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 al...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 on their similarities with those of mammalians involved in glycan perception.The gained knowledge holds the potential to facilitate the development of sustainable,glycan-based crop protection solutions.展开更多
Pyroptosis is the process of inflammatory cell death.The primary function of pyroptosis is to induce strong inflammatory responses that defend the host against microbe infection.Excessive pyroptosis,however,leads to s...Pyroptosis is the process of inflammatory cell death.The primary function of pyroptosis is to induce strong inflammatory responses that defend the host against microbe infection.Excessive pyroptosis,however,leads to several inflammatory diseases,including sepsis and autoimmune disorders.Pyroptosis can be canonical or noncanonical.Upon microbe infection,the canonical pathway responds to pathogen-associated molecular patterns(PAMPs) and damage-associated molecular patterns(DAMPs),while the noncanonical pathway responds to intracellular lipopolysaccharides(LPS) of Gram-negative bacteria.The last step of pyroptosis requires the cleavage of gasdermin D(GsdmD) at D275(numbering after human GSDMD) into N-and C-termini by caspase 1 in the canonical pathway and caspase 4/5/11(caspase 4/5 in humans,caspase 11 in mice) in the noncanonical pathway.Upon cleavage,the N-terminus of GsdmD(GsdmD-N) forms a transmembrane pore that releases cytokines such as IL-1β and IL-18 and disturbs the regulation of ions and water,eventually resulting in strong inflammation and cell death.Since GsdmD is the effector of pyroptosis,promising inhibitors of GsdmD have been developed for inflammatory diseases.This review will focus on the roles of GsdmD during pyroptosis and in diseases.展开更多
Plants employ a highly effective surveillance system to detect potential pathogens, which is critical for the success of land plants in an environment surrounded by numerous microbes. Recent efforts have led to the id...Plants employ a highly effective surveillance system to detect potential pathogens, which is critical for the success of land plants in an environment surrounded by numerous microbes. Recent efforts have led to the identification of a number of immune receptors and components of immune receptor complexes. It is now clear that receptor-like kinases （RLKs） and receptor-like proteins （RLPs） are key pattern-recognition receptors （PRRs） for microbe- and plant-derived molecular patterns that are associated with pathogen invasion. RLKs and RLPs involved in immune signaling belong to large gene families in plants and have undergone lineage specific expansion. Molecular evolution and population studies on phytopathogenic molecular signatures and their receptors have provided crucial insight into the co-evolution between plants and pathogens.展开更多
Toll-like receptors （TLRs） are germline-encoded pattern-recognition receptors that initiate innate immune re- sponses by recognizing molecular structures shared by a wide range of pathogens, known as pathogen-associ...Toll-like receptors （TLRs） are germline-encoded pattern-recognition receptors that initiate innate immune re- sponses by recognizing molecular structures shared by a wide range of pathogens, known as pathogen-associated molecular patterns （PAMPs）. After tissue injury or cellular stress, TLRs also detect endogenous ligands known as danger-associated molecular patterns （DAMPs）. TLRs are expressed in both non-neuronal and neuronal cell types in the central nervous system （CNS） and contribute to both infectious and non-infectious disorders in the CNS. Following tissue insult and nerve injury, TLRs （such as TLR2, TLR3, and TLR4） induce the activation of microglia and astrocytes and the production of the proinflammatory cytokines in the spinal cord, leading to the development and maintenance of inflammatory pain and neu- ropathic pain. In particular, primary sensory neurons, such as nociceptors, express TLRs （e.g., TLR4 and TLR7） to sense exogenous PAMPs and endogenous DAMPs released after tissue injury and cellular stress. These neuronal TLRs are new players in the processing of pain and itch by increasing the excitability of primary sensory neurons. Given the prevalence of chronic pain and itch and the suffering of affected people, insights into TLR signaling in the nervous system will open a new avenue for the management of clinical pain and itch.展开更多
The elusive task of defining the character of 76 T cells has been an evolving process for immunologists since stumbling upon their existence during the molecular characterization of the a and p T cell receptor genes o...The elusive task of defining the character of 76 T cells has been an evolving process for immunologists since stumbling upon their existence during the molecular characterization of the a and p T cell receptor genes of their better understood brethren. Defying the categorical rules used to distinctly characterize lymphocytes as either innate or adaptive in nature, 76 T cells inhabit a hybrid world of their own. At opposing ends of the simplified spectrum of modes of antigen recognition used by lymphocytes, natural killer and ap T cells are particularly well equipped to respond to the ＇missing self＇ and the ＇dangerous non-self＇, respectively. However, between these two reductive extremes, we are chronically faced with the challenge of making peace with the ＇safe non-self＇ and dealing with the inevitable ＇distressed self＇, and it is within this more complex realm 76 T cells excel thanks to their highly empathetic nature. This review gives an overview of the latest insights revealing the unfolding story of human 76 T cells, providing a biographical sketch of these unique lymphocytes in an attempt to capture the essence of their fundamental nature and events that influence their life trajectory. What hangs in their balance is their nuanced ability to differentiate the friends from the foe and the pathological from the benign to help us adapt swiftly and efficiently to life＇s many stresses.展开更多
Chemotherapy can induce a robust T cell antitumor immune response by triggering immunogenic cell death(ICD),a process in which tumor cells convert from nonimmunogenic to immunogenic forms.However,the antitumor immune ...Chemotherapy can induce a robust T cell antitumor immune response by triggering immunogenic cell death(ICD),a process in which tumor cells convert from nonimmunogenic to immunogenic forms.However,the antitumor immune response of ICD remains limited due to the low immunogenicity of tumor cells and the immunosuppressive tumor microenvironment.Although autophagy is involved in activating tumor immunity,the synergistic role of autophagy in ICD remains elusive and challenging.Herein,we report an autophagy amplification strategy using an ion-chelation reaction to augment chemoimmunotherapy in cancer treatments based on zinc ion(Zn^(2+))-doped,disulfiram(DSF)-loaded mesoporous silica nanoparticles(DSF@Zn-DMSNs).Upon pH-sensitive biodegradation of DSF@Zn-DMSNs,Zn2+and DSF are coreleased in the mildly acidic tumor microenvironment,leading to the formation of toxic Zn2+chelate through an in situ chelation reaction.Consequently,this chelate not only significantly stimulates cellular apoptosis and generates damage-associated molecular patterns(DAMPs)but also activates autophagy,which mediates the amplified release of DAMPs to enhance ICD.In vivo results demonstrated that DSF@Zn-DMSNs exhibit strong therapeutic efficacy via in situ ion chelation and possess the ability to activate autophagy,thus enhancing immunotherapy by promoting the infiltration of T cells.This study provides a smart in situ chelation strategy with tumor microenvironment-responsive autophagy amplification to achieve high tumor chemoimmunotherapy efficacy and biosafety.展开更多
Plant plasma membrane-resident immune receptors regulate plant immunity by recognizing microbe-associated molecular patterns(MAMPs),damage-associated molecular patterns(DAMPs),and phytocytokines.Phytocytokines are pla...Plant plasma membrane-resident immune receptors regulate plant immunity by recognizing microbe-associated molecular patterns(MAMPs),damage-associated molecular patterns(DAMPs),and phytocytokines.Phytocytokines are plant endogenous peptides,which are usually produced in the cytosol and released into the apoplast when plant encounters pathogen infections.Phytocytokines regulate plant immunity through activating an overlapping signaling pathway with MAMPs/DAMPs with some unique features.Here,we highlight the current understanding of phytocytokine production,perception and functions in plant immunity,and discuss how plants and pathogens manipulate phytocytokine signaling for their own benefits during the plant-pathogen warfare.展开更多
Background and aim:Acetaminophen(APAP)overdose is a major cause of acute liver injury,but the role of macrophages in the propagation of the hepatotoxicity is controversial.Early research revealed that macrophage inhib...Background and aim:Acetaminophen(APAP)overdose is a major cause of acute liver injury,but the role of macrophages in the propagation of the hepatotoxicity is controversial.Early research revealed that macrophage inhibitors protect against APAP injury.However,later work demonstrated that macrophage ablation by acute pre-treatment with liposomal clodronate(LC)exacerbates the toxicity.To our surprise,during other studies,we observed that pre-treatment twice with LC seemed to protect against APAP hepatotoxicity,in contrast to acute pre-treatment.The aim of this study was to confirm that observation and to explore the mechanisms.Methods:We treated mice with empty liposomes(LE)or LC twice per week for 1 week before APAP overdose and collected blood and liver tissue at 0,2,and 6 h post-APAP.We then measured liver injury(serum alanine aminotransferase activity,histology),APAP bioactivation(total glutathione,APAP-protein adducts),oxidative stress(oxidized glutathione(GSSG)),glutamate-cysteine ligase subunit c(Gclc)mRNA,and nuclear factor erythroid 2-related factor(Nrf2)immunofluorescence.We also confirmed the ablation of macrophages by F4/80 immunohistochemistry.Results:Pre-treatment twice with LC dramatically reduced F4/80 staining,protected against liver injury,and reduced oxidative stress at 6 h post-APAP,without affecting APAP bioactivation.Importantly,Gclc mRNA was higher in the LC group at 0 h and total glutathione was higher at 2 h,indicating accelerated glutathione re-synthesis after APAP overdose due to greater basal glutamate-cysteine ligase.Oxidative stress was lower in the LC groups at both time points.Finally,total Nrf2 immunofluorescence was higher in the LC group.Conclusions:We conclude that multiple pre-treatments with LC protect against APAP by accelerating glutathione re-synthesis through glutamate-cysteine ligase.Investigators using twice or possibly more LC pre-treatments to deplete macrophages,including peritoneal macrophages,should be aware of this possible confounder.展开更多
基金supported by grant PID2021-126006OB-I00 to A.M.and L.J.grant PID20220-113588RB-I00 to S.M.-S+6 种基金funded by MCIN/AEI/10.13039/501100011033by ERDF A way of making Europe.D.J.B.supported by PRE2019-091276 and P.F.-C.by postdoctoral fellowships financially supported by the Severo Ochoa Program for Centres of Excellence in R&D(grants SEV-2016-0672 and CEX2020-000999-S)funded by MCIN/AEI/10.13039/501100011033.M.M.-D.was recipient of PhD fellow(PRE2019-08812)funded by MCIN/AEI/10.13039/501100011033.E.G.-Rwas supported by Autonomous Region of Madrid fellowship(S2017/BMD-3673)the European Commission-Next Generation EU(Regulation EU2020/2094)through CSIC’s Global Health Platform PTI Salud Global.
文摘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 on their similarities with those of mammalians involved in glycan perception.The gained knowledge holds the potential to facilitate the development of sustainable,glycan-based crop protection solutions.
基金supported by a grant from the National Institute of General Medical Sciences(P20 GM103429,USA)grants from National Heart,Lung and Blood Institute(HL153876,USA)National Eye Institute(EY030621,USA)
文摘Pyroptosis is the process of inflammatory cell death.The primary function of pyroptosis is to induce strong inflammatory responses that defend the host against microbe infection.Excessive pyroptosis,however,leads to several inflammatory diseases,including sepsis and autoimmune disorders.Pyroptosis can be canonical or noncanonical.Upon microbe infection,the canonical pathway responds to pathogen-associated molecular patterns(PAMPs) and damage-associated molecular patterns(DAMPs),while the noncanonical pathway responds to intracellular lipopolysaccharides(LPS) of Gram-negative bacteria.The last step of pyroptosis requires the cleavage of gasdermin D(GsdmD) at D275(numbering after human GSDMD) into N-and C-termini by caspase 1 in the canonical pathway and caspase 4/5/11(caspase 4/5 in humans,caspase 11 in mice) in the noncanonical pathway.Upon cleavage,the N-terminus of GsdmD(GsdmD-N) forms a transmembrane pore that releases cytokines such as IL-1β and IL-18 and disturbs the regulation of ions and water,eventually resulting in strong inflammation and cell death.Since GsdmD is the effector of pyroptosis,promising inhibitors of GsdmD have been developed for inflammatory diseases.This review will focus on the roles of GsdmD during pyroptosis and in diseases.
基金supported by grants from Chinese Natural Science Foundation (31230007)Chinese Ministry of Science and Technology (2011CB1007002011CB100702) to J.M.Z
文摘Plants employ a highly effective surveillance system to detect potential pathogens, which is critical for the success of land plants in an environment surrounded by numerous microbes. Recent efforts have led to the identification of a number of immune receptors and components of immune receptor complexes. It is now clear that receptor-like kinases （RLKs） and receptor-like proteins （RLPs） are key pattern-recognition receptors （PRRs） for microbe- and plant-derived molecular patterns that are associated with pathogen invasion. RLKs and RLPs involved in immune signaling belong to large gene families in plants and have undergone lineage specific expansion. Molecular evolution and population studies on phytopathogenic molecular signatures and their receptors have provided crucial insight into the co-evolution between plants and pathogens.
基金supported by the US National Institutes of Health (R01-DE17794, R01-NS54362 and R01-NS67686)
文摘Toll-like receptors （TLRs） are germline-encoded pattern-recognition receptors that initiate innate immune re- sponses by recognizing molecular structures shared by a wide range of pathogens, known as pathogen-associated molecular patterns （PAMPs）. After tissue injury or cellular stress, TLRs also detect endogenous ligands known as danger-associated molecular patterns （DAMPs）. TLRs are expressed in both non-neuronal and neuronal cell types in the central nervous system （CNS） and contribute to both infectious and non-infectious disorders in the CNS. Following tissue insult and nerve injury, TLRs （such as TLR2, TLR3, and TLR4） induce the activation of microglia and astrocytes and the production of the proinflammatory cytokines in the spinal cord, leading to the development and maintenance of inflammatory pain and neu- ropathic pain. In particular, primary sensory neurons, such as nociceptors, express TLRs （e.g., TLR4 and TLR7） to sense exogenous PAMPs and endogenous DAMPs released after tissue injury and cellular stress. These neuronal TLRs are new players in the processing of pain and itch by increasing the excitability of primary sensory neurons. Given the prevalence of chronic pain and itch and the suffering of affected people, insights into TLR signaling in the nervous system will open a new avenue for the management of clinical pain and itch.
文摘The elusive task of defining the character of 76 T cells has been an evolving process for immunologists since stumbling upon their existence during the molecular characterization of the a and p T cell receptor genes of their better understood brethren. Defying the categorical rules used to distinctly characterize lymphocytes as either innate or adaptive in nature, 76 T cells inhabit a hybrid world of their own. At opposing ends of the simplified spectrum of modes of antigen recognition used by lymphocytes, natural killer and ap T cells are particularly well equipped to respond to the ＇missing self＇ and the ＇dangerous non-self＇, respectively. However, between these two reductive extremes, we are chronically faced with the challenge of making peace with the ＇safe non-self＇ and dealing with the inevitable ＇distressed self＇, and it is within this more complex realm 76 T cells excel thanks to their highly empathetic nature. This review gives an overview of the latest insights revealing the unfolding story of human 76 T cells, providing a biographical sketch of these unique lymphocytes in an attempt to capture the essence of their fundamental nature and events that influence their life trajectory. What hangs in their balance is their nuanced ability to differentiate the friends from the foe and the pathological from the benign to help us adapt swiftly and efficiently to life＇s many stresses.
基金the National Natural Science Foundation of China(Grant No.81730102,32271384)Shanghai Basic Research Program(Grant No.20JC1411702)Shanghai Science and Technology Program(Grant No.20ZR1456100).
文摘Chemotherapy can induce a robust T cell antitumor immune response by triggering immunogenic cell death(ICD),a process in which tumor cells convert from nonimmunogenic to immunogenic forms.However,the antitumor immune response of ICD remains limited due to the low immunogenicity of tumor cells and the immunosuppressive tumor microenvironment.Although autophagy is involved in activating tumor immunity,the synergistic role of autophagy in ICD remains elusive and challenging.Herein,we report an autophagy amplification strategy using an ion-chelation reaction to augment chemoimmunotherapy in cancer treatments based on zinc ion(Zn^(2+))-doped,disulfiram(DSF)-loaded mesoporous silica nanoparticles(DSF@Zn-DMSNs).Upon pH-sensitive biodegradation of DSF@Zn-DMSNs,Zn2+and DSF are coreleased in the mildly acidic tumor microenvironment,leading to the formation of toxic Zn2+chelate through an in situ chelation reaction.Consequently,this chelate not only significantly stimulates cellular apoptosis and generates damage-associated molecular patterns(DAMPs)but also activates autophagy,which mediates the amplified release of DAMPs to enhance ICD.In vivo results demonstrated that DSF@Zn-DMSNs exhibit strong therapeutic efficacy via in situ ion chelation and possess the ability to activate autophagy,thus enhancing immunotherapy by promoting the infiltration of T cells.This study provides a smart in situ chelation strategy with tumor microenvironment-responsive autophagy amplification to achieve high tumor chemoimmunotherapy efficacy and biosafety.
基金supported by National Science Foundation(NSF)(IOS-1951094)and National Institutes of Health(NIH)(R01GM092893)to P.H.,the Natural Science Foundation of Shandong Province(ZR2020MC022)and Youth Innovation Technology Project of Higher School in Shandong Province(2020KJF013)to S.H.The funding agencies have no roles in the design of the study and collection,analysis,and interpretation of data and in writing the manuscript.
文摘Plant plasma membrane-resident immune receptors regulate plant immunity by recognizing microbe-associated molecular patterns(MAMPs),damage-associated molecular patterns(DAMPs),and phytocytokines.Phytocytokines are plant endogenous peptides,which are usually produced in the cytosol and released into the apoplast when plant encounters pathogen infections.Phytocytokines regulate plant immunity through activating an overlapping signaling pathway with MAMPs/DAMPs with some unique features.Here,we highlight the current understanding of phytocytokine production,perception and functions in plant immunity,and discuss how plants and pathogens manipulate phytocytokine signaling for their own benefits during the plant-pathogen warfare.
基金This work was supported by the American Association for the Study of Liver Diseases Foundation,Alexandria,VA,USA(2018 Pinnacle Research Award)by the United States National Institutes of Health(grant numbers T32 GM106999,UL1 TR003107,R42 DK079387 and KL2 TR003108).
文摘Background and aim:Acetaminophen(APAP)overdose is a major cause of acute liver injury,but the role of macrophages in the propagation of the hepatotoxicity is controversial.Early research revealed that macrophage inhibitors protect against APAP injury.However,later work demonstrated that macrophage ablation by acute pre-treatment with liposomal clodronate(LC)exacerbates the toxicity.To our surprise,during other studies,we observed that pre-treatment twice with LC seemed to protect against APAP hepatotoxicity,in contrast to acute pre-treatment.The aim of this study was to confirm that observation and to explore the mechanisms.Methods:We treated mice with empty liposomes(LE)or LC twice per week for 1 week before APAP overdose and collected blood and liver tissue at 0,2,and 6 h post-APAP.We then measured liver injury(serum alanine aminotransferase activity,histology),APAP bioactivation(total glutathione,APAP-protein adducts),oxidative stress(oxidized glutathione(GSSG)),glutamate-cysteine ligase subunit c(Gclc)mRNA,and nuclear factor erythroid 2-related factor(Nrf2)immunofluorescence.We also confirmed the ablation of macrophages by F4/80 immunohistochemistry.Results:Pre-treatment twice with LC dramatically reduced F4/80 staining,protected against liver injury,and reduced oxidative stress at 6 h post-APAP,without affecting APAP bioactivation.Importantly,Gclc mRNA was higher in the LC group at 0 h and total glutathione was higher at 2 h,indicating accelerated glutathione re-synthesis after APAP overdose due to greater basal glutamate-cysteine ligase.Oxidative stress was lower in the LC groups at both time points.Finally,total Nrf2 immunofluorescence was higher in the LC group.Conclusions:We conclude that multiple pre-treatments with LC protect against APAP by accelerating glutathione re-synthesis through glutamate-cysteine ligase.Investigators using twice or possibly more LC pre-treatments to deplete macrophages,including peritoneal macrophages,should be aware of this possible confounder.
