Macrophages in the brain barrier system include microglia in the brain parenchyma,border-associated macrophages at the brain’s borders,and recruited macrophages.They are responsible for neural development,maintenance...Macrophages in the brain barrier system include microglia in the brain parenchyma,border-associated macrophages at the brain’s borders,and recruited macrophages.They are responsible for neural development,maintenance of homeostasis,and orchestrating immune responses.With the rapid exploitation and development of new technologies,there is a deeper understanding of macrophages in the brain barrier system.Here we review the origin,development,important molecules,and functions of macrophages,mainly focusing on microglia and border-associated macrophages.We also highlight some advances in single-cell sequencing and significant cell markers.We anticipate that more advanced methods will emerge to study resident and recruited macrophages in the future,opening new horizons for neuroimmunology and related peripheral immune fields.展开更多
Border-associated macrophages are located at the interface between the brain and the periphery, including the perivascular spaces, choroid plexus, and meninges. Until recently, the functions of border-associated macro...Border-associated macrophages are located at the interface between the brain and the periphery, including the perivascular spaces, choroid plexus, and meninges. Until recently, the functions of border-associated macrophages have been poorly understood and largely overlooked. However, a recent study reported that border-associated macrophages participate in stroke-induced inflammation, although many details and the underlying mechanisms remain unclear. In this study, we performed a comprehensive single-cell analysis of mouse border-associated macrophages using sequencing data obtained from the Gene Expression Omnibus(GEO) database(GSE174574 and GSE225948). Differentially expressed genes were identified, and enrichment analysis was performed to identify the transcription profile of border-associated macrophages. CellChat analysis was conducted to determine the cell communication network of border-associated macrophages. Transcription factors were predicted using the ‘pySCENIC' tool. We found that, in response to hypoxia, borderassociated macrophages underwent dynamic transcriptional changes and participated in the regulation of inflammatory-related pathways. Notably, the tumor necrosis factor pathway was activated by border-associated macrophages following ischemic stroke. The pySCENIC analysis indicated that the activity of signal transducer and activator of transcription 3(Stat3) was obviously upregulated in stroke, suggesting that Stat3 inhibition may be a promising strategy for treating border-associated macrophages-induced neuroinflammation. Finally, we constructed an animal model to investigate the effects of border-associated macrophages depletion following a stroke. Treatment with liposomes containing clodronate significantly reduced infarct volume in the animals and improved neurological scores compared with untreated animals. Taken together, our results demonstrate comprehensive changes in border-associated macrophages following a stroke, providing a theoretical basis for targeting border-associated macrophages-induced neuroinflammation in stroke treatment.展开更多
Objectives:This study aimed to determine the role and mechanism underlying migration and invasion inhibitory protein(MIIP)modulation in M2 macrophages within the tumor microenvironment and the potential of targeting t...Objectives:This study aimed to determine the role and mechanism underlying migration and invasion inhibitory protein(MIIP)modulation in M2 macrophages within the tumor microenvironment and the potential of targeting the MIIP-stimulator of interferon genes(STING)pathway in colorectal cancer(CRC)therapy.Methods:MIIP expression was analyzed for associations with the STING pathway and M2 macrophage infiltration using public datasets and clinical CRC samples.CRC cells were genetically modified using lentiviral vectors to overexpress or silence MIIP and STING.The interactions of genetically modified CRC cells with macrophages were studied in co-culture systems.Techniques,including immunofluorescence staining,RT‒qPCR,western blot,ELISA,flow cytometry,and Transwell migration and invasion assays,were used to evaluate the crosstalk between CRC cells and macrophages.An orthotopic mouse CRC model was developed to study the effects of MIIP on M2 macrophage polarization and tumor metastasis through the STING-NFκB2-IL10 axis.The therapeutic significance of a STING antagonist was also assessed in vivo.Results:Analyses of The Cancer Genome Atlas(TCGA)cohort and our CRC cohort revealed low MIIP expression is associated with STING pathway activation,increased M2 macrophage infiltration,and poor clinical outcomes.The results of functional experiments demonstrated that MIIP inhibits IL10 production via the STING-TRAF3-NFκB2 axis in CRC cells,suppressing M2 macrophage polarization in co-culture systems.Conversely,M2 macrophages promoted CRC cell migration and invasion in an IL10-dependent manner.In vitro and in vivo studies confirmed that the MIIP-mediated feedback loop between CRC cells and macrophages depends on the STING-NFκB2-IL10 axis.Furthermore,inhibition of STING expression in a mouse model reduced M2 macrophage polarization and tumor metastasis.Conclusions:This study established MIIP as a crucial regulator of macrophage polarization in the CRC tumor microenvironment,providing new insights into the role in suppressing CRC progression and immune-tumor crosstalk.These findings highlight the potential of targeting the STING pathway as a therapeutic strategy for CRC patients who respond poorly to immune checkpoint inhibitors.展开更多
Diabetes mellitus is an escalating global health issue,with 463 million adults affected in 2019.Without intervention,this number is projected to increase to 578 million by 2030 and 700 million by 2045[1].Diabetic woun...Diabetes mellitus is an escalating global health issue,with 463 million adults affected in 2019.Without intervention,this number is projected to increase to 578 million by 2030 and 700 million by 2045[1].Diabetic wound,a significant complication,is characterized by delayed healing,high disability rates,and elevated mortality[2].The challenges of wound healing in diabetic patients,compounded by their high morbidity and mortality rates,have drawn growing attention in biomedical research.展开更多
Neuronal degeneration and inflammation are hallmark features of spinal cord injury that severely hinder functional recovery.As key regulators of the post-injury microenvironment,macrophages can promote either tissue r...Neuronal degeneration and inflammation are hallmark features of spinal cord injury that severely hinder functional recovery.As key regulators of the post-injury microenvironment,macrophages can promote either tissue repair or exacerbate damage.Among macrophage secreted factors,transforming growth factor-beta 1 has emerged as a critical mediator of pathological changes.In this study,we show the pivotal role of macrophage-derived transforming growth factor-beta 1 in driving neuronal senescence and impairing functional recovery after spinal cord injury.In a mouse spinal cord injury model,transforming growth factor-beta 1 levels were significantly increased at the injury site,accompanied by increased mothers against decapentaplegic homolog 2(SMAD2)phosphorylation and upregulation of neuronal senescence markers such as p16INK4a andβ-galactosidase activity.Treatment with LY-364947,a SMAD2 phosphorylation inhibitor,markedly reduced the number of senescent neurons,mitigated tissue degeneration,and improved motor function recovery.Additionally,macrophage depletion using clodronate liposomes lowered transforming growth factor-beta 1 levels at the injury site and attenuated neuronal senescence.These findings highlight the transforming growth factor-beta 1-SMAD2 signaling axis as a potential therapeutic target to reduce neuronal senescence and enhance functional recovery following spinal cord injury.展开更多
Circadian sensitivity significantly influences the severity of noise-induced hearing loss(NIHL),but the underlying mechanisms remain unclear.Here,we applied single-cell RNA sequencing to 97,043 cochlear cells,identify...Circadian sensitivity significantly influences the severity of noise-induced hearing loss(NIHL),but the underlying mechanisms remain unclear.Here,we applied single-cell RNA sequencing to 97,043 cochlear cells,identifying macrophages as the primary immune responders to acoustic trauma,with a notable increase in their proportion in the cochlea.Immunofluorescence confirmed significant recruitment and activation of cochlear macrophages following noise exposure,while in vivo macrophage depletion resulted in the recovery of hearing.Furthermore,analyses of differentially-expressed genes and pathways revealed pronounced activation of NLRP3 inflammasome signaling in macrophages during night-time noise exposure.Measurements of elevated IL-1βand IL-18 expression in cochlear macrophages by multiplex immunohistochemistry correlated with heightened inflammation in the night-time exposure group.These findings were further confirmed by the administration of the selective NLRP3 inhibitor CY-09,which mitigated inflammasome activation,preserved synaptic integrity,and protect against hearing loss.In conclusion,our findings underscore the role of macrophage-driven NLRP3 inflammasome activation in mediating circadian variations in cochlear damage,offering a potential therapeutic target for mitigating NIHL.展开更多
Three-dimensional(3D)-printed hydrogel scaffolds are widely used in spinal cord injury repair,with gelatin methacrylate being particularly favored owing to its excellent biocompatibility.However,traditional scaffolds ...Three-dimensional(3D)-printed hydrogel scaffolds are widely used in spinal cord injury repair,with gelatin methacrylate being particularly favored owing to its excellent biocompatibility.However,traditional scaffolds have a small contact area with tissues and lack the ability to regulate the inflammatory microenvironment.Therefore,there is a need to develop smart scaffolds with drug delivery and immune regulation functions.In this study,a 3D-printed gelatin methacrylate scaffold was developed to deliver interferon regulatory factor 4 in a targeted and sustained manner.The scaffold showed good mechanical properties,biocompatibility,and sustained interferon regulatory factor 4 release.The sustained-release interferon regulatory factor 4 competitively bound to myeloid differentiation factor 88 to inhibit the pro-inflammatory effects of interferon regulatory factor 5,and activated the signal transducer and activator of transcription 6 pathway to promote M2 macrophage polarization,thereby facilitating neural regeneration and recovery of spinal cord function.This indicates that the constructed interferon regulatory factor 4-loaded 3D-printed methyl acrylate-modified gelatin scaffold can regulate macrophage polarization through the interferon regulatory factor 4/5 axis,improve the inflammatory microenvironment after spinal cord injury,and thus provide a new target for promoting neural regeneration.展开更多
1. Introduction Osteoarthritis(OA), traditionally viewed as a mechanical and degenerative condition, increasingly involves chronic,low-grade inflammation. Among implicated immune cells,activated macrophages are key dr...1. Introduction Osteoarthritis(OA), traditionally viewed as a mechanical and degenerative condition, increasingly involves chronic,low-grade inflammation. Among implicated immune cells,activated macrophages are key drivers of synovitis and cartilage degradation [1], spurring interest in therapies that selectively modulate macrophage activity within the joint while sparing other resident cells.展开更多
Objective:To investigate the effect of pectic polysaccharides isolated from Rauvolfia verticillata on ulcerative colitis and its underlying mechanisms.Methods:Pectic polysaccharides were characterized using high-perfo...Objective:To investigate the effect of pectic polysaccharides isolated from Rauvolfia verticillata on ulcerative colitis and its underlying mechanisms.Methods:Pectic polysaccharides were characterized using high-performance liquid chromatography with 1-phenyl-3-methyl-5-pyrazolone pre-column derivatization,phenol-sulfuric acid assay,and gel permeation chromatography.HT-29 cells were stimulated with lipopolysaccharide and then treated with pectic polysaccharides;conditioned medium was applied to THP-1-derived macrophages to assess cell viability and polarization,while tight junction protein expression was analyzed in HT-29 cells.Furthermore,a mouse model of dextran sulfate sodium-induced colitis was treated with oral pectic polysaccharides or NOS2 overexpression.Body weight,disease activity index,colon length,histopathology,and the protein expression related to the JAK2/STAT3-NOS2 signaling were evaluated.Results:The pectic polysaccharide was characterized as an acidic pectic polysaccharide,primarily composed of galacturonic acid and various neutral sugars,with a narrow molecular weight distribution and high purity.Pectic polysaccharides significantly enhanced THP-1 macrophage viability,promoted M1 to M2 polarization,and upregulated the expression of epithelial tight junction proteins.In addition,pectic polysaccharide treatment attenuated body weight loss,lowered disease activity index scores and improved colon histology in mice with dextran sulfate sodium-induced colitis.It also reduced JAK2/STAT3 phosphorylation and NOS2 expression,and increased the expression of tight junction proteins(ZO-1,occludin,and claudin-1).Conclusions:Pectic polysaccharides attenuate ulcerative colitis by increasing M2-related macrophage markers,inhibiting the JAK2/STAT3-NOS2 signaling,and enhancing epithelial barrier-related protein expression.These findings support pectic polysaccharides as a natural candidate for the treatment of ulcerative colitis.展开更多
Background:Hepatocellular carcinoma(HCC)is an aggressive and lethal malignancy.Metabolic reprogramming dynamically remodels the tumor microenvironment(TME)and drives HCC progression.This study investigated the mechani...Background:Hepatocellular carcinoma(HCC)is an aggressive and lethal malignancy.Metabolic reprogramming dynamically remodels the tumor microenvironment(TME)and drives HCC progression.This study investigated the mechanism through which metabolic reprogramming remodels the TME in HCC.Methods:HCC patient transcriptome data were subjected to bioinformatics analysis to identify differentially expressed genes and immune infiltration status.Immunohistochemical analysis was performed to determine the correlation between succinate dehydrogenase complex subunit A(SDHA)expression and M2 macrophage infiltration.SDHA-knockdown or SDHA-overexpressing HCC cells were used for in vitro experiments,including co-culturing,flow cytometry,and enzyme-linked immunosorbent assay.Western blotting assay,functional assays,and subcutaneous tumor model mice were used to elucidate the molecular mechanisms underlying succinate-mediated HCC cell-macrophage interactions in the TME.Results:Higher infiltration of M2 macrophages correlated with worse prognosis in HCC patients.SDHA was downregulated in HCC tumor tissues and showed a negative correlation with M2 macrophage infiltration.SDHA knockdown promoted M2 macrophage polarization,whereas SDHA overexpression reversed this effect.Mechanistically,SDHA deficiency in HCC cells induced succinate accumulation,which promoted M2 macrophage polarization by activating the G protein-coupled receptor 91(GPR91)/signal transducer and activator of transcription 3(STAT3)pathway.Concurrently,succinate stimulation enhanced mitochondrial oxidative phosphorylation in M2 macrophages,thereby promoting HCC progression.Serum succinate levels were elevated in HCC patients.The receiver operating characteristic curve analysis indicated that serum succinate is a promising diagnostic marker for HCC(area under the curve=0.815).Conclusion:SDHA deficiency leads to succinate accumulation,which promotes M2 macrophage polarization through the GPR91/STAT3 pathway,thereby facilitating HCC progression.Based on these findings,serum succinate could be a promising diagnostic biomarker for HCC.展开更多
Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neu...Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neurodegenerative and demyelinating diseases(Borst et al.,2021).Together with infiltrating monocyte-derived macrophages,microglia also play a critical role for brain tumor development,since immunosuppressive interactions between tumor cells and tumor-associated microglia and macrophages(TAM)are linked to malignant progression.This mechanism is of particular relevance in glioblastoma(GB),the deadliest form of brain cancer with a median overall survival of less than 15 months(Khan et al.,2023).Therefore,targeting microglia and macrophage activation is a promising strategy for therapeutic interference in brain disease.展开更多
Colitis-associated colorectal cancer(CAC)is a major contributor to cancer-related mortality worldwide.Titanium dioxide(TiO_(2),E171),a widely used food additive,has been insufficiently studied regarding its effects on...Colitis-associated colorectal cancer(CAC)is a major contributor to cancer-related mortality worldwide.Titanium dioxide(TiO_(2),E171),a widely used food additive,has been insufficiently studied regarding its effects on macrophages within colon tumors during CAC development.In this study,CAC mouse models were used to investigate the biological impact of dietary E171 on macrophages in vivo,while lipopolysaccharide(LPS)-stimulated RAW264.7 macrophage cell lines were employed to elucidate the underlying mechanisms in vitro.We found that dietary E171 intake accelerated CAC development,exacerbated inflammatory responses and oxidative stress,and upregulated CAC-associated genes,including S100a8,S100a9,Lcn2,S100a11,Cxcl2,and interleukin-1α(Il-1α).E171 also increased the expression of S100A8,S100A9,NOD-like receptor family pyrin domain-containing 3(NLRP3),and gasdermin-D Nterminal(GSDMD-N)in macrophages within colon tumors.In inflammatory macrophages,E171 exposure enhanced cell viability,increased reactive oxygen species(ROS)levels,and elevated the expression and secretion of S100A8 and S100A9,consistent with in vivo histological observations.Furthermore,E171-induced secretion of S100A8 and S100A9 in macrophages was suppressed by specific inhibitors,including N-acetylcysteine(NAC,ROS inhibitor),MCC950(NLRP3 inhibitor),Z-YVAD-FMK(caspase 1 inhibitor),disulfiram(GSDMD inhibitor),and transfection of NLRP3 small interfering ribonucleic acid(siRNA).These results indicate that dietary E171 promotes CAC development by activating macrophages,with S100A8 and S100A9 serving as key mediators,and the NLRP3/caspase 1/GSDMD pathway acting as a critical mechanism.展开更多
Tendon-related diseases(TRDs)are increasingly common in the current aging society and impose a significant burden on patients.Despite therapeutic advances,the pathophysiology of TRDs remains poorly understood,hinderin...Tendon-related diseases(TRDs)are increasingly common in the current aging society and impose a significant burden on patients.Despite therapeutic advances,the pathophysiology of TRDs remains poorly understood,hindering effective clinical management.The macrophages are highly plastic immune cells involved in the maintenance of in vivo homeostasis and the injury-healing process.Their dual role in TRDs has been widely investigated,either promoting tenogenic and chondrogenic differentiation or amplifying inflammatory response,underscoring their therapeutic potential for TRDs treatment.Therefore,the review aims to summarize the roles of macrophages in the healing of TRDs,characterized by limited regenerative capacity,and examine strategies for the modulation of macrophage phenotypes to accelerate the regeneration process.Finally,we review applications involving macrophage modulation within the context of tissue engineering of TRDs,providing novel insights for the design of biomaterials-based targeted delivery systems.展开更多
Acute ischemic stroke remains a significant health concern owing to the limited efficacy of current therapeutic options.In recent years,Neuregulin-1 has exhibited promising neuroprotective effects in cerebral ischemia...Acute ischemic stroke remains a significant health concern owing to the limited efficacy of current therapeutic options.In recent years,Neuregulin-1 has exhibited promising neuroprotective effects in cerebral ischemia.However,the sources and functions of Neuregulin-1 have not yet been fully understood,which hinders its translation and broad application.Here,we collected paired clot and peripheral blood samples from patients with acute ischemic stroke to determine the sources of Neuregulin-1.In addition,we established an in vivo transient middle cerebral artery occlusion mouse model to investigate the therapeutic effects of Neuregulin-1 and its underlying molecular biological mechanisms.We observed a significant elevation in serum Neuregulin-1 levels among patients with acute ischemic stroke that correlated with severity of neurological impairment and clinical outcome.Using single-cell sequencing,we identified Neuregulin-1-positive macrophages among peripheral blood mononuclear cells that produced Neuregulin-1 post-ischemia.In addition,Neuregulin-1 promoted repair of the infarcted area,alleviating neuronal and myelin damage and improving overall behavioral recovery in mice.We found that Neuregulin-1 may exert these neuroprotective effects by promoting angiogenesis in the infarct area,and that this effect is mediated by Akt/mTOR/VEGF-dependent signaling.Our findings suggest that peripheral macrophages are a source of Neuregulin-1 post-stroke.Neuregulin-1 exerts its neuroprotective effects by promoting angiogenesis via Akt/mTOR/VEGF-dependent signaling,showing promising clinical translation potential.展开更多
The regenerative capacities of organs in adult mammals vary significantly.Unlike the liver,which possesses remarkable regenerative potential,the repair of cardiac injuries has long posed a critical medical challenge.R...The regenerative capacities of organs in adult mammals vary significantly.Unlike the liver,which possesses remarkable regenerative potential,the repair of cardiac injuries has long posed a critical medical challenge.Recent studies have highlighted the pivotal role of the immune microenvironment in repairing damage in these tissues,but the key cell types and their mechanisms of action remain incompletely understood.In this study,we established a model of concurrent physical trauma to the hearts and livers of adult mice,revealing that these two injured tissues drive distinct immune microenvironments.The liver primarily accumulates lymphocytes,whereas the heart recruits macrophages and neutrophils.Notably,CD160^(+)CD8^(+)intraepithelial lymphocytes in the liver were found to suppress fibrosis postliver injury and mitigate cardiac fibrosis when delivered via hydrogel patches.Conversely,in response to heart trauma,recruited inflammatory macrophages not only express proinflammatory cytokines but also coexpress CCRL2.While CCRL2 did not directly alter the intensity of the inflammatory response,it facilitated fibroblast proliferation and migration through its interaction with Na^(+)/K^(+)-ATPase on fibroblasts.These findings elucidated the contrasting immune microenvironments between the heart and liver following injury and provided novel insights and strategies for diagnosing and treating cardiac diseases.展开更多
Objective:This study explores the role of methoxy polyethylene glycol@Elabela-11(mPEG@ELA-11),a pHresponsive ELA-11 conjugate,in modulating macrophage function and attenuating atherosclerosis,focusing on the protein k...Objective:This study explores the role of methoxy polyethylene glycol@Elabela-11(mPEG@ELA-11),a pHresponsive ELA-11 conjugate,in modulating macrophage function and attenuating atherosclerosis,focusing on the protein kinase B(AKT)-mediated endoplasmic reticulum(ER)stress pathway as a molecular target.Impact Statement:We reveal that ELA-11 alleviates atherosclerosis by suppressing macrophage foam cell formation,M1 polarization,and apoptosis via the AKT-ER stress pathway.We also develop mPEG@ELA-11,a novel pH-responsive nanocarrier,to enhance targeted drug delivery and therapeutic efficacy,offering a breakthrough for peptide-based cardiovascular nanomedicine.Introduction:Atherosclerosis,driven by macrophage dysfunction and lipid accumulation,is a major global killer.ELA-11,a fragment of Elabela peptide,shows cardiovascular protective effects,but its role in atherosclerosis and optimal delivery remain unstudied.Methods:Elabela mRNA(APELA)expression was analyzed in human carotid atherosclerotic plaques using real-time quantitative PCR analysis,and serum ELA levels were quantified via enzyme-linked immunosorbent assay in patients with carotid stenosis.In vitro studies on RAW264.7 macrophages evaluated mPEG@ELA-11 effects on oxidized low-density lipoprotein-induced foam cell formation,polarization,and apoptosis.In vivo efficacy was tested in ApoE-/-mice,comparing mPEG@ELA-11 with free ELA-11,and its pH-responsive release mechanism was characterized.Results:APELA was downregulated in human atherosclerotic plaques,especially unstable lesions.mPEG@ELA-11 suppressed foam cell formation,M1 polarization,and apoptosis by inhibiting the AKT-ER stress pathway in vitro.In mice,it reduced plaque area more effectively than free ELA-11 attributed to pH-triggered release.Conclusion:The pH-responsive mPEG@ELA-11 alleviates atherosclerosis by modulating macrophages via the AKT-ER stress pathway,with favorable targeting and safety,representing a promising targeted peptide nanomedicine for atherosclerosis.展开更多
Background:The aim was to explore the effect of macrophage polarization and macrophage-to-myofibroblast transition(MMT)in silicosis.Methods:Male Wistar rats were divided into a control group and a silicosis group deve...Background:The aim was to explore the effect of macrophage polarization and macrophage-to-myofibroblast transition(MMT)in silicosis.Methods:Male Wistar rats were divided into a control group and a silicosis group developed using a HOPE MED 8050 dynamic automatic dusting system.Murine mac-rophage MH-S cells were randomly divided into a control group and an SiO_(2) group.The pathological changes in lung tissue were observed using hematoxylin and eosin(HE)and Van Gieson(VG)staining.The distribution and location of macrophage marker(F4/80),M1 macrophage marker(iNOS),M2 macrophage marker(CD206),and myofibroblast marker(α-smooth muscle actin[α-SMA])were detected using immu-nohistochemical and immunofluorescent staining.The expression changes in iNOS,Arg,α-SMA,vimentin,and type I collagen(Col I)were measured using Western blot.Results:The results of HE and VG staining showed obvious silicon nodule formation and the distribution of thick collagen fibers in the lung tissue of the silicosis group.Macrophage marker F4/80 increased gradually from 8 to 32 weeks after exposure to silica.Immunohistochemical and immunofluorescent staining results revealed that there were more iNOS-positive cells and some CD206-positive cells in the lung tissue of the silicosis group at 8 weeks.More CD206-positive cells were found in the silicon nodules of the lung tissues in the silicosis group at 32 weeks.Western blot analysis showed that the expressions of Inducible nitric oxide synthase and Arg protein in the lung tissues of the silicosis group were upregulated compared with those of the con-trol group.The results of immunofluorescence staining showed the co-expression of F4/80,α-SMA,and Col I,and CD206 andα-SMA were co-expressed in the lung tissue of the silicosis group.The extracted rat alveolar lavage fluid revealed F4/80+α-SMA+,CD206+α-SMA+,and F4/80+α-SMA+Col I+cells using immunofluorescence staining.Similar results were also found in MH-S cells induced by SiO_(2).Conclusions:The development of silicosis is accompanied by macrophage polarization and MMT.展开更多
Background Sustained lipolysis exacerbates subclinical ketosis(SCK)in dairy cows and is associated with inflammation and adipose tissue macrophage(ATM)infiltration.While ATM involvement in adipose homeostasis and infl...Background Sustained lipolysis exacerbates subclinical ketosis(SCK)in dairy cows and is associated with inflammation and adipose tissue macrophage(ATM)infiltration.While ATM involvement in adipose homeostasis and inflammation in early lactation is recognized,a comprehensive exploration of ATM polarization phenotypes in SCK cows is lacking.This study aimed to characterize ATM polarization and its link to lipolysis and inflammation in SCK cows.Results Subcutaneous adipose tissue samples were obtained from dairy cows to analyze protein expression and gene profiles.Compared with healthy cows,SCK cows had higher serum BHBA and NEFA,smaller adipocytes,and increased expression of lipolytic enzymes(LIPE,ATGL),indicating enhanced lipolysis.Decreased levels of FASN,PPARγ,p-SMAD3,and TGFβsuggested impaired adipogenesis.Inflammatory markers(TNF-α,IFN-γ,TLR4,Caspase1)and NFκB signaling activity were elevated.ATM infiltration was supported by increased CD9,CD68,TREM2,and CXCL1 expression.Protein abundance of M1 polarization markers(iNOS,CD86 and CCL2)in ATMs were associated with greater levels of NOS2,IL1B,CD86 and CCL2 mRNA expression in SCK cows;fluorescence intensity of NOS2 and CD86 also was elevated,alongside a higher proportion of CD68+/CD86+immunopositive cells within adipose tissue.ELISA further quantified increased concentrations of IL-1β and CCL2.Conversely,the abundance of ATM M2 polarization markers,including CD206,IL-10,KLF4,and Arg1,at both the protein and mRNA levels demonstrated a decline.Meanwhile,the proportion of CD68+/CD206+immune response cells was relatively low in SCK cows.Conclusions Overall,the present study indicated an augmented macrophage presence within adipose tissue during subclinical ketosis,with a predominance of pro-inflammatory macrophages(M1 ATM).This observation suggested a vicious cycle wherein macrophage infiltration and pro-inflammatory polarization coincide with enhanced lipolysis and an amplified inflammatory cascade.展开更多
Objective:Current laboratory studies on the effect of biomaterial properties on immune reactions are incomplete and based on a single or a few combination features of the biomaterial design.This study utilizes intelli...Objective:Current laboratory studies on the effect of biomaterial properties on immune reactions are incomplete and based on a single or a few combination features of the biomaterial design.This study utilizes intelligent prediction models to explore the key features of titanium implant materials in macrophage polarization.Impact Statement:This pilot study provided some insights into the great potential of machine learning in exploring bone immunomodulatory biomaterials.Introduction:Titanium materials are commonly utilized as bone replacement materials to treat missing teeth and bone defects.The immune response caused by implant materials after implantation in the body has a double-edged sword effect on osseointegration.Macrophage polarization has been extensively explored to understand early material-mediated immunomodulation.However,understanding of implant material surface properties and immunoregulations remains limited due to current experimental settings,which are based on trial-by-trial approaches.Artificial intelligence,with its capacity to analyze large datasets,can help explore complex material–cell interactions.Methods:In this study,the effect of titanium surface properties on macrophage polarization was analyzed using intelligent prediction models,including random forest,extreme gradient boosting,and multilayer perceptron.Additionally,data extracted from the newly published literature were further input into the trained models to validate their performance.Results:The analysis identified“cell seeding density”,“contact angle”,and“roughness”as the most important features regulating interleukin 10 and tumor necrosis factorαsecretion.Additionally,the predicted interleukin 10 levels closely matched the experimental results from newly published literature,while the tumor necrosis factorαpredictions exhibited consistent trends.Conclusion:The polarization response of macrophages seeded on titanium materials is influenced by multiple factors,and artificial intelligence can assist in extracting the key features of implant materials for immunoregulation.展开更多
BACKGROUND Macrophages play a crucial role in the tumor microenvironment,displaying remarkable plasticity that allows them to either suppress or promote tumor progression.Their polarization into M1 or M2 phenotypes co...BACKGROUND Macrophages play a crucial role in the tumor microenvironment,displaying remarkable plasticity that allows them to either suppress or promote tumor progression.Their polarization into M1 or M2 phenotypes could have significant prognostic implications,and manipulating this polarization may offer a novel approach to controlling colorectal neoplasms.AIM To evaluate the infiltration rates of M1 and M2 macrophages in colorectal neoplasia,specifically comparing cases with and without metalloproteinase mutations.Additionally,it sought to explore potential prognostic factors as-sociated with the disease.展开更多
基金supported by Ministry of Science and Technology China Brain Initiative Grant,No.2022ZD0204702(to ZY)the National Natural Science Foundation of China,No.82371357(to LC)+2 种基金Foundation for Military Medicine,No.16QNP085(to ZY)Navy Medical University Basic Medical College“Yi Zhang”Basic Medical Talent Development and Support Program,Nos.JCYZRC-D-022(to TC)and JCYZRC-D-024(to HD)Science and Technology Innovation Special Fund of Shanghai Baoshan District,No.2023-E-05(to YW).
文摘Macrophages in the brain barrier system include microglia in the brain parenchyma,border-associated macrophages at the brain’s borders,and recruited macrophages.They are responsible for neural development,maintenance of homeostasis,and orchestrating immune responses.With the rapid exploitation and development of new technologies,there is a deeper understanding of macrophages in the brain barrier system.Here we review the origin,development,important molecules,and functions of macrophages,mainly focusing on microglia and border-associated macrophages.We also highlight some advances in single-cell sequencing and significant cell markers.We anticipate that more advanced methods will emerge to study resident and recruited macrophages in the future,opening new horizons for neuroimmunology and related peripheral immune fields.
基金supported by Qingdao Key Medical and Health Discipline ProjectThe Intramural Research Program of the Affiliated Hospital of Qingdao University,No. 4910Qingdao West Coast New Area Science and Technology Project,No. 2020-55 (all to SW)。
文摘Border-associated macrophages are located at the interface between the brain and the periphery, including the perivascular spaces, choroid plexus, and meninges. Until recently, the functions of border-associated macrophages have been poorly understood and largely overlooked. However, a recent study reported that border-associated macrophages participate in stroke-induced inflammation, although many details and the underlying mechanisms remain unclear. In this study, we performed a comprehensive single-cell analysis of mouse border-associated macrophages using sequencing data obtained from the Gene Expression Omnibus(GEO) database(GSE174574 and GSE225948). Differentially expressed genes were identified, and enrichment analysis was performed to identify the transcription profile of border-associated macrophages. CellChat analysis was conducted to determine the cell communication network of border-associated macrophages. Transcription factors were predicted using the ‘pySCENIC' tool. We found that, in response to hypoxia, borderassociated macrophages underwent dynamic transcriptional changes and participated in the regulation of inflammatory-related pathways. Notably, the tumor necrosis factor pathway was activated by border-associated macrophages following ischemic stroke. The pySCENIC analysis indicated that the activity of signal transducer and activator of transcription 3(Stat3) was obviously upregulated in stroke, suggesting that Stat3 inhibition may be a promising strategy for treating border-associated macrophages-induced neuroinflammation. Finally, we constructed an animal model to investigate the effects of border-associated macrophages depletion following a stroke. Treatment with liposomes containing clodronate significantly reduced infarct volume in the animals and improved neurological scores compared with untreated animals. Taken together, our results demonstrate comprehensive changes in border-associated macrophages following a stroke, providing a theoretical basis for targeting border-associated macrophages-induced neuroinflammation in stroke treatment.
文摘Objectives:This study aimed to determine the role and mechanism underlying migration and invasion inhibitory protein(MIIP)modulation in M2 macrophages within the tumor microenvironment and the potential of targeting the MIIP-stimulator of interferon genes(STING)pathway in colorectal cancer(CRC)therapy.Methods:MIIP expression was analyzed for associations with the STING pathway and M2 macrophage infiltration using public datasets and clinical CRC samples.CRC cells were genetically modified using lentiviral vectors to overexpress or silence MIIP and STING.The interactions of genetically modified CRC cells with macrophages were studied in co-culture systems.Techniques,including immunofluorescence staining,RT‒qPCR,western blot,ELISA,flow cytometry,and Transwell migration and invasion assays,were used to evaluate the crosstalk between CRC cells and macrophages.An orthotopic mouse CRC model was developed to study the effects of MIIP on M2 macrophage polarization and tumor metastasis through the STING-NFκB2-IL10 axis.The therapeutic significance of a STING antagonist was also assessed in vivo.Results:Analyses of The Cancer Genome Atlas(TCGA)cohort and our CRC cohort revealed low MIIP expression is associated with STING pathway activation,increased M2 macrophage infiltration,and poor clinical outcomes.The results of functional experiments demonstrated that MIIP inhibits IL10 production via the STING-TRAF3-NFκB2 axis in CRC cells,suppressing M2 macrophage polarization in co-culture systems.Conversely,M2 macrophages promoted CRC cell migration and invasion in an IL10-dependent manner.In vitro and in vivo studies confirmed that the MIIP-mediated feedback loop between CRC cells and macrophages depends on the STING-NFκB2-IL10 axis.Furthermore,inhibition of STING expression in a mouse model reduced M2 macrophage polarization and tumor metastasis.Conclusions:This study established MIIP as a crucial regulator of macrophage polarization in the CRC tumor microenvironment,providing new insights into the role in suppressing CRC progression and immune-tumor crosstalk.These findings highlight the potential of targeting the STING pathway as a therapeutic strategy for CRC patients who respond poorly to immune checkpoint inhibitors.
基金supported by a grant from General Scientific Research Project of Zhejiang Provincial Department of Education(No.Y202455614).
文摘Diabetes mellitus is an escalating global health issue,with 463 million adults affected in 2019.Without intervention,this number is projected to increase to 578 million by 2030 and 700 million by 2045[1].Diabetic wound,a significant complication,is characterized by delayed healing,high disability rates,and elevated mortality[2].The challenges of wound healing in diabetic patients,compounded by their high morbidity and mortality rates,have drawn growing attention in biomedical research.
基金supported by grants from Tianjin Key Medical Discipline(Specialty)Construct Project,No.TJYXZDXK-027A(to SF)National Key Research and Development Project of Stem Cell and Transformation Research,No.2019YFA0112100(to SF)+3 种基金the National Natural Science Foundation of China,Nos.81930070(to SF),82402825(to XS)Tianjin Health Science and Technology Project Key Discipline Special Project,No.hUCMSC preferred subgroup,No.TJWJ2022XK002(to SF)2022 Beijing-Tianjin-Hebei Basic Research Cooperation Project,No.22JCZXJC00050(to SF)Youth Research Incubation Fund of School of Basic Medical Sciences,Tianjin Medical University,No.023FY05(to XS).
文摘Neuronal degeneration and inflammation are hallmark features of spinal cord injury that severely hinder functional recovery.As key regulators of the post-injury microenvironment,macrophages can promote either tissue repair or exacerbate damage.Among macrophage secreted factors,transforming growth factor-beta 1 has emerged as a critical mediator of pathological changes.In this study,we show the pivotal role of macrophage-derived transforming growth factor-beta 1 in driving neuronal senescence and impairing functional recovery after spinal cord injury.In a mouse spinal cord injury model,transforming growth factor-beta 1 levels were significantly increased at the injury site,accompanied by increased mothers against decapentaplegic homolog 2(SMAD2)phosphorylation and upregulation of neuronal senescence markers such as p16INK4a andβ-galactosidase activity.Treatment with LY-364947,a SMAD2 phosphorylation inhibitor,markedly reduced the number of senescent neurons,mitigated tissue degeneration,and improved motor function recovery.Additionally,macrophage depletion using clodronate liposomes lowered transforming growth factor-beta 1 levels at the injury site and attenuated neuronal senescence.These findings highlight the transforming growth factor-beta 1-SMAD2 signaling axis as a potential therapeutic target to reduce neuronal senescence and enhance functional recovery following spinal cord injury.
基金supported by the Scientific and Innovative Action Plan of Shanghai(CN)(22Y11902000)the National Natural Science Foundation of China(82371144 and 82201273)+2 种基金the Cross-Disciplinary Research Fund of Shanghai Ninth People's Hospital,Shanghai Jiao Tong University School of Medicine(JYJC202231)the Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases(14DZ2260300)We extend our gratitude to Prof.Hao Wu and the Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases for providing essential resources and laboratory facilities,and to Prof.Lei Song and Prof.Zhiyong Liu for valuable insights and guidance.
文摘Circadian sensitivity significantly influences the severity of noise-induced hearing loss(NIHL),but the underlying mechanisms remain unclear.Here,we applied single-cell RNA sequencing to 97,043 cochlear cells,identifying macrophages as the primary immune responders to acoustic trauma,with a notable increase in their proportion in the cochlea.Immunofluorescence confirmed significant recruitment and activation of cochlear macrophages following noise exposure,while in vivo macrophage depletion resulted in the recovery of hearing.Furthermore,analyses of differentially-expressed genes and pathways revealed pronounced activation of NLRP3 inflammasome signaling in macrophages during night-time noise exposure.Measurements of elevated IL-1βand IL-18 expression in cochlear macrophages by multiplex immunohistochemistry correlated with heightened inflammation in the night-time exposure group.These findings were further confirmed by the administration of the selective NLRP3 inhibitor CY-09,which mitigated inflammasome activation,preserved synaptic integrity,and protect against hearing loss.In conclusion,our findings underscore the role of macrophage-driven NLRP3 inflammasome activation in mediating circadian variations in cochlear damage,offering a potential therapeutic target for mitigating NIHL.
基金supported by the National Natural Science Foundation of China,Nos.81930070(to SF),82002309(to ZS)the Tianjin Key Medical Discipline(Specialty)Construct Project,No.TJYXZDXK-027A(to SF)a grant from Tianjin Institute of Orthopedic Innovation and Transformation(to SF).
文摘Three-dimensional(3D)-printed hydrogel scaffolds are widely used in spinal cord injury repair,with gelatin methacrylate being particularly favored owing to its excellent biocompatibility.However,traditional scaffolds have a small contact area with tissues and lack the ability to regulate the inflammatory microenvironment.Therefore,there is a need to develop smart scaffolds with drug delivery and immune regulation functions.In this study,a 3D-printed gelatin methacrylate scaffold was developed to deliver interferon regulatory factor 4 in a targeted and sustained manner.The scaffold showed good mechanical properties,biocompatibility,and sustained interferon regulatory factor 4 release.The sustained-release interferon regulatory factor 4 competitively bound to myeloid differentiation factor 88 to inhibit the pro-inflammatory effects of interferon regulatory factor 5,and activated the signal transducer and activator of transcription 6 pathway to promote M2 macrophage polarization,thereby facilitating neural regeneration and recovery of spinal cord function.This indicates that the constructed interferon regulatory factor 4-loaded 3D-printed methyl acrylate-modified gelatin scaffold can regulate macrophage polarization through the interferon regulatory factor 4/5 axis,improve the inflammatory microenvironment after spinal cord injury,and thus provide a new target for promoting neural regeneration.
基金supported by the National Natural Science Foundation of China (82372125 and 32471403)the Zhejiang Provincial Natural Science Foundation (LHDMY23H310002)Health Innovation Talents Program (Longfa Kou) from Health Commission of Zhejiang Province。
文摘1. Introduction Osteoarthritis(OA), traditionally viewed as a mechanical and degenerative condition, increasingly involves chronic,low-grade inflammation. Among implicated immune cells,activated macrophages are key drivers of synovitis and cartilage degradation [1], spurring interest in therapies that selectively modulate macrophage activity within the joint while sparing other resident cells.
基金supported by the Key Research and Development Project of Hainan Province(ZDYF2022SHFZ099)the Academic Enhancement Support Program of Hainan Medical University(XSTS2025040 and XSTS2025063).
文摘Objective:To investigate the effect of pectic polysaccharides isolated from Rauvolfia verticillata on ulcerative colitis and its underlying mechanisms.Methods:Pectic polysaccharides were characterized using high-performance liquid chromatography with 1-phenyl-3-methyl-5-pyrazolone pre-column derivatization,phenol-sulfuric acid assay,and gel permeation chromatography.HT-29 cells were stimulated with lipopolysaccharide and then treated with pectic polysaccharides;conditioned medium was applied to THP-1-derived macrophages to assess cell viability and polarization,while tight junction protein expression was analyzed in HT-29 cells.Furthermore,a mouse model of dextran sulfate sodium-induced colitis was treated with oral pectic polysaccharides or NOS2 overexpression.Body weight,disease activity index,colon length,histopathology,and the protein expression related to the JAK2/STAT3-NOS2 signaling were evaluated.Results:The pectic polysaccharide was characterized as an acidic pectic polysaccharide,primarily composed of galacturonic acid and various neutral sugars,with a narrow molecular weight distribution and high purity.Pectic polysaccharides significantly enhanced THP-1 macrophage viability,promoted M1 to M2 polarization,and upregulated the expression of epithelial tight junction proteins.In addition,pectic polysaccharide treatment attenuated body weight loss,lowered disease activity index scores and improved colon histology in mice with dextran sulfate sodium-induced colitis.It also reduced JAK2/STAT3 phosphorylation and NOS2 expression,and increased the expression of tight junction proteins(ZO-1,occludin,and claudin-1).Conclusions:Pectic polysaccharides attenuate ulcerative colitis by increasing M2-related macrophage markers,inhibiting the JAK2/STAT3-NOS2 signaling,and enhancing epithelial barrier-related protein expression.These findings support pectic polysaccharides as a natural candidate for the treatment of ulcerative colitis.
基金supported by the Central Government-Guided Local Science and Technology Development Fund Project(Science and Technology Innovation Base Project)(Grant No.236Z7749G)Hebei Provincial Precision Medicine Innovation and Development Joint Fund Incubation Project(Grant No.H2025206547)Hebei Provincial Basic Research Special Youth Science Fund Project(Grant No.H2025206274).
文摘Background:Hepatocellular carcinoma(HCC)is an aggressive and lethal malignancy.Metabolic reprogramming dynamically remodels the tumor microenvironment(TME)and drives HCC progression.This study investigated the mechanism through which metabolic reprogramming remodels the TME in HCC.Methods:HCC patient transcriptome data were subjected to bioinformatics analysis to identify differentially expressed genes and immune infiltration status.Immunohistochemical analysis was performed to determine the correlation between succinate dehydrogenase complex subunit A(SDHA)expression and M2 macrophage infiltration.SDHA-knockdown or SDHA-overexpressing HCC cells were used for in vitro experiments,including co-culturing,flow cytometry,and enzyme-linked immunosorbent assay.Western blotting assay,functional assays,and subcutaneous tumor model mice were used to elucidate the molecular mechanisms underlying succinate-mediated HCC cell-macrophage interactions in the TME.Results:Higher infiltration of M2 macrophages correlated with worse prognosis in HCC patients.SDHA was downregulated in HCC tumor tissues and showed a negative correlation with M2 macrophage infiltration.SDHA knockdown promoted M2 macrophage polarization,whereas SDHA overexpression reversed this effect.Mechanistically,SDHA deficiency in HCC cells induced succinate accumulation,which promoted M2 macrophage polarization by activating the G protein-coupled receptor 91(GPR91)/signal transducer and activator of transcription 3(STAT3)pathway.Concurrently,succinate stimulation enhanced mitochondrial oxidative phosphorylation in M2 macrophages,thereby promoting HCC progression.Serum succinate levels were elevated in HCC patients.The receiver operating characteristic curve analysis indicated that serum succinate is a promising diagnostic marker for HCC(area under the curve=0.815).Conclusion:SDHA deficiency leads to succinate accumulation,which promotes M2 macrophage polarization through the GPR91/STAT3 pathway,thereby facilitating HCC progression.Based on these findings,serum succinate could be a promising diagnostic biomarker for HCC.
基金Deutsche Forschungsgemeinschaft(DFG,German Research Foundation),project numbers 324633948 and 409784463(DFG grants Hi 678/9-3 and Hi 678/10-2,FOR2953)to HHBundesministerium für Bildung und Forschung-BMBF,project number 16LW0463K to HT.
文摘Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neurodegenerative and demyelinating diseases(Borst et al.,2021).Together with infiltrating monocyte-derived macrophages,microglia also play a critical role for brain tumor development,since immunosuppressive interactions between tumor cells and tumor-associated microglia and macrophages(TAM)are linked to malignant progression.This mechanism is of particular relevance in glioblastoma(GB),the deadliest form of brain cancer with a median overall survival of less than 15 months(Khan et al.,2023).Therefore,targeting microglia and macrophage activation is a promising strategy for therapeutic interference in brain disease.
基金supported by the National Natural Science Foundation of China(Nos.81974441 and 82203619)the Science and Technology Planning Project of Shenzhen Municipality(Nos.JCYJ20190814105619048 and JCYJ20220530154202005)。
文摘Colitis-associated colorectal cancer(CAC)is a major contributor to cancer-related mortality worldwide.Titanium dioxide(TiO_(2),E171),a widely used food additive,has been insufficiently studied regarding its effects on macrophages within colon tumors during CAC development.In this study,CAC mouse models were used to investigate the biological impact of dietary E171 on macrophages in vivo,while lipopolysaccharide(LPS)-stimulated RAW264.7 macrophage cell lines were employed to elucidate the underlying mechanisms in vitro.We found that dietary E171 intake accelerated CAC development,exacerbated inflammatory responses and oxidative stress,and upregulated CAC-associated genes,including S100a8,S100a9,Lcn2,S100a11,Cxcl2,and interleukin-1α(Il-1α).E171 also increased the expression of S100A8,S100A9,NOD-like receptor family pyrin domain-containing 3(NLRP3),and gasdermin-D Nterminal(GSDMD-N)in macrophages within colon tumors.In inflammatory macrophages,E171 exposure enhanced cell viability,increased reactive oxygen species(ROS)levels,and elevated the expression and secretion of S100A8 and S100A9,consistent with in vivo histological observations.Furthermore,E171-induced secretion of S100A8 and S100A9 in macrophages was suppressed by specific inhibitors,including N-acetylcysteine(NAC,ROS inhibitor),MCC950(NLRP3 inhibitor),Z-YVAD-FMK(caspase 1 inhibitor),disulfiram(GSDMD inhibitor),and transfection of NLRP3 small interfering ribonucleic acid(siRNA).These results indicate that dietary E171 promotes CAC development by activating macrophages,with S100A8 and S100A9 serving as key mediators,and the NLRP3/caspase 1/GSDMD pathway acting as a critical mechanism.
基金supported by the Guangxi Natural Science Foundation(AD21220065 to JX)the National Natural Science Foundation of China(82102632 and 82160412 to JX)the Guangdong Basic and Applied Basic Research Foundation(2023A1515220072 to ZHD)。
文摘Tendon-related diseases(TRDs)are increasingly common in the current aging society and impose a significant burden on patients.Despite therapeutic advances,the pathophysiology of TRDs remains poorly understood,hindering effective clinical management.The macrophages are highly plastic immune cells involved in the maintenance of in vivo homeostasis and the injury-healing process.Their dual role in TRDs has been widely investigated,either promoting tenogenic and chondrogenic differentiation or amplifying inflammatory response,underscoring their therapeutic potential for TRDs treatment.Therefore,the review aims to summarize the roles of macrophages in the healing of TRDs,characterized by limited regenerative capacity,and examine strategies for the modulation of macrophage phenotypes to accelerate the regeneration process.Finally,we review applications involving macrophage modulation within the context of tissue engineering of TRDs,providing novel insights for the design of biomaterials-based targeted delivery systems.
基金Chongqing Technology lnnovation and Application Development Program,No.CSTB2023TIAD-KPX0061(to ZZ)the National Natural Science Foundation of China,Nos.81971130(to ZZ),82201464(to XC).
文摘Acute ischemic stroke remains a significant health concern owing to the limited efficacy of current therapeutic options.In recent years,Neuregulin-1 has exhibited promising neuroprotective effects in cerebral ischemia.However,the sources and functions of Neuregulin-1 have not yet been fully understood,which hinders its translation and broad application.Here,we collected paired clot and peripheral blood samples from patients with acute ischemic stroke to determine the sources of Neuregulin-1.In addition,we established an in vivo transient middle cerebral artery occlusion mouse model to investigate the therapeutic effects of Neuregulin-1 and its underlying molecular biological mechanisms.We observed a significant elevation in serum Neuregulin-1 levels among patients with acute ischemic stroke that correlated with severity of neurological impairment and clinical outcome.Using single-cell sequencing,we identified Neuregulin-1-positive macrophages among peripheral blood mononuclear cells that produced Neuregulin-1 post-ischemia.In addition,Neuregulin-1 promoted repair of the infarcted area,alleviating neuronal and myelin damage and improving overall behavioral recovery in mice.We found that Neuregulin-1 may exert these neuroprotective effects by promoting angiogenesis in the infarct area,and that this effect is mediated by Akt/mTOR/VEGF-dependent signaling.Our findings suggest that peripheral macrophages are a source of Neuregulin-1 post-stroke.Neuregulin-1 exerts its neuroprotective effects by promoting angiogenesis via Akt/mTOR/VEGF-dependent signaling,showing promising clinical translation potential.
基金supported by the National Key Research and Development Program of China(2025YFA1309100)the distinguished Young Scientist Fund of NSFC(82125016)+6 种基金the National Natural Science Foundation of China Key Program(82230061)supported by the National Natural Science Foundation of China,Special Program(82341216)the Zhejiang Provincial Natural Science Foundation of China(LHDMD22H100002)supported by the National Key Research and Development Program of China(2021YFA1101803 and 2021ZD0203304)supported by the Jiangsu Science and Technology Project(Social Development)(BE2019669)the National Natural Science Foundation of China(82071046,82100540)supported by the 111 Program(D20036).
文摘The regenerative capacities of organs in adult mammals vary significantly.Unlike the liver,which possesses remarkable regenerative potential,the repair of cardiac injuries has long posed a critical medical challenge.Recent studies have highlighted the pivotal role of the immune microenvironment in repairing damage in these tissues,but the key cell types and their mechanisms of action remain incompletely understood.In this study,we established a model of concurrent physical trauma to the hearts and livers of adult mice,revealing that these two injured tissues drive distinct immune microenvironments.The liver primarily accumulates lymphocytes,whereas the heart recruits macrophages and neutrophils.Notably,CD160^(+)CD8^(+)intraepithelial lymphocytes in the liver were found to suppress fibrosis postliver injury and mitigate cardiac fibrosis when delivered via hydrogel patches.Conversely,in response to heart trauma,recruited inflammatory macrophages not only express proinflammatory cytokines but also coexpress CCRL2.While CCRL2 did not directly alter the intensity of the inflammatory response,it facilitated fibroblast proliferation and migration through its interaction with Na^(+)/K^(+)-ATPase on fibroblasts.These findings elucidated the contrasting immune microenvironments between the heart and liver following injury and provided novel insights and strategies for diagnosing and treating cardiac diseases.
基金supported by the National Natural Science Foundation of China(82270481,82470481,and 82370498)the Shuang Bai Ren Project of Shanghai Jiao Tong University(JYYJXYS20240821)the Medical Scientific Research Project of Shanghai Hongkou Health Commission(Hongwei 2302-17 and 2302-22).
文摘Objective:This study explores the role of methoxy polyethylene glycol@Elabela-11(mPEG@ELA-11),a pHresponsive ELA-11 conjugate,in modulating macrophage function and attenuating atherosclerosis,focusing on the protein kinase B(AKT)-mediated endoplasmic reticulum(ER)stress pathway as a molecular target.Impact Statement:We reveal that ELA-11 alleviates atherosclerosis by suppressing macrophage foam cell formation,M1 polarization,and apoptosis via the AKT-ER stress pathway.We also develop mPEG@ELA-11,a novel pH-responsive nanocarrier,to enhance targeted drug delivery and therapeutic efficacy,offering a breakthrough for peptide-based cardiovascular nanomedicine.Introduction:Atherosclerosis,driven by macrophage dysfunction and lipid accumulation,is a major global killer.ELA-11,a fragment of Elabela peptide,shows cardiovascular protective effects,but its role in atherosclerosis and optimal delivery remain unstudied.Methods:Elabela mRNA(APELA)expression was analyzed in human carotid atherosclerotic plaques using real-time quantitative PCR analysis,and serum ELA levels were quantified via enzyme-linked immunosorbent assay in patients with carotid stenosis.In vitro studies on RAW264.7 macrophages evaluated mPEG@ELA-11 effects on oxidized low-density lipoprotein-induced foam cell formation,polarization,and apoptosis.In vivo efficacy was tested in ApoE-/-mice,comparing mPEG@ELA-11 with free ELA-11,and its pH-responsive release mechanism was characterized.Results:APELA was downregulated in human atherosclerotic plaques,especially unstable lesions.mPEG@ELA-11 suppressed foam cell formation,M1 polarization,and apoptosis by inhibiting the AKT-ER stress pathway in vitro.In mice,it reduced plaque area more effectively than free ELA-11 attributed to pH-triggered release.Conclusion:The pH-responsive mPEG@ELA-11 alleviates atherosclerosis by modulating macrophages via the AKT-ER stress pathway,with favorable targeting and safety,representing a promising targeted peptide nanomedicine for atherosclerosis.
基金The National Natural Science Foundation of China(no.82204006)the Science and Technology of Project of Hebei Education Department(QN2022009)+1 种基金the Provincial Graduate Student Innovation Funding Project of Hebei Province(CXZZBS2022104)the National Natural Science Foundation of Hebei Province(H2020209292).
文摘Background:The aim was to explore the effect of macrophage polarization and macrophage-to-myofibroblast transition(MMT)in silicosis.Methods:Male Wistar rats were divided into a control group and a silicosis group developed using a HOPE MED 8050 dynamic automatic dusting system.Murine mac-rophage MH-S cells were randomly divided into a control group and an SiO_(2) group.The pathological changes in lung tissue were observed using hematoxylin and eosin(HE)and Van Gieson(VG)staining.The distribution and location of macrophage marker(F4/80),M1 macrophage marker(iNOS),M2 macrophage marker(CD206),and myofibroblast marker(α-smooth muscle actin[α-SMA])were detected using immu-nohistochemical and immunofluorescent staining.The expression changes in iNOS,Arg,α-SMA,vimentin,and type I collagen(Col I)were measured using Western blot.Results:The results of HE and VG staining showed obvious silicon nodule formation and the distribution of thick collagen fibers in the lung tissue of the silicosis group.Macrophage marker F4/80 increased gradually from 8 to 32 weeks after exposure to silica.Immunohistochemical and immunofluorescent staining results revealed that there were more iNOS-positive cells and some CD206-positive cells in the lung tissue of the silicosis group at 8 weeks.More CD206-positive cells were found in the silicon nodules of the lung tissues in the silicosis group at 32 weeks.Western blot analysis showed that the expressions of Inducible nitric oxide synthase and Arg protein in the lung tissues of the silicosis group were upregulated compared with those of the con-trol group.The results of immunofluorescence staining showed the co-expression of F4/80,α-SMA,and Col I,and CD206 andα-SMA were co-expressed in the lung tissue of the silicosis group.The extracted rat alveolar lavage fluid revealed F4/80+α-SMA+,CD206+α-SMA+,and F4/80+α-SMA+Col I+cells using immunofluorescence staining.Similar results were also found in MH-S cells induced by SiO_(2).Conclusions:The development of silicosis is accompanied by macrophage polarization and MMT.
基金supported by grants from National Natural Science Foundation of China(32125038)National Key Research and Development Program of China(grant number 2023YFD1801100 and 2023YFD1800804)+1 种基金the Key Research and Development Program of the Xinjiang Uygur Autonomous Region(No.2024B02016)the 2115 Talent Development Program of China Agricultural University.
文摘Background Sustained lipolysis exacerbates subclinical ketosis(SCK)in dairy cows and is associated with inflammation and adipose tissue macrophage(ATM)infiltration.While ATM involvement in adipose homeostasis and inflammation in early lactation is recognized,a comprehensive exploration of ATM polarization phenotypes in SCK cows is lacking.This study aimed to characterize ATM polarization and its link to lipolysis and inflammation in SCK cows.Results Subcutaneous adipose tissue samples were obtained from dairy cows to analyze protein expression and gene profiles.Compared with healthy cows,SCK cows had higher serum BHBA and NEFA,smaller adipocytes,and increased expression of lipolytic enzymes(LIPE,ATGL),indicating enhanced lipolysis.Decreased levels of FASN,PPARγ,p-SMAD3,and TGFβsuggested impaired adipogenesis.Inflammatory markers(TNF-α,IFN-γ,TLR4,Caspase1)and NFκB signaling activity were elevated.ATM infiltration was supported by increased CD9,CD68,TREM2,and CXCL1 expression.Protein abundance of M1 polarization markers(iNOS,CD86 and CCL2)in ATMs were associated with greater levels of NOS2,IL1B,CD86 and CCL2 mRNA expression in SCK cows;fluorescence intensity of NOS2 and CD86 also was elevated,alongside a higher proportion of CD68+/CD86+immunopositive cells within adipose tissue.ELISA further quantified increased concentrations of IL-1β and CCL2.Conversely,the abundance of ATM M2 polarization markers,including CD206,IL-10,KLF4,and Arg1,at both the protein and mRNA levels demonstrated a decline.Meanwhile,the proportion of CD68+/CD206+immune response cells was relatively low in SCK cows.Conclusions Overall,the present study indicated an augmented macrophage presence within adipose tissue during subclinical ketosis,with a predominance of pro-inflammatory macrophages(M1 ATM).This observation suggested a vicious cycle wherein macrophage infiltration and pro-inflammatory polarization coincide with enhanced lipolysis and an amplified inflammatory cascade.
基金funded by the National Natural Science Foundation of China(32301129 and 31971262)Science and Technology Projects in Guangzhou(202201020396).
文摘Objective:Current laboratory studies on the effect of biomaterial properties on immune reactions are incomplete and based on a single or a few combination features of the biomaterial design.This study utilizes intelligent prediction models to explore the key features of titanium implant materials in macrophage polarization.Impact Statement:This pilot study provided some insights into the great potential of machine learning in exploring bone immunomodulatory biomaterials.Introduction:Titanium materials are commonly utilized as bone replacement materials to treat missing teeth and bone defects.The immune response caused by implant materials after implantation in the body has a double-edged sword effect on osseointegration.Macrophage polarization has been extensively explored to understand early material-mediated immunomodulation.However,understanding of implant material surface properties and immunoregulations remains limited due to current experimental settings,which are based on trial-by-trial approaches.Artificial intelligence,with its capacity to analyze large datasets,can help explore complex material–cell interactions.Methods:In this study,the effect of titanium surface properties on macrophage polarization was analyzed using intelligent prediction models,including random forest,extreme gradient boosting,and multilayer perceptron.Additionally,data extracted from the newly published literature were further input into the trained models to validate their performance.Results:The analysis identified“cell seeding density”,“contact angle”,and“roughness”as the most important features regulating interleukin 10 and tumor necrosis factorαsecretion.Additionally,the predicted interleukin 10 levels closely matched the experimental results from newly published literature,while the tumor necrosis factorαpredictions exhibited consistent trends.Conclusion:The polarization response of macrophages seeded on titanium materials is influenced by multiple factors,and artificial intelligence can assist in extracting the key features of implant materials for immunoregulation.
文摘BACKGROUND Macrophages play a crucial role in the tumor microenvironment,displaying remarkable plasticity that allows them to either suppress or promote tumor progression.Their polarization into M1 or M2 phenotypes could have significant prognostic implications,and manipulating this polarization may offer a novel approach to controlling colorectal neoplasms.AIM To evaluate the infiltration rates of M1 and M2 macrophages in colorectal neoplasia,specifically comparing cases with and without metalloproteinase mutations.Additionally,it sought to explore potential prognostic factors as-sociated with the disease.
