Pattern recognition receptors(PRRs) play important roles in innate immunity system and trigger the specific pathogen recognition by detecting the pathogen-associated molecular patterns. The main four PRRs components i...Pattern recognition receptors(PRRs) play important roles in innate immunity system and trigger the specific pathogen recognition by detecting the pathogen-associated molecular patterns. The main four PRRs components including Toll-like receptors(TLRs), RIG-I-like receptors(RLRs), NOD-like receptors(NLRs) and C-type lectin receptors(CLRs) were surveyed in the five genomes of non-teleost ray-finned fishes(NTR) including bichir(Polypterus senegalus), American paddlefish(Polyodon spathula), alligator gar(Atractosteus spatula), spotted gar(Lepisosteus oculatus) and bowfin(Amia calva), representing all the four major basal groups of ray-finned fishes. The result indicates that all the four PRRs components have been well established in these NTR fishes. In the RLR-MAVS signal pathway, which detects intracellular RNA ligands to induce production of type I interferons(IFNs), the MAVS was lost in bichir particularly. Also, the essential genes of recognition of Lipopolysaccharide(LPS) commonly in mammals like MD2, LY96 and LBP could not be identified in NTR fishes. It is speculated that TLR4 in NTR fishes may act as a cooperator with other PRRs and has a different pathway of recognizing LPS compared with that in mammals. In addition, we provide a survey of NLR and CLR in NTR fishes. The CLRs results suggest that Group V receptors are absent in fishes and Group II and VI receptors are well established in the early vertebrate evolution. Our comprehensive research of PRRs involving NTR fishes provides a new insight into PRR evolution in primitive vertebrate.展开更多
Rasmussen's encephalitis(RE) is a rare pediatric neurological disorder, the etiology of which remains unclear. It has been speculated that the immunopathogenesis of RE involves damage to neurons, which eventually ...Rasmussen's encephalitis(RE) is a rare pediatric neurological disorder, the etiology of which remains unclear. It has been speculated that the immunopathogenesis of RE involves damage to neurons, which eventually leads to the occurrence of RE. Viral infection may be a critical factor in triggering RE immunopathogenesis. In this study, we analyzed the expression of Epstein-Barr virus(EBV) antigens as well as of Toll-like receptor 3(TLR3), TLR9, and downstream adapter TIRdomain-containing adapter-inducing interferon-β(TRIF) in the brain tissues of 26 patients with RE and 16 control individuals using immunohistochemistry(IHC). In the RE group, EBV antigens were detected in 53% of individuals at various expression levels. In contrast, there was no detectable EBV antigen expression in control brain tissues. Moreover, we found marked increases in the expression of TLR3, TLR9, and TRIF in the brain tissues of RE patients compared with levels in the control group. Furthermore, among RE cases, EBV expression and high TLR3 expression were associated with more severe brain atrophy. Our results suggest that the elevated expression of EBV and TLRs may be involved in RE occurrence through the activation of downstream molecules.展开更多
Although IL-12 plays a critical role in priming Th1 and cytotoxic T lymphocyte(CTL) responses, Toll-like receptor(TLR) signaling only induces low amounts of IL-12 in dendritic cells and macrophages, implying the exist...Although IL-12 plays a critical role in priming Th1 and cytotoxic T lymphocyte(CTL) responses, Toll-like receptor(TLR) signaling only induces low amounts of IL-12 in dendritic cells and macrophages, implying the existence of stringent regulatory mechanisms. In this study, we sought to uncover the mechanisms underlying TLR-induced IL-12 expression and the Th1 response. By systemic screening, we identified a number of protein kinases involved in the regulation of TLRinduced IL-12 expression. In particular, PI3 K, ERK, and m TOR play critical roles in the TLR-induced Th1 response by regulating IL-12 and IL-10 production in innate immune cells. Moreover, we identified c-fos as a key molecule that mediates m TOR-regulated IL-12 and IL-10 expression in TLR signaling. Mechanistically, m TOR plays a crucial role in c-fos expression, thereby modulating NFκB binding to promoters of IL-12 and IL-10. By controlling the expression of a special innate gene program, m TOR can specifically regulate the TLR-induced T cell response in vivo. Furthermore, blockade of m TOR by rapamycin efficiently boosted TLR-induced antigen-specific T and B cell responses to HBV and HCV vaccines. Taken together, these results reveal a novel mechanism through which m TOR regulates TLR-induced IL-12 and IL-10 production, contributing new insights for strategies to improve vaccine efficacy.展开更多
Nanoparticles(NPs)which are innovation and research focus in drug delivery systems,still have some disadvantages limiting its application in clinical use,such as short circulation time,recognition and clearance by ret...Nanoparticles(NPs)which are innovation and research focus in drug delivery systems,still have some disadvantages limiting its application in clinical use,such as short circulation time,recognition and clearance by reticuloendothelial system(RES)and passive targeting in certain organs.However,the recent combination of natural components and nanotechnology has offered new solutions to address these problems.A novel biomimetic platform consisting of nanoparticle core and membrane shell,such as cell membrane,exosome or vesicle vastly improves properties of nanoparticles.These coated nanoparticles can replicate the unique functions of the membrane,such as prolonged blood circulation,active targeting capability and enhanced internalization.In this review,we focus on the newest development of biological-camouflaged nanoparticles and mainly introduce its application related to cancer therapy and toll-like receptor.展开更多
Sterile inflammation is a ubiquitous response of tissues to stress and injury,and occurs to a high degree in the liver.This results in high levels of tissue damage after development of the metabolic syndrome,and with ...Sterile inflammation is a ubiquitous response of tissues to stress and injury,and occurs to a high degree in the liver.This results in high levels of tissue damage after development of the metabolic syndrome,and with alcohol excess.Inflammatory cytokines such as interleukin(IL)-1βare key in the initiation and propagation of inflammation and tissue damage.IL-1βis activated by a cytosolic machinery collectively termed the inflammasome,and by proteases released by neutrophils.Most of the inflammatory response is driven by macrophages,but hepatocytes,stellate and sinusoidal endothelial cells also have key roles.Hepatocytes for example release acute phase reactants which have pro-and anti-inflammatory effects,and are also a major source of pro-inflammatory damage associated molecules.Stellate cells can regulate differentiation of regulatory T cells by the production of transforming growth factor(TGF)βand all-trans retinoic acid,but the overall effect seems to be context dependent.The strong hepatic inflammatory response is regulated in many ways,with epigenetic regulation playing a major role.This is seen most notably with the rapid development of non-alcoholic steatohepatitis(NASH)in pups of female mice kept on a high fat diet prior to conception,but is likely occurring in adults that have been under metabolic stress for extended periods of time.Epigenetic regulation is of key importance due to its clinical implications,and potential to reveal new pathways for liver inflammation.展开更多
基金supported by the National Natural Science Foundation of China(31372190)
文摘Pattern recognition receptors(PRRs) play important roles in innate immunity system and trigger the specific pathogen recognition by detecting the pathogen-associated molecular patterns. The main four PRRs components including Toll-like receptors(TLRs), RIG-I-like receptors(RLRs), NOD-like receptors(NLRs) and C-type lectin receptors(CLRs) were surveyed in the five genomes of non-teleost ray-finned fishes(NTR) including bichir(Polypterus senegalus), American paddlefish(Polyodon spathula), alligator gar(Atractosteus spatula), spotted gar(Lepisosteus oculatus) and bowfin(Amia calva), representing all the four major basal groups of ray-finned fishes. The result indicates that all the four PRRs components have been well established in these NTR fishes. In the RLR-MAVS signal pathway, which detects intracellular RNA ligands to induce production of type I interferons(IFNs), the MAVS was lost in bichir particularly. Also, the essential genes of recognition of Lipopolysaccharide(LPS) commonly in mammals like MD2, LY96 and LBP could not be identified in NTR fishes. It is speculated that TLR4 in NTR fishes may act as a cooperator with other PRRs and has a different pathway of recognizing LPS compared with that in mammals. In addition, we provide a survey of NLR and CLR in NTR fishes. The CLRs results suggest that Group V receptors are absent in fishes and Group II and VI receptors are well established in the early vertebrate evolution. Our comprehensive research of PRRs involving NTR fishes provides a new insight into PRR evolution in primitive vertebrate.
基金the National Natural Science Foundation of China (81471957, 81571275, 81671971, and 81701992)the Beijing Municipal Natural Science Foundation (7144217)the Scientific Research Common Program of Beijing Municipal Commission of Education (KM201610025001)
文摘Rasmussen's encephalitis(RE) is a rare pediatric neurological disorder, the etiology of which remains unclear. It has been speculated that the immunopathogenesis of RE involves damage to neurons, which eventually leads to the occurrence of RE. Viral infection may be a critical factor in triggering RE immunopathogenesis. In this study, we analyzed the expression of Epstein-Barr virus(EBV) antigens as well as of Toll-like receptor 3(TLR3), TLR9, and downstream adapter TIRdomain-containing adapter-inducing interferon-β(TRIF) in the brain tissues of 26 patients with RE and 16 control individuals using immunohistochemistry(IHC). In the RE group, EBV antigens were detected in 53% of individuals at various expression levels. In contrast, there was no detectable EBV antigen expression in control brain tissues. Moreover, we found marked increases in the expression of TLR3, TLR9, and TRIF in the brain tissues of RE patients compared with levels in the control group. Furthermore, among RE cases, EBV expression and high TLR3 expression were associated with more severe brain atrophy. Our results suggest that the elevated expression of EBV and TLRs may be involved in RE occurrence through the activation of downstream molecules.
基金support by National Natural Science Foundation of China grants 31070779 and 31170862 (to H.X.), 31100623 (to A.Z.) and 31270917 (to M.D.)National Key laboratory of Virology grant (2014IOV006)+3 种基金H.X. is supported by Chinese Academy of Sciences "100-talent" programNational program for returned oversea talentsthe CAS/SAFEA International Partnership Program for Creative Research TeamsShanghai Pasteur foundation
文摘Although IL-12 plays a critical role in priming Th1 and cytotoxic T lymphocyte(CTL) responses, Toll-like receptor(TLR) signaling only induces low amounts of IL-12 in dendritic cells and macrophages, implying the existence of stringent regulatory mechanisms. In this study, we sought to uncover the mechanisms underlying TLR-induced IL-12 expression and the Th1 response. By systemic screening, we identified a number of protein kinases involved in the regulation of TLRinduced IL-12 expression. In particular, PI3 K, ERK, and m TOR play critical roles in the TLR-induced Th1 response by regulating IL-12 and IL-10 production in innate immune cells. Moreover, we identified c-fos as a key molecule that mediates m TOR-regulated IL-12 and IL-10 expression in TLR signaling. Mechanistically, m TOR plays a crucial role in c-fos expression, thereby modulating NFκB binding to promoters of IL-12 and IL-10. By controlling the expression of a special innate gene program, m TOR can specifically regulate the TLR-induced T cell response in vivo. Furthermore, blockade of m TOR by rapamycin efficiently boosted TLR-induced antigen-specific T and B cell responses to HBV and HCV vaccines. Taken together, these results reveal a novel mechanism through which m TOR regulates TLR-induced IL-12 and IL-10 production, contributing new insights for strategies to improve vaccine efficacy.
基金We thank the financial support from the National Natural Science Foundation of China(No.81773558)the Natural Science Foundation of Guangdong Province(Nos.2020A 151501518 and 2018B 030312010)the Science and Technology Program of Guangzhou(No.201904010380)for this work.
文摘Nanoparticles(NPs)which are innovation and research focus in drug delivery systems,still have some disadvantages limiting its application in clinical use,such as short circulation time,recognition and clearance by reticuloendothelial system(RES)and passive targeting in certain organs.However,the recent combination of natural components and nanotechnology has offered new solutions to address these problems.A novel biomimetic platform consisting of nanoparticle core and membrane shell,such as cell membrane,exosome or vesicle vastly improves properties of nanoparticles.These coated nanoparticles can replicate the unique functions of the membrane,such as prolonged blood circulation,active targeting capability and enhanced internalization.In this review,we focus on the newest development of biological-camouflaged nanoparticles and mainly introduce its application related to cancer therapy and toll-like receptor.
文摘Sterile inflammation is a ubiquitous response of tissues to stress and injury,and occurs to a high degree in the liver.This results in high levels of tissue damage after development of the metabolic syndrome,and with alcohol excess.Inflammatory cytokines such as interleukin(IL)-1βare key in the initiation and propagation of inflammation and tissue damage.IL-1βis activated by a cytosolic machinery collectively termed the inflammasome,and by proteases released by neutrophils.Most of the inflammatory response is driven by macrophages,but hepatocytes,stellate and sinusoidal endothelial cells also have key roles.Hepatocytes for example release acute phase reactants which have pro-and anti-inflammatory effects,and are also a major source of pro-inflammatory damage associated molecules.Stellate cells can regulate differentiation of regulatory T cells by the production of transforming growth factor(TGF)βand all-trans retinoic acid,but the overall effect seems to be context dependent.The strong hepatic inflammatory response is regulated in many ways,with epigenetic regulation playing a major role.This is seen most notably with the rapid development of non-alcoholic steatohepatitis(NASH)in pups of female mice kept on a high fat diet prior to conception,but is likely occurring in adults that have been under metabolic stress for extended periods of time.Epigenetic regulation is of key importance due to its clinical implications,and potential to reveal new pathways for liver inflammation.
