尖牙为实验组,分别于开髓处理后1周、2周、3周处死一组实验犬,取动物颌骨。2.选取45天龄本地杂交犬12只,建立乳牙挫入伤模型。左上乳切牙及尖牙齐龈挫入,右下乳切牙及尖牙不做处理为空白对照组。将12只犬随机分为4组,每组3只,分别于术后24小时、48小时、72小时、96小时各处死一组实验犬,取动物颌骨。3.选取45天龄本地杂交犬12只,建立乳牙挫入伤拔除挫入乳牙模型,每只犬的右上乳切牙及尖牙齐龈挫入并于半小时后拔除,为拔除挫入乳牙组;右下乳切牙及尖牙不做处理为空白对照组。4.对标本摄CBCT,制取石蜡切片,HE染色观察恒牙胚组织形态,免疫组织化学检测乳牙挫入伤模型中HMGB1的表达,检测乳牙尖周炎和乳牙挫入伤模型中TLR4受体的表达。5.收集来我科就诊的特纳牙患者30例,统计分析病因和临床表现。结果:1.成功建立乳牙挫入伤和乳牙尖周炎实验犬模型。2.免疫组织化学结果显示:在乳牙挫入伤模型中,TLR4及HMGB1在对照组及24h组无表达或偶尔可见,48h组表达明显升高,72h时强阳性表达仍维持较高水平,96h组表达减弱;且HMGB1与TLR4的表达呈现正相关;在乳牙根尖炎模型中,TLR4在空白组无表达或偶尔可见,在1w组弱阳性表达,在2w组阳性表达,在3w组强阳性表达;乳牙挫入伤中TLR4和乳牙根尖炎中TLR4表达呈正相关;3.拔除挫入乳牙组中的HMGB1和TLR4的表达均弱于同时期保留挫入乳牙组,差异有统计学意义。4.特纳牙的病因主要有乳牙感染,其次为乳牙外伤;同时存在釉质缺损和变色为特纳牙表现最常见者,其次有有釉质缺损,棕黄色变及白垩色变。结论:1.犬乳牙封脂多糖以及犬乳牙齐龈挫入可以成功复制特纳牙的动物模型;2.损伤相关模式分子及其受体和病原体相关模式分子及受体参与了特纳牙的形成;3.乳牙挫入性损伤后,拔除挫入乳牙可以使局部炎症减轻。4.特纳牙的病因主要有乳牙感染,其次为乳牙外伤;临床表现以同时存在釉质缺损和变色最为常见。

关键词：特纳牙 damps PAMPs HMGB1 乳牙外伤治疗

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Antagonism of toll-like receptor 2 attenuates the formation and progression of abdominal aortic aneurysm

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Acta Pharmaceutica Sinica B 2015年第3期5卷 176-187页

作者： Huimin Yan Bing Cui Xiaowei Zhang Xiaoming Fu Jun Yan Xiaoxing Wang Xiaoxi Lv Zhong Chen Zhuowei Hu Molecular Immunology and Pharmacology Group State Key Laboratory of Bioactive Substance and Function of Natural MedicinesInstitute of Materia MedicaChinese Academy of Medical Sciences & Peking Union Medical College Beijing Institute of Heart lung and Blood Vessel Diseases An Zhen Hospital of the Capital Medical University

Abdominal aortic aneurysm(AAA) is an inflammatory vascular disorder with high mortality.Accumulating evidence shows that toll-like receptor 2(TLR2) plays a critical role in the regulation of wound-repairing process after tissue injury.We wondered if TLR2 signaling contributed to the pathogenesis of AAA and that targeting TLR2 would attenuate AAA development and progression.In this study,enhanced expression of TLR2 and its ligands were observed in human AAA tissue.Neutralization of TLR2 protected against AAA development and caused established AAA to regress in mouse models of AAA.In addition,TLR2-deficient mice also failed to develop AAA.The prophylactic and therapeutic effects of blocking TLR2 were accompanied by a significant resolution of inflammation and vascular remodeling,as indicated by the decreased expression or activity of MMP-2/9,α-SMA,inflammatory cytokines,and transcription factors NF-κB,AP-1 and STAT1/3 in AAA tissue.Mechanistically,blocking TLR2 decreased the expression and interaction of TLR2 and several endogenousligands,which diminished chronic inflammation and vascular remodeling in the vascular tissue of AAA.Our studies indicate that the interactions between TLR2 and its endogenous ligands contribute to the pathogenesis of AAA and that targeting TLR2 offers great potential toward the development of therapeutic agents against AAA.

关键词： Abdominal aortic aneurysm damps Vascular remodeling TLR2 Immune microenvironment

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新冠肺炎患者血浆damps及FGL1、GDF-15表达特点及其临床意义研究

新冠肺炎患者血浆DAMPs及FGL1、GDF-15表达特点及其临床意义研究

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作者：王秀雯中国人民解放军医学院

学位级别：硕士

研究背景:新冠肺炎(COVID-19)与全身性炎症反应相关,过度的炎症反应会造成多器官损伤或衰竭,可导致患者死亡。新冠肺炎病情恶化往往发生在病毒消退时;除了病毒产物外,仍不清楚是否还有其他因素参与炎症级联反应。损伤相关分子模式(Damag... 详细信息

研究背景:新冠肺炎(COVID-19)与全身性炎症反应相关,过度的炎症反应会造成多器官损伤或衰竭,可导致患者死亡。新冠肺炎病情恶化往往发生在病毒消退时;除了病毒产物外,仍不清楚是否还有其他因素参与炎症级联反应。损伤相关分子模式(Damage-associated molecular patterns,damps)为受损的组织细胞释放的胞内分子,是反映组织损伤严重程度的指标,通过与模式识别受体(Pattern recognition receptors,PRRs)的相互作用,启动非感染性炎症反应,进一步放大细胞因子介导的炎症信号。damps分子在新冠病毒感染后的变化特点和临床意义还不是很清楚。此外,IL-6在新冠肺炎患者细胞因子风暴发生发展中扮演重要角色,是患者发展为ICU患者的预测指标之一,与组织损伤密切相关。有研究表明纤维蛋白原样蛋白1(Plasma fibrinogen-like protein 1,FGL1)在急性感染中能够被IL-6诱导产生,在肝细胞稳态维持方面发挥重要作用。生长分化因子15(Growth differentiation facor,GDF-15)属于转化生长因子β(Transforming growth factorβ,TGF-β)超家族成员,在细菌或病毒感染后诱导产生,促进对全身炎症反应的代谢适应,在维持心肌细胞的稳态中发挥重要作用。目前FGL1、GDF-15在新冠肺炎患者体内的变化特点及其临床意义的尚不清楚。目的:明确几种损伤相关分子模式(damps)及细胞因子FGL1、GDF-15在新冠肺炎患者血浆中的表达特点及其临床意义。方法:本研究入组2个队列,队列一:入组28例急性感染期新冠肺炎感染者(9例轻型患者、10例普通型患者和9例重/危重型患者)和9例健康对照者,分析血浆中的damps和GDF-15。队列二:入组37例新冠肺炎患者(14例轻型患者、13例普通型患者和10例重/危重型患者)和14例健康对照者,分析血浆中的FGL1。(1)收集入组患者临床资料。(2)通过Elisa法检测健康对照者、新冠肺炎患者入院时及出院时血浆damps分子(CIRBP、HMGB1、SP-A、S100A8/A9、Histone H4)、GDF-15和FGL1的含量;Aimplex法检测新冠肺炎患者血浆中相关炎症因子表达水平。(3)ROC曲线分析damps分子(S100A8/A9、HMGB1、SP-A、CIRBP、Histone H4)、FGL1、GDF-15和实验室临床指标对于新冠肺炎病情严重程度的价值。(4)分析上述几种分子与患者血浆中IFN-r、MCP-1、IL-10、TNF-α、IL-18、IP-10等实验室指标的相关性。(5)应用流式细胞技术检测新冠患者外周静脉血中PBMC上的CD4+、CD8+T细胞的数目及其上活化分子(HLA-DR、CD38)的表达,分析5种DAMP分子、GDF-15和FGL1与淋巴细胞计数及CD4+、CD8+T细胞活化的关系。(6)分析5种DAMP分子、GDF-15和FGL1与患者心肌、肾脏等组织损伤标志物,包括AST、ALT、e GFR、pro-BNP、c Tn T等的相关性。结果:(1)和健康对照相比,感染新冠肺炎病毒的患者其血浆中HMGB1、SP-A、S100A8/A9含量增高,CIRBP表达水平降低;FGL1、GDF-15表达水平较健康对照者明显增高。(2)HMGB1及FGL1、GDF-15表达水平与患者病情严重程度相关。(3)ROC曲线显示CIRBP、HMGB1、S100A8/A9能够较为敏感地区分新冠肺炎患者和健康对照者;在评估中重型新冠肺炎时,FGL1和GDF15较CRP、IL-6等曲线下面积更大。(4)S100A8/A9水平与血浆IL-12呈正相关;HMGB1水平与血浆IP-10和IFN-γ呈正相关;SP-A水平与IL-1Ra、MCP-1、IP-10、IFN-γ、IL-6、IL-8、CRP水平及最高体温呈正相关;CIRBP水平与IL-1Ra、MCP-1、IP-10水平及最高体温呈负相关。FGL1、GDF-15均与IL-6强正相关。(5)HMGB1水平与T细胞、CD4+T细胞、CD8+T细胞计数呈正相关,与CD4+HLA-DR+T细胞数量呈正相关;S100A8/A9与T细胞、CD4+T细胞计数负相关。(6)入院患者血浆中GDF-15水平与患者心肌损伤标志物c Tn T、pro-BNP成正相关;与肾小球滤过率负相关。结论:1.不同damps分子新冠肺炎患者血浆中的表达变化可能有所不同,其发挥的作用可能也不同。其中,HMGB1、S100A8/A9及SP-A可能参与机体炎症反应,CIRBP与炎症因子水平负相关,可能对机体有保护作用。2.新冠肺炎患者血浆中FGL1和GDF-15的表达可能受到炎症因子的调控,并可能作为疾病严重程度的辅助评估指标。此外,GDF-15还可能作为新冠肺

关键词：新冠肺炎病情严重程度 damps FGL1 GDF-15

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