BACKGROUND Serum small extracellular vesicles(sEVs)and their small RNA(sRNA)cargoes could be promising biomarkers for the diagnosis of liver injury.However,the dynamic changes in serum sEVs and their sRNA components d...BACKGROUND Serum small extracellular vesicles(sEVs)and their small RNA(sRNA)cargoes could be promising biomarkers for the diagnosis of liver injury.However,the dynamic changes in serum sEVs and their sRNA components during liver injury have not been well characterized.Given that hepatic macrophages can quickly clear intravenously injected sEVs,the effect of liver injury-related serum sEVs on hepatic macrophages deserves to be explored.AIM To identify the characteristics of serum sEVs and the sRNAs during liver injury and explore their effects on hepatic macrophages.METHODS To identify serum sEV biomarkers for liver injury,we established a CCL4-induced mouse liver injury model in C57BL/6 mice to simulate acute liver injury(ALI),chronic liver injury(CLI)and recovery.Serum sEVs were obtained and characterized by transmission electron microscopy and nanoparticle tracking analysis.Serum sEV sRNAs were profiled by sRNA sequencing.Differentially expressed microRNAs(miRNAs)were compared to mouse liver-enriched miRNAs and previously reported circulating miRNAs related to human liver diseases.The biological significance was evaluated by Ingenuity Pathway Analysis of altered sEV miRNAs and conditioned cultures of ALI serum sEVs with primary hepatic macrophages.RESULTS We found that both ALI and CLI changed the concentration and morphology of serum sEVs.The proportion of serum sEV miRNAs increased upon liver injury,with the liver as the primary contributor.The altered serum sEV miRNAs based on mouse studies were consistent with human liver disease-related circulating miRNAs.We established serum sEV miRNA signatures for ALI and CLI and a panel of miRNAs(miR-122-5p,miR-192-5p,and miR-22-3p)as a common marker for liver injury.The differential serum sEV miRNAs in ALI contributed mainly to liver steatosis and inflammation,while those in CLI contributed primarily to hepatocellular carcinoma and hyperplasia.ALI serum sEVs decreased both CD86 and CD206 expression in monocyte-derived macrophages but increased CD206 expression in resident macrophages in vitro.CONCLUSION Serum sEVs acquired different concentrations,sizes,morphologies and sRNA contents upon liver injury and could change the phenotype of liver macrophages.Serum sEVs therefore have good diagnostic and therapeutic potential for liver injury.展开更多
Rheumatoid arthritis(RA)is an autoimmune disease with a complex etiology.Monocyte-derived macrophages(MDMs)infiltration are associated with RA severity.We have reported the deletion of G-protein-coupled receptor kinas...Rheumatoid arthritis(RA)is an autoimmune disease with a complex etiology.Monocyte-derived macrophages(MDMs)infiltration are associated with RA severity.We have reported the deletion of G-protein-coupled receptor kinase 2(GRK2)reprograms macrophages toward an anti-inflammatory phenotype by recovering G-protein-coupled receptor signaling.However,as more GRK2-interacting proteins were discovered,the GRK2 interactome mechanisms in RA have been understudied.Thus,in the collagen-induced arthritis mouse model,we performed genetic GRK2 deletion using GRK2^(f/f)Lyz2-Cre^(+/−)mice.Synovial inflammation and M1 polarization were improved in GRK2^(f/f)Lyz2-Cre^(+/−)mice.Supporting experiments with RNA-seq and dual-luciferase reporter assays identified peroxisome proliferator-activated receptorγ(PPARγ)as a new GRK2-interacting protein.We further confirmed that fms-related tyrosine kinase 1(Flt-1),which promoted macrophage migration to induce angiogenesis,was inhibited by GRK2-PPARγsignaling.Mechanistically,excess GRK2 membrane recruitment in CIA MDMs reduced the activation of PPARγligand-binding domain and enhanced Flt-1 transcription.Furthermore,the treatment of mice with GRK2 activity inhibitor resulted in significantly diminished CIA pathology,Flt-1^(+)macrophages induced-synovial inflammation,and angiogenesis.Altogether,we anticipate to facilitate the elucidation of previously unappreciated details of GRK2-specific intracellular signaling.Targeting GRK2 activity is a viable strategy to inhibit MDMs infiltration,affording a distinct way to control joint inflammation and angiogenesis of RA.展开更多
Macrophages,which are key cellular components of the liver,have emerged as essential players in the maintenance of hepatic homeostasis and in injury and repair processes in acute and chronic liver diseases.Upon liver ...Macrophages,which are key cellular components of the liver,have emerged as essential players in the maintenance of hepatic homeostasis and in injury and repair processes in acute and chronic liver diseases.Upon liver injury,resident Kupffer cells(KCs)sense disturbances in homeostasis,interact with hepatic cell populations and release chemokines to recruit circulating leukocytes,including monocytes,which subsequently differentiate into monocyte-derived macrophages(MoMφs)in the liver.Both KCs and MoMφs contribute to both the progression and resolution of tissue inflammation and injury in various liver diseases.The diversity of hepatic macrophage subsets and their plasticity explain their different functional responses in distinct liver diseases.In this review,we highlight novel findings regarding the origins and functions of hepatic macrophages and discuss the potential of targeting macrophages as a therapeutic strategy for liver disease.展开更多
Early and strong interferon type I (IFN-I) responses are usually associated with mild COVID-19 disease, whereas persistent orunregulated proinflammatory cytokine responses are associated with severe disease outcomes. ...Early and strong interferon type I (IFN-I) responses are usually associated with mild COVID-19 disease, whereas persistent orunregulated proinflammatory cytokine responses are associated with severe disease outcomes. Previous work suggested thatmonocyte-derived macrophages (MDMs) are resistant and unresponsive to SARS-CoV-2 infection. Here, we demonstrate that uponphagocytosis of SARS-CoV-2-infected cells, MDMs are activated and secrete IL-6 and TNF. Importantly, activated MDMs in turnmediate strong activation of plasmacytoid dendritic cells (pDCs), leading to the secretion of high levels of IFN-α and TNF.Furthermore, pDC activation promoted IL-6 production by MDMs. This kind of pDC activation was dependent on direct integrinmediated cell‒cell contacts and involved stimulation of the TLR7 and STING signaling pathways. Overall, the present studydescribes a novel and potent pathway of pDC activation that is linked to the macrophage-mediated clearance of infected cells.These findings suggest that a high infection rate by SARS-CoV-2 may lead to exaggerated cytokine responses, which maycontribute to tissue damage and severe disease.展开更多
Interactions between brain-resident and periph-eral infiltrated immune cells are thought to contribute to neuroplasticity after cerebral ischemia.However,con-ventional bulk sequencing makes it challenging to depict th...Interactions between brain-resident and periph-eral infiltrated immune cells are thought to contribute to neuroplasticity after cerebral ischemia.However,con-ventional bulk sequencing makes it challenging to depict this complex immune network.Using single-cell RNA sequencing,we mapped compositional and transcriptional features of peri-infarct immune cells.Microglia were the predominant cell type in the peri-infarct region,displaying a more diverse activation pattern than the typical pro-and anti-inflammatory state,with axon tract-associated micro-glia(ATMs)being associated with neuronal regeneration.Trajectory inference suggested that infiltrated monocyte-derived macrophages(MDMs)exhibited a gradual fate trajectory transition to activated MDMs.Inter-cellular crosstalk between MDMs and microglia orchestrated anti-inflammatory and repair-promoting microglia phenotypes and promoted post-stroke neurogenesis,with SOX2 and related Akt/CREB signaling as the underlying mechanisms.This description of the brain's immune landscape and its relationship with neurogenesis provides new insight into promoting neural repair by regulating neuroinflammatory responses.展开更多
Neonatal arterial ischemic stroke(NAIS)and neonatal hypoxic-ischemic encephalopathy(HIE)are common causes of neurological impairments in infants,for which treatment options are very limited.NAIS and HIE induce an inna...Neonatal arterial ischemic stroke(NAIS)and neonatal hypoxic-ischemic encephalopathy(HIE)are common causes of neurological impairments in infants,for which treatment options are very limited.NAIS and HIE induce an innate immune response that involves the recruitment of peripheral immune cells,including monocytes,into the brain.Monocytes and monocyte-derived cells have the potential to contribute to both harmful and beneficial pathophysiological processes,such as neuroinflammation and brain repair,but their roles in NAIS and HIE remain poorly understood.Furthermore,recent evidence indicates that monocyte-derived macrophages can persist in the brain for several months following NAIS and HIE in mice,with possible long-lasting consequences that are still unknown.This review provides a comprehensive overview of the mechanisms of monocyte infiltration and their potential functions in the ischemic brain,focusing on HIE and NAIS.Therapeutic strategies targeting monocytes and the possibility of using monocytes for cell-based therapies are also discussed.展开更多
文摘BACKGROUND Serum small extracellular vesicles(sEVs)and their small RNA(sRNA)cargoes could be promising biomarkers for the diagnosis of liver injury.However,the dynamic changes in serum sEVs and their sRNA components during liver injury have not been well characterized.Given that hepatic macrophages can quickly clear intravenously injected sEVs,the effect of liver injury-related serum sEVs on hepatic macrophages deserves to be explored.AIM To identify the characteristics of serum sEVs and the sRNAs during liver injury and explore their effects on hepatic macrophages.METHODS To identify serum sEV biomarkers for liver injury,we established a CCL4-induced mouse liver injury model in C57BL/6 mice to simulate acute liver injury(ALI),chronic liver injury(CLI)and recovery.Serum sEVs were obtained and characterized by transmission electron microscopy and nanoparticle tracking analysis.Serum sEV sRNAs were profiled by sRNA sequencing.Differentially expressed microRNAs(miRNAs)were compared to mouse liver-enriched miRNAs and previously reported circulating miRNAs related to human liver diseases.The biological significance was evaluated by Ingenuity Pathway Analysis of altered sEV miRNAs and conditioned cultures of ALI serum sEVs with primary hepatic macrophages.RESULTS We found that both ALI and CLI changed the concentration and morphology of serum sEVs.The proportion of serum sEV miRNAs increased upon liver injury,with the liver as the primary contributor.The altered serum sEV miRNAs based on mouse studies were consistent with human liver disease-related circulating miRNAs.We established serum sEV miRNA signatures for ALI and CLI and a panel of miRNAs(miR-122-5p,miR-192-5p,and miR-22-3p)as a common marker for liver injury.The differential serum sEV miRNAs in ALI contributed mainly to liver steatosis and inflammation,while those in CLI contributed primarily to hepatocellular carcinoma and hyperplasia.ALI serum sEVs decreased both CD86 and CD206 expression in monocyte-derived macrophages but increased CD206 expression in resident macrophages in vitro.CONCLUSION Serum sEVs acquired different concentrations,sizes,morphologies and sRNA contents upon liver injury and could change the phenotype of liver macrophages.Serum sEVs therefore have good diagnostic and therapeutic potential for liver injury.
基金We thank LetPub(www.letpub.com)for its linguistic assistance during the preparation of this manuscript.We thank all the patients who participated in providing us with synovial tissues and blood samples.Graphical abstract was created with BioRender.com(publication and licensing rights number JZ25ROGTF8)This study was supported by the National Natural Science Foundation of China(No.82003763,No.81973332,No.82173824,No.82204405,No.82204402)+2 种基金Research Fund of Anhui Institute of translational medicine(2022zhyx-B04,China)The 2022 Basic and Clinical Collaborative Research of Anhui Medical University(2022sfy015,China)Natural Science Foundation of Anhui Provincial(2108085QH383,China).
文摘Rheumatoid arthritis(RA)is an autoimmune disease with a complex etiology.Monocyte-derived macrophages(MDMs)infiltration are associated with RA severity.We have reported the deletion of G-protein-coupled receptor kinase 2(GRK2)reprograms macrophages toward an anti-inflammatory phenotype by recovering G-protein-coupled receptor signaling.However,as more GRK2-interacting proteins were discovered,the GRK2 interactome mechanisms in RA have been understudied.Thus,in the collagen-induced arthritis mouse model,we performed genetic GRK2 deletion using GRK2^(f/f)Lyz2-Cre^(+/−)mice.Synovial inflammation and M1 polarization were improved in GRK2^(f/f)Lyz2-Cre^(+/−)mice.Supporting experiments with RNA-seq and dual-luciferase reporter assays identified peroxisome proliferator-activated receptorγ(PPARγ)as a new GRK2-interacting protein.We further confirmed that fms-related tyrosine kinase 1(Flt-1),which promoted macrophage migration to induce angiogenesis,was inhibited by GRK2-PPARγsignaling.Mechanistically,excess GRK2 membrane recruitment in CIA MDMs reduced the activation of PPARγligand-binding domain and enhanced Flt-1 transcription.Furthermore,the treatment of mice with GRK2 activity inhibitor resulted in significantly diminished CIA pathology,Flt-1^(+)macrophages induced-synovial inflammation,and angiogenesis.Altogether,we anticipate to facilitate the elucidation of previously unappreciated details of GRK2-specific intracellular signaling.Targeting GRK2 activity is a viable strategy to inhibit MDMs infiltration,affording a distinct way to control joint inflammation and angiogenesis of RA.
基金supported by the Federal Ministry of Education and Research(BMBF,ImmuneAvatar)supported by NIH grants DK109574,DK121330,DK122708,and DK122796supported by the German Research Foundation(DFG SFB/TRR296,CRC1382,Ta434/3-1,and Ta434/5-1).
文摘Macrophages,which are key cellular components of the liver,have emerged as essential players in the maintenance of hepatic homeostasis and in injury and repair processes in acute and chronic liver diseases.Upon liver injury,resident Kupffer cells(KCs)sense disturbances in homeostasis,interact with hepatic cell populations and release chemokines to recruit circulating leukocytes,including monocytes,which subsequently differentiate into monocyte-derived macrophages(MoMφs)in the liver.Both KCs and MoMφs contribute to both the progression and resolution of tissue inflammation and injury in various liver diseases.The diversity of hepatic macrophage subsets and their plasticity explain their different functional responses in distinct liver diseases.In this review,we highlight novel findings regarding the origins and functions of hepatic macrophages and discuss the potential of targeting macrophages as a therapeutic strategy for liver disease.
文摘Early and strong interferon type I (IFN-I) responses are usually associated with mild COVID-19 disease, whereas persistent orunregulated proinflammatory cytokine responses are associated with severe disease outcomes. Previous work suggested thatmonocyte-derived macrophages (MDMs) are resistant and unresponsive to SARS-CoV-2 infection. Here, we demonstrate that uponphagocytosis of SARS-CoV-2-infected cells, MDMs are activated and secrete IL-6 and TNF. Importantly, activated MDMs in turnmediate strong activation of plasmacytoid dendritic cells (pDCs), leading to the secretion of high levels of IFN-α and TNF.Furthermore, pDC activation promoted IL-6 production by MDMs. This kind of pDC activation was dependent on direct integrinmediated cell‒cell contacts and involved stimulation of the TLR7 and STING signaling pathways. Overall, the present studydescribes a novel and potent pathway of pDC activation that is linked to the macrophage-mediated clearance of infected cells.These findings suggest that a high infection rate by SARS-CoV-2 may lead to exaggerated cytokine responses, which maycontribute to tissue damage and severe disease.
基金supported by the National Natural Science Foundation of China(82071467)the International(Regional)Cooperation and Exchange Program of the National Natural Science Foundation of China(82111330075)+3 种基金the National Natural Science Foundation for Youth Scholars of China(81801053)the Innovation Team Support Plan of Universities in Liaoning Province(LT2019015)the Liaoning Provincial Key Research and Development Guidance Program(2019JH8/10300002)the Liaoning Revitalization Talents Plan(XLYC1802097).
文摘Interactions between brain-resident and periph-eral infiltrated immune cells are thought to contribute to neuroplasticity after cerebral ischemia.However,con-ventional bulk sequencing makes it challenging to depict this complex immune network.Using single-cell RNA sequencing,we mapped compositional and transcriptional features of peri-infarct immune cells.Microglia were the predominant cell type in the peri-infarct region,displaying a more diverse activation pattern than the typical pro-and anti-inflammatory state,with axon tract-associated micro-glia(ATMs)being associated with neuronal regeneration.Trajectory inference suggested that infiltrated monocyte-derived macrophages(MDMs)exhibited a gradual fate trajectory transition to activated MDMs.Inter-cellular crosstalk between MDMs and microglia orchestrated anti-inflammatory and repair-promoting microglia phenotypes and promoted post-stroke neurogenesis,with SOX2 and related Akt/CREB signaling as the underlying mechanisms.This description of the brain's immune landscape and its relationship with neurogenesis provides new insight into promoting neural repair by regulating neuroinflammatory responses.
基金Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq),Grant/Award Number:13757/2020-8Fundação de AmparoàPesquisa do Estado do Rio de Janeiro(FAPERJ),Grant/Award Numbers:E-26/201.279/2021,E-26/203.227/2017。
文摘Neonatal arterial ischemic stroke(NAIS)and neonatal hypoxic-ischemic encephalopathy(HIE)are common causes of neurological impairments in infants,for which treatment options are very limited.NAIS and HIE induce an innate immune response that involves the recruitment of peripheral immune cells,including monocytes,into the brain.Monocytes and monocyte-derived cells have the potential to contribute to both harmful and beneficial pathophysiological processes,such as neuroinflammation and brain repair,but their roles in NAIS and HIE remain poorly understood.Furthermore,recent evidence indicates that monocyte-derived macrophages can persist in the brain for several months following NAIS and HIE in mice,with possible long-lasting consequences that are still unknown.This review provides a comprehensive overview of the mechanisms of monocyte infiltration and their potential functions in the ischemic brain,focusing on HIE and NAIS.Therapeutic strategies targeting monocytes and the possibility of using monocytes for cell-based therapies are also discussed.
