Spinal cord injury(SCI)is a severe neurological condition with limited regenerative capacity and no effective curative treatments.Interleukin-13(IL-13),an immunomodulatory cytokine,has shown therapeutic potential by p...Spinal cord injury(SCI)is a severe neurological condition with limited regenerative capacity and no effective curative treatments.Interleukin-13(IL-13),an immunomodulatory cytokine,has shown therapeutic potential by promoting alternative immune activation and improving recovery after SCI in mice.However,cellbased IL-13 delivery is hindered by poor graft survival and limited localisation at the injury site.Here,we developed an injectable hydrogel-based delivery system(HGIL13)composed of IL-13-loaded poly(lactic-co-glycolic acid)(PLGA)microparticles embedded in a photocrosslinkable gelatin methacrylate(GelMA)matrix,enabling sustained and localised IL-13 release.HGIL13 achieved IL-13 release for up to six weeks and significantly reduced lipopolysaccharide(LPS)-induced inflammation in BV2 microglia in vitro.In a mouse contusion SCI model,HGIL13 enhanced functional recovery,reduced lesion volume,and decreased demyelinated area.Using the Hexbtd^(Tomato)mouse we show that HGIL13 modulated the neuroimmune response by decreasing resident microglia density,downregulating CD86 expression,and upregulating Arginase-1 in both microglia and infiltrating monocyte-derived macrophages.RT-qPCR and RNA-seq analyses confirmed sustained immunomodulation over 28 days and indicated early reduction of activated microglia at 7 days post-injury as a key therapeutic mechanism.This study presents a safe,effective,and translatable strategy for localised cytokine delivery,demonstrating strong potential for immunomodulation and improved functional recovery following SCI.展开更多
Microglia,the resident immune cells of the central nervous system,exhibit conserved developmental origins and core molecular signatures across vertebrate species,highlighting their crucial importance in the central ne...Microglia,the resident immune cells of the central nervous system,exhibit conserved developmental origins and core molecular signatures across vertebrate species,highlighting their crucial importance in the central nervous system.While homeostatic microglia maintain similar functions during phylogeny—such as immune surveillance,debris clearance,and synaptic pruning—their morphology,gene expression,and responses to stimuli remarkably vary by species.These differences reflect evolutionary divergence shaped by factors such as lifespan,regenerative potential,and immune architecture.This review integrates current findings from basic vertebrates such as zebrafish,rodents,and nonhuman primates with those from humans to highlight conserved and divergent aspects of microglial biology throughout evolution.Integrating these evolutionary differences is crucial for translating mechanistic insights across model organisms and advancing microglia-targeted therapies for neurological disorders.展开更多
Viral encephalitis is a devastating disease with high mortality,and survivors often suffer from severe neurological complications.Microglia are innate immune cells of the central nervous system(CNS)parenchyma whose tu...Viral encephalitis is a devastating disease with high mortality,and survivors often suffer from severe neurological complications.Microglia are innate immune cells of the central nervous system(CNS)parenchyma whose turnover is reliant on local proliferation.Microglia express a diverse range of proteins,which allows them to continuously sense the environment and quickly react to changes.Under inflammatory conditions such as CNS viral infection,microglia promote innate and adaptive immune responses to protect the host.However,during viral infection,a dysregulated microglia-T-cell interplay may result in altered phagocytosis of neuronal synapses by microglia that causes neurocognitive impairment.In this review,we summarize the current knowledge on the role of microglia in viral encephalitis,propose questions to be answered in the future and suggest possible therapeutic targets.展开更多
In their recent paper published in Nature Cell Biology,1 Wang and colleagues defined a pathogenetic mechanism among a variety of lysosomal storage disorders(LSDs)mediating neuronal death and disease progression.The au...In their recent paper published in Nature Cell Biology,1 Wang and colleagues defined a pathogenetic mechanism among a variety of lysosomal storage disorders(LSDs)mediating neuronal death and disease progression.The authors observed neuron-intrinsic activated cGAS-STING signaling triggered by accumulating cytosolic dsDNA,and thus,they provide a valuable target for directed therapies.展开更多
Macrophages(MΦs)are versatile cells found in every organ.Throughout the body,they work tirelessly to maintain tissues.To this end,they are instructed by their respective niches to express organ-specific genes and pro...Macrophages(MΦs)are versatile cells found in every organ.Throughout the body,they work tirelessly to maintain tissues.To this end,they are instructed by their respective niches to express organ-specific genes and proteins,resulting in a variety of cell morphologies and highly specialized functions across different tissues[1].A recent study by Wang et al.used single-cell RNA sequencing to comprehensively profile human MΦphenotypes across 19 organs between postconception weeks(PCW)4 and 26[2].This study revealed a surprising diversity of these cells and suggests new avenues of research.展开更多
In their paper published in Cell,1 Xu et al.leveraged single-cell sequencing and cell lineage tracing tools combined with two-photon live imaging to characterise the spatiotemporal immune recruitment and infiltration ...In their paper published in Cell,1 Xu et al.leveraged single-cell sequencing and cell lineage tracing tools combined with two-photon live imaging to characterise the spatiotemporal immune recruitment and infiltration to the choroid plexus(ChP).They provide seminal insights into the communication between specialised ChP epithelial and macrophage populations,which coordinate the stepwise response to inflammation and its resolution.展开更多
基金supported by University College Dublin and Taighde ireann-Research Ireland(19/FFP/6642 to DD,16/IA/4584 to DB,and GOIPG/2021/304 to CW)supported by the Medical Research Center Initiative for High Depth Omics,and CURE:JPMXP1323015486 for MIB,and AMRC,Kyushu University+1 种基金by AMED JP23gm1910004,JP23jf0126004,24zf0127012,JSPS KAKENHIJP25H01009Ono Pharmaceutical Foundation for Oncology,Immunology and Neurology,and the Takeda Science Foundation.
文摘Spinal cord injury(SCI)is a severe neurological condition with limited regenerative capacity and no effective curative treatments.Interleukin-13(IL-13),an immunomodulatory cytokine,has shown therapeutic potential by promoting alternative immune activation and improving recovery after SCI in mice.However,cellbased IL-13 delivery is hindered by poor graft survival and limited localisation at the injury site.Here,we developed an injectable hydrogel-based delivery system(HGIL13)composed of IL-13-loaded poly(lactic-co-glycolic acid)(PLGA)microparticles embedded in a photocrosslinkable gelatin methacrylate(GelMA)matrix,enabling sustained and localised IL-13 release.HGIL13 achieved IL-13 release for up to six weeks and significantly reduced lipopolysaccharide(LPS)-induced inflammation in BV2 microglia in vitro.In a mouse contusion SCI model,HGIL13 enhanced functional recovery,reduced lesion volume,and decreased demyelinated area.Using the Hexbtd^(Tomato)mouse we show that HGIL13 modulated the neuroimmune response by decreasing resident microglia density,downregulating CD86 expression,and upregulating Arginase-1 in both microglia and infiltrating monocyte-derived macrophages.RT-qPCR and RNA-seq analyses confirmed sustained immunomodulation over 28 days and indicated early reduction of activated microglia at 7 days post-injury as a key therapeutic mechanism.This study presents a safe,effective,and translatable strategy for localised cytokine delivery,demonstrating strong potential for immunomodulation and improved functional recovery following SCI.
基金supported by a JSPS Overseas Research Fellowship(grant no.20260306).
文摘Microglia,the resident immune cells of the central nervous system,exhibit conserved developmental origins and core molecular signatures across vertebrate species,highlighting their crucial importance in the central nervous system.While homeostatic microglia maintain similar functions during phylogeny—such as immune surveillance,debris clearance,and synaptic pruning—their morphology,gene expression,and responses to stimuli remarkably vary by species.These differences reflect evolutionary divergence shaped by factors such as lifespan,regenerative potential,and immune architecture.This review integrates current findings from basic vertebrates such as zebrafish,rodents,and nonhuman primates with those from humans to highlight conserved and divergent aspects of microglial biology throughout evolution.Integrating these evolutionary differences is crucial for translating mechanistic insights across model organisms and advancing microglia-targeted therapies for neurological disorders.
基金Open Access funding enabled and organized by Projekt DEAL.M.P.was supported by the Sobek Foundation,the Ernst-Jung Foundation,the DFG(SFB 992,SFB1160,SFB/TRR167,Reinhart-Koselleck-Grant,and Gottfried Wilhelm Leibniz-Prize)and the Ministry of Science,Research and Arts,Baden-Wuerttemberg(Sonderlinie“Neuroinflammation”).This study was supported by the DFG under Germany’s Excellence Strategy(CIBSS-EXC-2189-Project ID390939984).The figures were created with BioRender.com。
文摘Viral encephalitis is a devastating disease with high mortality,and survivors often suffer from severe neurological complications.Microglia are innate immune cells of the central nervous system(CNS)parenchyma whose turnover is reliant on local proliferation.Microglia express a diverse range of proteins,which allows them to continuously sense the environment and quickly react to changes.Under inflammatory conditions such as CNS viral infection,microglia promote innate and adaptive immune responses to protect the host.However,during viral infection,a dysregulated microglia-T-cell interplay may result in altered phagocytosis of neuronal synapses by microglia that causes neurocognitive impairment.In this review,we summarize the current knowledge on the role of microglia in viral encephalitis,propose questions to be answered in the future and suggest possible therapeutic targets.
基金supported by the Sobek Foundationthe Faber Foundation+2 种基金the Ernst-Jung Foundationthe DFG(SFB 992,SFB1160,SFB 1479,SFB/TRR167,Reinhart-Koselleck-Grant,Gottfried Wilhelm Leibniz-Prize,Novo-Nordisk Prize)the Ministry of Science,Research and Arts,Baden-Wuerttemberg(Sonderlinie“Neuroinflammation”).
文摘In their recent paper published in Nature Cell Biology,1 Wang and colleagues defined a pathogenetic mechanism among a variety of lysosomal storage disorders(LSDs)mediating neuronal death and disease progression.The authors observed neuron-intrinsic activated cGAS-STING signaling triggered by accumulating cytosolic dsDNA,and thus,they provide a valuable target for directed therapies.
基金supported by the IMMediate Advanced Clinician Scientist-Program,Department of Medicine II,Medical Center–University of Freiburg and Faculty of Medicine,University of Freiburg,funded by the Bundesministerium für Bildung und Forschung(BMBF,Federal Ministry of Education and Research)–01EO2103.Furthermore,RS is supported by the Else Kröner Fresenius Foundation,Fritz Thyssen Foundation and the German Research Foundation(SFB-1479–Project ID:441891347)MP is supported by the DFG(CRC/TRR167 Project ID 259373024“NeuroMac”),the Sobek Foundation,the Ernst-Jung Foundation,the Klaus Faber Foundation,the Novo Nordisk Foundation,the German Research Foundation(SFB 992 Project ID 192904750,SFB 1160,SFB 1479 Project ID 441891347,TRR 359 Project ID 491676693,Gottfried Wilhelm Leibniz Prize)and the DFG under Germany’s Excellence Strategy(CIBSS–EXC-2189–Project ID 390939984).
文摘Macrophages(MΦs)are versatile cells found in every organ.Throughout the body,they work tirelessly to maintain tissues.To this end,they are instructed by their respective niches to express organ-specific genes and proteins,resulting in a variety of cell morphologies and highly specialized functions across different tissues[1].A recent study by Wang et al.used single-cell RNA sequencing to comprehensively profile human MΦphenotypes across 19 organs between postconception weeks(PCW)4 and 26[2].This study revealed a surprising diversity of these cells and suggests new avenues of research.
基金supported by the Sobek Foundation,the Faber Foundation,the Ernst-Jung Foundation,the DFG(SFB 992,SFB1160,SFB 1479,SFB/TRR167,Reinhart-Koselleck-Grant,Gottfried Wilhelm Leibniz-Prize,Novo-Nordisk Prize)the Ministry of Science,Research and Arts,Baden-Wuerttemberg(Sonderlinie“Neuroinflammation”).
文摘In their paper published in Cell,1 Xu et al.leveraged single-cell sequencing and cell lineage tracing tools combined with two-photon live imaging to characterise the spatiotemporal immune recruitment and infiltration to the choroid plexus(ChP).They provide seminal insights into the communication between specialised ChP epithelial and macrophage populations,which coordinate the stepwise response to inflammation and its resolution.
