Previous studies showed that acetyl-11-keto-beta-boswellic acid(AKBA),the active ingredient in the natural Chinese medicine Boswellia,can stimulate sciatic nerve injury repair via promoting Schwann cell proliferation....Previous studies showed that acetyl-11-keto-beta-boswellic acid(AKBA),the active ingredient in the natural Chinese medicine Boswellia,can stimulate sciatic nerve injury repair via promoting Schwann cell proliferation.However,the underlying molecular mechanism remains poorly understood.In this study,we performed genomic sequencing in a rat model of sciatic nerve crush injury after gastric AKBA administration for 30 days.We found that the phagosome pathway was related to AKBA treatment,and brain-derived neurotrophic factor expression in the neurotrophic factor signaling pathway was also highly up-regulated.We further investigated gene and protein expression changes in the phagosome pathway and neurotrophic factor signaling pathway.Myeloperoxidase expression in the phagosome pathway was markedly decreased,and brain-derived neurotrophic factor,nerve growth factor,and nerve growth factor receptor expression levels in the neurotrophic factor signaling pathway were greatly increased.Additionally,expression levels of the inflammatory factors CD68,interleukin-1β,pro-interleukin-1β,and tumor necrosis factor-αwere also decreased.Myelin basic protein-andβ3-tubulin-positive expression as well as the axon diameter-to-total nerve diameter ratio in the injured sciatic nerve were also increased.These findings suggest that,at the molecular level,AKBA can increase neurotrophic factor expression through inhibiting myeloperoxidase expression and reducing inflammatory reactions,which could promote myelin sheath and axon regeneration in the injured sciatic nerve.展开更多
Lipid droplets(LDs)are intracellular organelles that can be induced and interact with phagosomes during the process of pathogen phagocytosis in macrophages.However,the function of LDs in phagocytosis remains elusive.H...Lipid droplets(LDs)are intracellular organelles that can be induced and interact with phagosomes during the process of pathogen phagocytosis in macrophages.However,the function of LDs in phagocytosis remains elusive.Here,we unveil the role of LDs in modulating phagosome formation via a fungal infection model.Specifically,LD accumulation restricted the degree of phagosome formation and protected macrophages from death.Mechanistically,LD formation competitively consumed the intracellular endoplasmic reticulum membrane and altered RAC1 translocation and GTPase activity,which resulted in limited phagosome formation in macrophages during fungal engulfment.Mice with Hilpda-deficient macrophages were more susceptible to the lethal sequelae of systemic infection with C.albicans.Notably,administration of the ATGL inhibitor atglistatin improved host outcomes in disseminated fungal infections.Taken together,our study elucidates the mechanism by which LDs control phagosome formation to prevent immune cell death and offers a potential drug target for the treatment of C.albicans infections.展开更多
The ubiquitin system comprises enzymes that are responsible for ubiquitination and deubiquitination, as well as ubiquitin receptors that are capable of recognizing and deciphering the ubiquitin code, which act in coor...The ubiquitin system comprises enzymes that are responsible for ubiquitination and deubiquitination, as well as ubiquitin receptors that are capable of recognizing and deciphering the ubiquitin code, which act in coordination to regulate almost all host cellular processes, including host-pathogen interactions. In response to pathogen infection, the host innate immune system launches an array of distinct antimicrobial activities encompassing inflammatory signaling, phagosomal maturation, autophagy and apoptosis, all of which are fine-tuned by the ubiquitin system to eradicate the invading pathogens and to reduce concomitant host damage. By contrast, pathogens have evolved a cohort of exquisite strategies to evade host innate immunity by usurping the ubiquitin system for their own benefits. Here, we present recent advances regarding the ubiquitin system-mediated modulation of host-pathogen interplay, with a specific focus on host innate immune defenses and bacterial pathogen immune evasion.展开更多
Bacterial cell wall component-induced tolerance represents an important protective mechanism during microbial infection.Tolerance induced by the TLR2 agonist bacterial lipoprotein(BLP)has been shown to attenuate the i...Bacterial cell wall component-induced tolerance represents an important protective mechanism during microbial infection.Tolerance induced by the TLR2 agonist bacterial lipoprotein(BLP)has been shown to attenuate the inflammatory response,and simultaneously to augment antimicrobial function,thereby conferring its protection against microbial sepsis.However,the underlying mechanism by which BLP tolerance augments bactericidal activity has not been fully elucidated.Here,we reported that the induction of BLP tolerance in murine macrophages upregulated the expression of Rab20,a membrane trafficking regulator,at both the mRNA and protein levels upon bacterial infection.The knockdown of Rab20 with Rab20 specific siRNA(siRab20)did not affect the phagocytosis of Escherichia coli(E.coli),but substantially impaired the intracellular killing of the ingested E.coli in BLP-tolerized macrophages.Furthermore,Rab20 was associated with GFP-E.coli containing phagosomes,and BLP tolerization resulted in the enhanced maturation of GFP-E.coli-containing phagosomes associated with Rab20 and strong lysosomal acidification.The knockdown of Rab20 substantially diminished lysosome acidification and disturbed the fusion of GFP-E.coli containing phagosomes with lysosomes in BLP-tolerized macrophages.These results demonstrate that Rab20 plays a critical role in BLP tolerization-induced augmentation of bactericidal activity via promoting phagosome maturation and the fusion of bacteria containing phagosomes with lysosomes.展开更多
基金supported by the National Natural Science Foundation of China, No.31972725(to WHY)
文摘Previous studies showed that acetyl-11-keto-beta-boswellic acid(AKBA),the active ingredient in the natural Chinese medicine Boswellia,can stimulate sciatic nerve injury repair via promoting Schwann cell proliferation.However,the underlying molecular mechanism remains poorly understood.In this study,we performed genomic sequencing in a rat model of sciatic nerve crush injury after gastric AKBA administration for 30 days.We found that the phagosome pathway was related to AKBA treatment,and brain-derived neurotrophic factor expression in the neurotrophic factor signaling pathway was also highly up-regulated.We further investigated gene and protein expression changes in the phagosome pathway and neurotrophic factor signaling pathway.Myeloperoxidase expression in the phagosome pathway was markedly decreased,and brain-derived neurotrophic factor,nerve growth factor,and nerve growth factor receptor expression levels in the neurotrophic factor signaling pathway were greatly increased.Additionally,expression levels of the inflammatory factors CD68,interleukin-1β,pro-interleukin-1β,and tumor necrosis factor-αwere also decreased.Myelin basic protein-andβ3-tubulin-positive expression as well as the axon diameter-to-total nerve diameter ratio in the injured sciatic nerve were also increased.These findings suggest that,at the molecular level,AKBA can increase neurotrophic factor expression through inhibiting myeloperoxidase expression and reducing inflammatory reactions,which could promote myelin sheath and axon regeneration in the injured sciatic nerve.
基金supported by grants from the National Natural Science Foundation of China(82321002,32230033 and 81930039 to CG)the National Key Research and Development Program of China(2021YFC2300603 and 2023YFC2306102 to CG)supported by the Future Scholar Program of Shandong University(21510082364125).
文摘Lipid droplets(LDs)are intracellular organelles that can be induced and interact with phagosomes during the process of pathogen phagocytosis in macrophages.However,the function of LDs in phagocytosis remains elusive.Here,we unveil the role of LDs in modulating phagosome formation via a fungal infection model.Specifically,LD accumulation restricted the degree of phagosome formation and protected macrophages from death.Mechanistically,LD formation competitively consumed the intracellular endoplasmic reticulum membrane and altered RAC1 translocation and GTPase activity,which resulted in limited phagosome formation in macrophages during fungal engulfment.Mice with Hilpda-deficient macrophages were more susceptible to the lethal sequelae of systemic infection with C.albicans.Notably,administration of the ATGL inhibitor atglistatin improved host outcomes in disseminated fungal infections.Taken together,our study elucidates the mechanism by which LDs control phagosome formation to prevent immune cell death and offers a potential drug target for the treatment of C.albicans infections.
文摘The ubiquitin system comprises enzymes that are responsible for ubiquitination and deubiquitination, as well as ubiquitin receptors that are capable of recognizing and deciphering the ubiquitin code, which act in coordination to regulate almost all host cellular processes, including host-pathogen interactions. In response to pathogen infection, the host innate immune system launches an array of distinct antimicrobial activities encompassing inflammatory signaling, phagosomal maturation, autophagy and apoptosis, all of which are fine-tuned by the ubiquitin system to eradicate the invading pathogens and to reduce concomitant host damage. By contrast, pathogens have evolved a cohort of exquisite strategies to evade host innate immunity by usurping the ubiquitin system for their own benefits. Here, we present recent advances regarding the ubiquitin system-mediated modulation of host-pathogen interplay, with a specific focus on host innate immune defenses and bacterial pathogen immune evasion.
基金This work was supported by the National Natural Science Foundation of China(81471901,81272149)the Guangdong Provincial Natural Science Foundation(2015A030311031,2018A0303130289)+1 种基金the Guangdong Provincial Key Laboratory Construction Project of China(2014B030301044)the South Wisdom Valley Innovative Research Team Program(CXTD-001).
文摘Bacterial cell wall component-induced tolerance represents an important protective mechanism during microbial infection.Tolerance induced by the TLR2 agonist bacterial lipoprotein(BLP)has been shown to attenuate the inflammatory response,and simultaneously to augment antimicrobial function,thereby conferring its protection against microbial sepsis.However,the underlying mechanism by which BLP tolerance augments bactericidal activity has not been fully elucidated.Here,we reported that the induction of BLP tolerance in murine macrophages upregulated the expression of Rab20,a membrane trafficking regulator,at both the mRNA and protein levels upon bacterial infection.The knockdown of Rab20 with Rab20 specific siRNA(siRab20)did not affect the phagocytosis of Escherichia coli(E.coli),but substantially impaired the intracellular killing of the ingested E.coli in BLP-tolerized macrophages.Furthermore,Rab20 was associated with GFP-E.coli containing phagosomes,and BLP tolerization resulted in the enhanced maturation of GFP-E.coli-containing phagosomes associated with Rab20 and strong lysosomal acidification.The knockdown of Rab20 substantially diminished lysosome acidification and disturbed the fusion of GFP-E.coli containing phagosomes with lysosomes in BLP-tolerized macrophages.These results demonstrate that Rab20 plays a critical role in BLP tolerization-induced augmentation of bactericidal activity via promoting phagosome maturation and the fusion of bacteria containing phagosomes with lysosomes.
