Neuroinflammation contributes to a wide range of neurodegenerative diseases including Alzheimer's disease,Parkinson's disease,Huntington's disease,and multiple sclerosis.It is driven by non-neuronal glial ...Neuroinflammation contributes to a wide range of neurodegenerative diseases including Alzheimer's disease,Parkinson's disease,Huntington's disease,and multiple sclerosis.It is driven by non-neuronal glial cells,mainly microglia and astrocytes.Microglia are the resident immune cells of the central nervous system,while astrocytes are the main support cells for neuronal functions but can also participate in neuroimmune responses.Both these glial cell types can become reactive upon detection of certain endogenous intracellular molecules that appear in the extracellular space under specific circumstances;these can be pathology-associated abnormal structures,such as amyloidβproteins,or damage-associated molecular patterns released from injured cells,including their mitochondria.Once in the extracellular space,damage-associated molecular patterns act as ligands for specific pattern recognition receptors expressed by glia inducing their reactivity and neuroimmune responses.This review considers the following mitochondrial damage-associated molecular patterns:heme,cytochrome c,cardiolipin,adenosine triphosphate,mitochondrial DNA,mitochondrial transcription factor A,N-formyl peptides,and the tricarboxylic acid cycle metabolites:succinate,fumarate,and itaconate.We describe their well-established functions as damage-associated molecular patterns of the peripheral tissues before summarizing available evidence indicating these molecules may also play significant roles in the neuroimmune processes of the central nervous system.We highlight the pattern recognition receptors that mitochondrial damage-associated molecular patterns interact with and the cellular signaling mechanisms they modulate.Our review demonstrates that some mitochondrial damage-associated molecular patterns,such as cytochrome c,adenosine triphosphate,and mitochondrial transcription factor A,have already demonstrated significant effects on the central nervous system.In contrast,others including cardiolipin,mitochondrial DNA,N-formyl peptides,succinate,fumarate,and itaconate,will require additional studies corroborating their roles as damageassociated molecular patterns in the central nervous system.For all of the reviewed mitochondrial damage-associated molecular patterns,there is a shortage of studies using human cells and tissues,which is identified as a significant knowledge gap.We also assess the need for targeted research on the effects of mitochondrial damage-associated molecular patterns in the central nervous system pathologies where their roles are understudied.Such studies could identify novel treatment strategies for multiple neurodegenerative diseases,which are characterized by chronic neuroinflammation and currently lack effective therapies.展开更多
Type I interferons (IFN) are well studied cytokines with anti-viral and immune-modulating functions. Type I IFNsare produced following viral infections, but until recently, the mechanisms of viral recognition leading ...Type I interferons (IFN) are well studied cytokines with anti-viral and immune-modulating functions. Type I IFNsare produced following viral infections, but until recently, the mechanisms of viral recognition leading to IFN productionwere largely unknown. Toll like receptors (TLRs) have emerged as key transducers of type I IFN during viral infectionsby recognizing various viral components. Furthermore, much progress has been made in defining the signaling path-ways downstream of TLRs for type I IFN production. TLR7 and TLR9 have become apparent as universally importantin inducing type I IFN during infection with most viruses, particularly by plasmacytoid dendritic cells. New intracellularviral pattern recognition receptors leading to type I IFN production have been identified. Many bacteria can also inducethe up-regulation of these cytokines. Interestingly, recent studies have found a detrimental effect on host cells if type IIFN is produced during infection with the intracellular gram-positive bacterial pathogen, Listeria monocytogenes. Thisreview will discuss the recent advances made in defining the signaling pathways leading to type I IFN production.展开更多
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 neuro...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 also supported by several of the identified studies.It can be concluded that further studies of DAMPs and RAMPs of the central nervous system will continue to be an important and productive field of neuroimmunology.展开更多
We investigate responses of the Hodgkin-Huxley globally neuronal systems to periodic spike-train inputs. The firing activities of the neuronal networks show different rhythmic patterns for different parameters. These ...We investigate responses of the Hodgkin-Huxley globally neuronal systems to periodic spike-train inputs. The firing activities of the neuronal networks show different rhythmic patterns for different parameters. These rhyth- mic patterns can be used to explain cycles of firing in real brain. These activity patterns, average activity and coherence measure are affected by two quantities such as the percentage of excitatory couplings and stimulus intensity, in which the percentage of excitatory couplings is more important than stimulus intensity since the transition phenomenon of average activity comes about.展开更多
The flagellin-sensing mechanism is one of the most extensively studied topics in plant defense systems.This widespread interest arises from the ability of flagellin to trigger robust and extensive responses,establishi...The flagellin-sensing mechanism is one of the most extensively studied topics in plant defense systems.This widespread interest arises from the ability of flagellin to trigger robust and extensive responses,establishing it as a cornerstone for research into other defense mechanisms.Plants recognize bacterial flagellin epitopes through plasma-membrane-localized pattern-recognition receptors,initiating pattern-triggered immunity as the frontline defense against bacterial pathogens.In this review,we comprehensively summarize flagellin-sensing mechanisms and signal transduction pathways in plants.We compare the flagellin-sensing mechanisms of plants and mammals,focusing on epitope processing and recognition.We present detailed downstream signaling events,from receptor complex formation to transcriptional reprogramming.Furthermore,we highlight the evolutionary arms race between plants and bacteria and incorporate emerging insights into how flagellin-triggered responses are modulated by receptor networking,phytocytokines,and environmental factors.These findings suggest that flagellin-mediated immune responses are highly dynamic and context dependent.By synthesizing current knowledge and recent discoveries,this review provides updated perspectives on plant–microbe interactions and aims to inspire future research in plant immunity.展开更多
Innate sensing of pathogens by pattern-recognition receptors （PRRs） plays essential roles in the innate discrimination between self and non-self components, leading to the generation of innate immune defense and inf...Innate sensing of pathogens by pattern-recognition receptors （PRRs） plays essential roles in the innate discrimination between self and non-self components, leading to the generation of innate immune defense and inflammatory responses. The initiation, activation and resolution of innate inflammatory response are mediated by a complex network of interactions among the numerous cellular and molecular components of immune and non- immune system. While a controlled and beneficial innate inflammatory response is critical for the elimination of pathogens and maintenance of tissue homeostasis, dysregulated or sustained inflammation leads to pathological conditions such as chronic infection, inflammatory autoimmune diseases. In this review, we discuss some of the recent advances in our understanding of the cellular and molecular mechanisms for the establishment and reJzulation of innate immunity and inflammatory responses.展开更多
Inflammation is an essential response provided by the immune systems that ensures the survival duringinfection and tissue injury. Inflammatory responses are essential for the maintenance of normal tissue homeostasis. ...Inflammation is an essential response provided by the immune systems that ensures the survival duringinfection and tissue injury. Inflammatory responses are essential for the maintenance of normal tissue homeostasis. Themolecular mechanism of inflammation is quite a complicated process which is initiated by the recognition of specificmolecular patterns associated with either infection or tissue injury. The entire process of the inflammatory response ismediated by several key regulators involved in the selective expression of proinflammatory molecules. Prolongedinflammations are often associated with severe detrimental side effects on health. Alterations in inflammatory responsesdue to persistent inducers or genetic variations are on the rise over the last couple of decades, causing a variety ofinflammatory diseases and pathophysiological conditions.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
Plant cells recognize microbial patterns with the plasma-membrane-localized pattern-recognition receptors consisting mainly of receptor kinases(RKs) and receptor-like proteins(RLPs). RKs, such as bacterial flagellin r...Plant cells recognize microbial patterns with the plasma-membrane-localized pattern-recognition receptors consisting mainly of receptor kinases(RKs) and receptor-like proteins(RLPs). RKs, such as bacterial flagellin receptor FLS2, and their downstream signaling components have been studied extensively. However, newly discovered regulatory components of RLP-mediated immune signaling, such as the nlp20 receptor RLP23, await identification. Unlike RKs, RLPs lack a cytoplasmic kinase domain, instead recruiting the receptor-like kinases(RLKs) BAK1 and SOBIR1. SOBIR1 specifically works as an adapter for RLP-mediated immunity. To identify new regulators of RLP-mediated signaling, we looked for SOBIR1-binding proteins(SBPs) in Arabidopsis thaliana using protein immunoprecipitation and mass spectrometry,identifying two G-type lectin RLKs, SBP1 and SBP2, that physically interacted with SOBIR1.SBP1 and SBP2 showed high sequence similarity,were tandemly repeated on chromosome 4, and also interacted with both RLP23 and BAK1. sbp1 sbp2 double mutants obtained via CRISPR-Cas9 gene editing showed severely impaired nlp20-induced reactive oxygen species burst, mitogenactivated protein kinase(MAPK) activation, and defense gene expression, but normal flg22-induced immune responses. We showed that SBP1 regulated nlp20-induced immunity in a kinase activityindependent manner. Furthermore, the nlp20-induced the RLP23–BAK1 interaction, although not the flg22-induced FLS2–BAK1 interaction, was significantly reduced in sbp1 sbp2. This study identified SBPs as new regulatory components in RLP23 receptor complex that may specifically modulate RLP23-mediated immunity by positively regulating the interaction between the RLP23 receptor and the BAK1 co-receptor.展开更多
基金supported by grants from the Jack Brown and Family Alzheimer’s Disease Research Foundationthe Natural Sciences and Engineering Research Council of Canada(No.2020-04407)+1 种基金the University of British Columbia Okanagan CampusThe authors also thank Gentmed SIA for financial assistance。
文摘Neuroinflammation contributes to a wide range of neurodegenerative diseases including Alzheimer's disease,Parkinson's disease,Huntington's disease,and multiple sclerosis.It is driven by non-neuronal glial cells,mainly microglia and astrocytes.Microglia are the resident immune cells of the central nervous system,while astrocytes are the main support cells for neuronal functions but can also participate in neuroimmune responses.Both these glial cell types can become reactive upon detection of certain endogenous intracellular molecules that appear in the extracellular space under specific circumstances;these can be pathology-associated abnormal structures,such as amyloidβproteins,or damage-associated molecular patterns released from injured cells,including their mitochondria.Once in the extracellular space,damage-associated molecular patterns act as ligands for specific pattern recognition receptors expressed by glia inducing their reactivity and neuroimmune responses.This review considers the following mitochondrial damage-associated molecular patterns:heme,cytochrome c,cardiolipin,adenosine triphosphate,mitochondrial DNA,mitochondrial transcription factor A,N-formyl peptides,and the tricarboxylic acid cycle metabolites:succinate,fumarate,and itaconate.We describe their well-established functions as damage-associated molecular patterns of the peripheral tissues before summarizing available evidence indicating these molecules may also play significant roles in the neuroimmune processes of the central nervous system.We highlight the pattern recognition receptors that mitochondrial damage-associated molecular patterns interact with and the cellular signaling mechanisms they modulate.Our review demonstrates that some mitochondrial damage-associated molecular patterns,such as cytochrome c,adenosine triphosphate,and mitochondrial transcription factor A,have already demonstrated significant effects on the central nervous system.In contrast,others including cardiolipin,mitochondrial DNA,N-formyl peptides,succinate,fumarate,and itaconate,will require additional studies corroborating their roles as damageassociated molecular patterns in the central nervous system.For all of the reviewed mitochondrial damage-associated molecular patterns,there is a shortage of studies using human cells and tissues,which is identified as a significant knowledge gap.We also assess the need for targeted research on the effects of mitochondrial damage-associated molecular patterns in the central nervous system pathologies where their roles are understudied.Such studies could identify novel treatment strategies for multiple neurodegenerative diseases,which are characterized by chronic neuroinflammation and currently lack effective therapies.
基金A. K. Perry is supported by the Howard Hughes Medi-cal Institute predoctoral fellowship (Grant No. 59003787).Part of this work was also supported by National Insti-tutes of Health research grants RO1 CA87924, RO1AI056154, and R37 AI47868 to G. Cheng and from the MajorResearch Plan (30170461, 30430640) +1 种基金Natural ScienceFoundation of China, and the National Basic ResearchProgram of MOST (2002CB513001, 2001CB-510002)H. Tang. H. Tang is also a fellow of Outstanding YoungInvestigators of National Naturual Science Foundation ofChina (30025010).
文摘Type I interferons (IFN) are well studied cytokines with anti-viral and immune-modulating functions. Type I IFNsare produced following viral infections, but until recently, the mechanisms of viral recognition leading to IFN productionwere largely unknown. Toll like receptors (TLRs) have emerged as key transducers of type I IFN during viral infectionsby recognizing various viral components. Furthermore, much progress has been made in defining the signaling path-ways downstream of TLRs for type I IFN production. TLR7 and TLR9 have become apparent as universally importantin inducing type I IFN during infection with most viruses, particularly by plasmacytoid dendritic cells. New intracellularviral pattern recognition receptors leading to type I IFN production have been identified. Many bacteria can also inducethe up-regulation of these cytokines. Interestingly, recent studies have found a detrimental effect on host cells if type IIFN is produced during infection with the intracellular gram-positive bacterial pathogen, Listeria monocytogenes. Thisreview will discuss the recent advances made in defining the signaling pathways leading to type I IFN production.
基金supported by grants from the Natural Sciences and Engineering Research Council of Canada and the Jack Brown and Family Alzheimer's Disease Research Foundation。
文摘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 also supported by several of the identified studies.It can be concluded that further studies of DAMPs and RAMPs of the central nervous system will continue to be an important and productive field of neuroimmunology.
文摘We investigate responses of the Hodgkin-Huxley globally neuronal systems to periodic spike-train inputs. The firing activities of the neuronal networks show different rhythmic patterns for different parameters. These rhyth- mic patterns can be used to explain cycles of firing in real brain. These activity patterns, average activity and coherence measure are affected by two quantities such as the percentage of excitatory couplings and stimulus intensity, in which the percentage of excitatory couplings is more important than stimulus intensity since the transition phenomenon of average activity comes about.
基金supported by grants from the Institute for Basic Science(IBS-R021-D1-2025-a00)the National Research Foundation of Korea(RS-2024-00338015)to H.-S.L.and by the Startup Fund from Duke Kunshan University to E.Y.K.D.-H.Lsupported by a postdoctoral fellowship from the National Research Foundation of Korea(NRF-2021R1A6A3A03039464).No conflict of interest is declared.
文摘The flagellin-sensing mechanism is one of the most extensively studied topics in plant defense systems.This widespread interest arises from the ability of flagellin to trigger robust and extensive responses,establishing it as a cornerstone for research into other defense mechanisms.Plants recognize bacterial flagellin epitopes through plasma-membrane-localized pattern-recognition receptors,initiating pattern-triggered immunity as the frontline defense against bacterial pathogens.In this review,we comprehensively summarize flagellin-sensing mechanisms and signal transduction pathways in plants.We compare the flagellin-sensing mechanisms of plants and mammals,focusing on epitope processing and recognition.We present detailed downstream signaling events,from receptor complex formation to transcriptional reprogramming.Furthermore,we highlight the evolutionary arms race between plants and bacteria and incorporate emerging insights into how flagellin-triggered responses are modulated by receptor networking,phytocytokines,and environmental factors.These findings suggest that flagellin-mediated immune responses are highly dynamic and context dependent.By synthesizing current knowledge and recent discoveries,this review provides updated perspectives on plant–microbe interactions and aims to inspire future research in plant immunity.
文摘Innate sensing of pathogens by pattern-recognition receptors （PRRs） plays essential roles in the innate discrimination between self and non-self components, leading to the generation of innate immune defense and inflammatory responses. The initiation, activation and resolution of innate inflammatory response are mediated by a complex network of interactions among the numerous cellular and molecular components of immune and non- immune system. While a controlled and beneficial innate inflammatory response is critical for the elimination of pathogens and maintenance of tissue homeostasis, dysregulated or sustained inflammation leads to pathological conditions such as chronic infection, inflammatory autoimmune diseases. In this review, we discuss some of the recent advances in our understanding of the cellular and molecular mechanisms for the establishment and reJzulation of innate immunity and inflammatory responses.
文摘Inflammation is an essential response provided by the immune systems that ensures the survival duringinfection and tissue injury. Inflammatory responses are essential for the maintenance of normal tissue homeostasis. Themolecular mechanism of inflammation is quite a complicated process which is initiated by the recognition of specificmolecular patterns associated with either infection or tissue injury. The entire process of the inflammatory response ismediated by several key regulators involved in the selective expression of proinflammatory molecules. Prolongedinflammations are often associated with severe detrimental side effects on health. Alterations in inflammatory responsesdue to persistent inducers or genetic variations are on the rise over the last couple of decades, causing a variety ofinflammatory diseases and pathophysiological conditions.
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supported by grants from the National Natural Science Foundation of China (32000202, 32270282, 32000200)the open competition program of the top 10 critical priorities of Agricultural Science and Technology Innovation for the 14th Five-Year Plan of Guangdong Province (2022SDZG07)Double First-class Discipline Promotion Project (2021B10564001)。
文摘Plant cells recognize microbial patterns with the plasma-membrane-localized pattern-recognition receptors consisting mainly of receptor kinases(RKs) and receptor-like proteins(RLPs). RKs, such as bacterial flagellin receptor FLS2, and their downstream signaling components have been studied extensively. However, newly discovered regulatory components of RLP-mediated immune signaling, such as the nlp20 receptor RLP23, await identification. Unlike RKs, RLPs lack a cytoplasmic kinase domain, instead recruiting the receptor-like kinases(RLKs) BAK1 and SOBIR1. SOBIR1 specifically works as an adapter for RLP-mediated immunity. To identify new regulators of RLP-mediated signaling, we looked for SOBIR1-binding proteins(SBPs) in Arabidopsis thaliana using protein immunoprecipitation and mass spectrometry,identifying two G-type lectin RLKs, SBP1 and SBP2, that physically interacted with SOBIR1.SBP1 and SBP2 showed high sequence similarity,were tandemly repeated on chromosome 4, and also interacted with both RLP23 and BAK1. sbp1 sbp2 double mutants obtained via CRISPR-Cas9 gene editing showed severely impaired nlp20-induced reactive oxygen species burst, mitogenactivated protein kinase(MAPK) activation, and defense gene expression, but normal flg22-induced immune responses. We showed that SBP1 regulated nlp20-induced immunity in a kinase activityindependent manner. Furthermore, the nlp20-induced the RLP23–BAK1 interaction, although not the flg22-induced FLS2–BAK1 interaction, was significantly reduced in sbp1 sbp2. This study identified SBPs as new regulatory components in RLP23 receptor complex that may specifically modulate RLP23-mediated immunity by positively regulating the interaction between the RLP23 receptor and the BAK1 co-receptor.
