Myelin-associated inhibitory factors within the central nervous system(CNS) are considered to be one of the main obstacles for axonal regeneration following disease or injury. The nogo receptor 1(NgR1) has been we...Myelin-associated inhibitory factors within the central nervous system(CNS) are considered to be one of the main obstacles for axonal regeneration following disease or injury. The nogo receptor 1(NgR1) has been well documented to play a key role in limiting axonal regrowth in the injured and diseased mammalian CNS. However, the role of nogo receptor in immune cell activation during CNS inflammation is yet to be mechanistically elucidated. Microglia/macrophages are immune cells that are regarded as pathogenic contributors to inflammatory demyelinating lesions in multiple sclerosis(MS). In this study, the animal model of MS, experimental autoimmune encephalomyelitis(EAE) was induced in ngr1^+/+ and ngr1^–/– female mice following injection with the myelin oligodendrocyte glycoprotein(MOG_(35–55)) peptide. A fatemap analysis of microglia/macrophages was performed throughout spinal cord sections of EAE-induced mice at clinical scores of 0, 1, 2 and 3, respectively(increasing locomotor disability) from both genotypes, using the CD11 b and Iba1 cell markers. Western immunoblotting using lysates from isolated spinal cord microglia/macrophages, along with immunohistochemistry and flow cytometric analysis, was performed to demonstrate the expression of nogo receptor and its two homologs during EAE progression. Myelin protein engulfment during EAE progression in ngr1^+/+ and ngr1^–/– mice was demonstrated by western immunblotting of lysates from isolated spinal cord microglia/macrophages, detecting levels of Nogo-A and MOG. The numbers of M1 and M2 microglia/macrophage phenotypes present in the spinal cords of EAE-induced ngr1^+/+ and ngr1^–/– mice, were assessed by flow cytometric analysis using CD38 and Erg-2 markers. A significant difference in microglia/macrophage numbers between ngr1^+/+ and ngr1^–/– mice was identified during the progression of the clinical symptoms of EAE, in the white versus gray matter regions of the spinal cord. This difference was unrelated to the expression of Ng R on these macrophage/microglial cells. We have identified that as EAE progresses, the phagocytic activity of microglia/macrophages with myelin debris, in ngr1^–/– mice, was enhanced. Moreover, we show a modulation from a predominant M1-pathogenic to the M2-neurotrophic cell phenotype in the ngr1^–/– mice during EAE progression. These findings suggest that CNS-specific macrophages and microglia of ngr1^–/– mice may exhibit an enhanced capacity to clear inhibitory molecules that are sequestered in inflammatory lesions.展开更多
MIcroglia/macrophage-mediated erythrophagocytosis plays a crucial role in hematoma clearance after intracerebral hemorrhage.Dynamic cytoskeletal changes accompany phagocytosis.However,whether and how these changes are...MIcroglia/macrophage-mediated erythrophagocytosis plays a crucial role in hematoma clearance after intracerebral hemorrhage.Dynamic cytoskeletal changes accompany phagocytosis.However,whether and how these changes are associated with microglia/macrophage-mediated erythrophagocytosis remain unclear.In this study,we investigated the function of acetylatedα-tubulin,a stabilized microtubule form,in microglia/macrophage erythrophagocytosis after intracerebral hemorrhage both in vitro and in vivo.We first assessed the function of acetylatedα-tubulin in erythrophagocytosis using primary DiO GFP-labeled red blood cells co-cultured with the BV2 microglia or RAW264.7 macrophage cell lines.Acetylatedα-tubulin expression was significantly decreased in BV2 and RAW264.7 cells during erythrophagocytosis.Moreover,silencingα-tubulin acetyltransferase 1(ATAT1),a newly discoveredα-tubulin acetyltransferase,decreased Ac-α-tub levels and enhanced the erythrophagocytosis by BV2 and RAW264.7 cells.Consistent with these findings,in ATAT1-/-mice,we observed increased ionized calcium binding adapter molecule 1(Iba1)and Perls-positive microglia/macrophage phagocytes of red blood cells in peri-hematoma and reduced hematoma volume in mice with intracerebral hemorrhage.Additionally,knocking out ATAT1 alleviated neuronal apoptosis and pro-inflammatory cytokines and increased anti-inflammatory cytokines around the hematoma,ultimately improving neurological recovery of mice after intracerebral hemorrhage.These findings suggest that ATAT1 deficiency accelerates erythrophagocytosis by microglia/macrophages and hematoma absorption after intracerebral hemorrhage.These results provide novel insights into the mechanisms of hematoma clearance and suggest ATAT1 as a potential target for the treatment of intracerebral hemorrhage.展开更多
Preclinical and clinical studies have shown that microglia and macrophages participate in a multiphasic brain damage repair process following intracerebral hemorrhage.The E26 transformation-specific sequence-related t...Preclinical and clinical studies have shown that microglia and macrophages participate in a multiphasic brain damage repair process following intracerebral hemorrhage.The E26 transformation-specific sequence-related transcription factor Spi1 regulates microglial/macrophage commitment and maturation.However,the effect of Spi1 on intracerebral hemorrhage remains unclear.In this study,we found that Spi1 may regulate recovery from the neuroinflammation and neurofunctional damage caused by intracerebral hemorrhage by modulating the microglial/macrophage transcriptome.We showed that high Spi1expression in microglia/macrophages after intracerebral hemorrhage is associated with the activation of many pathways that promote phagocytosis,glycolysis,and autophagy,as well as debris clearance and sustained remyelination.Notably,microglia with higher levels of Soil expression were chara cterized by activation of pathways associated with a variety of hemorrhage-related cellular processes,such as complement activation,angiogenesis,and coagulation.In conclusion,our results suggest that Spi1 plays a vital role in the microglial/macrophage inflammatory response following intracerebral hemorrhage.This new insight into the regulation of Spi1 and its target genes may advance our understanding of neuroinflammation in intracerebral hemorrhage and provide therapeutic targets for patients with intracerebral hemorrhage.展开更多
Tumor-associated macrophages(TAMs)are emerging as targets for tumor therapy because of their primary role in promoting tumor progression.Several studies have been conducted to target TAMs by reducing their infiltratio...Tumor-associated macrophages(TAMs)are emerging as targets for tumor therapy because of their primary role in promoting tumor progression.Several studies have been conducted to target TAMs by reducing their infiltration,depleting their numbers,and reversing their phenotypes to suppress tumor progression,leading to the development of drugs in preclinical and clinical trials.However,the heterogeneous characteristics of TAMs,including their ontogenetic and functional heterogeneity,limit their targeting.Therefore,in-depth exploration of the heterogeneity of TAMs,combined with immune checkpoint therapy or other therapeutic modalities could improve the efficiency of tumor treatment.This review focuses on the heterogeneous ontogeny and function of TAMs,as well as the current development of tumor therapies targeting TAMs and combination strategies.展开更多
Skeletal muscle has a robust regeneration ability that is impaired by severe injury,disease,and aging.resulting in a decline in skeletal muscle function.Therefore,improving skeletal muscle regeneration is a key challe...Skeletal muscle has a robust regeneration ability that is impaired by severe injury,disease,and aging.resulting in a decline in skeletal muscle function.Therefore,improving skeletal muscle regeneration is a key challenge in treating skeletal muscle-related disorders.Owing to their significant role in tissue regeneration,implantation of M2 macrophages(M2MФ)has great potential for improving skeletal muscle regeneration.Here,we present a short-wave infrared(SWIR)fluorescence imaging technique to obtain more in vivo information for an in-depth evaluation of the skeletal muscle regeneration effect after M2MФtransplantation.SWIR fluorescence imaging was employed to track implanted M2MФin the injured skeletal muscle of mouse models.It is found that the implanted M2MФaccumulated at the injury site for two weeks.Then,SWIR fluorescence imaging of blood vessels showed that M2MФimplantation could improve the relative perfusion ratio on day 5(1.09±0.09 vs 0.85±0.05;p=0.01)and day 9(1.38±0.16 vs 0.95±0.03;p=0.01)post-injury,as well as augment the degree of skeletal muscle regencration on day 13 post-injury.Finally,multiple linear regression analyses determined that post-injury time and relative perfusion ratio could be used as predictive indicators to evaluate skeletal muscle regeneration.These results provide more in vivo details about M2MФin skeletal muscle regeneration and confirm that M2MФcould promote angiogenesis and improve the degree of skeletal muscle repair,which will guide the research and development of M2MФimplantation to improve skeletal muscle regeneration.展开更多
The biological activity of plant polysaccharides can be enhanced by sulfated modification.In this study,the immunomodulatory effect of sulfated Cyclocarya paliurus polysaccharides(SCP3)on macrophages RAW264.7 and its ...The biological activity of plant polysaccharides can be enhanced by sulfated modification.In this study,the immunomodulatory effect of sulfated Cyclocarya paliurus polysaccharides(SCP3)on macrophages RAW264.7 and its potential molecular mechanism were investigated.Results showed that SCP3 at 25-100μg/m L increased viability and improved phagocytosis of RAW264.7 cells.Meanwhile,SCP3 could activate mitogen-activated protein kinase(MAPK)and nuclear factor kappa B(NF-κB)signaling pathways,which increased the phosphorylation of Erk1/2,JNK,p38 and NF-κB p65,promoting secretion of cytokines tumor necrosis factorα(TNF-α),interleukin 6(IL-6)and nitric oxide(NO)as well as the production of reactive oxygen species(ROS).In addition,Toll-like receptor 4(TLR4)receptor inhibitors were able to block the production of NO and TNF-αby SCP3-stimulated macrophages.Based on Western blot analysis and validation using specific inhibitors against MAPK and NF-κB signaling pathways,the results demonstrated that SCP3 induced macrophages activation and enhanced TNF-αand NO production via TLR4-mediated MAPK and NF-κB pathways.In summary,SCP3 has significant immunomodulatory potential.The underlying molecular mechanism was that SCP3 activates macrophages via TLR4 receptors to promote ROS production,which in turn activates the downstream MAPK/NF-κB signaling pathway and then increases the secretion levels of cytokines and NO.展开更多
Multiple sclerosis is characterized by demyelination and neuronal loss caused by inflammatory cell activation and infiltration into the central nervous system.Macrophage polarization plays an important role in the pat...Multiple sclerosis is characterized by demyelination and neuronal loss caused by inflammatory cell activation and infiltration into the central nervous system.Macrophage polarization plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis,a traditional experimental model of multiple sclerosis.This study investigated the effect of Fasudil on macrophages and examined the therapeutic potential of Fasudil-modified macrophages in experimental autoimmune encephalomyelitis.We found that Fasudil induced the conversion of macrophages from the pro-inflammatory M1 type to the anti-inflammatory M2 type,as shown by reduced expression of inducible nitric oxide synthase/nitric oxide,interleukin-12,and CD16/32 and increased expression of arginase-1,interleukin-10,CD14,and CD206,which was linked to inhibition of Rho kinase activity,decreased expression of toll-like receptors,nuclear factor-κB,and components of the mitogen-activated protein kinase signaling pathway,and generation of the pro-inflammatory cytokines tumor necrosis factor-α,interleukin-1β,and interleukin-6.Crucially,Fasudil-modified macrophages effectively decreased the impact of experimental autoimmune encephalomyelitis,resulting in later onset of disease,lower symptom scores,less weight loss,and reduced demyelination compared with unmodified macrophages.In addition,Fasudil-modified macrophages decreased interleukin-17 expression on CD4^(+)T cells and CD16/32,inducible nitric oxide synthase,and interleukin-12 expression on F4/80^(+)macrophages,as well as increasing interleukin-10 expression on CD4^(+)T cells and arginase-1,CD206,and interleukin-10 expression on F4/80^(+)macrophages,which improved immune regulation and reduced inflammation.These findings suggest that Fasudil-modified macrophages may help treat experimental autoimmune encephalomyelitis by inducing M2 macrophage polarization and inhibiting the inflammatory response,thereby providing new insight into cell immunotherapy for multiple sclerosis.展开更多
Our previous study has demonstrated that lnc_000048 is upregulated in large-artery atherosclerotic stroke and promotes atherosclerosis in ApoE^(-/-)mice.However,little is known about the role of lnc_000048 in classica...Our previous study has demonstrated that lnc_000048 is upregulated in large-artery atherosclerotic stroke and promotes atherosclerosis in ApoE^(-/-)mice.However,little is known about the role of lnc_000048 in classically activated macrophage(M1)polarization.In this study,we established THP-1-derived testing state macrophages(M0),M1 macrophages,and alternately activated macrophages(M2).Real-time fluorescence quantitative PCR was used to verify the expression of marker genes and the expression of lnc_000048 in macrophages.Flow cytometry was used to detect phenotypic proteins(CD11b,CD38,CD80).We generated cell lines with lentivirus-mediated upregulation or downregulation of lnc_000048.Flow cytometry,western blot,and real-time fluorescence quantitative PCR results showed that down-regulation of lnc_000048 reduced M1 macrophage polarization and the inflammation response,while over-expression of lnc_000048 led to the opposite effect.Western blot results indicated that lnc_000048 enhanced the activation of the STAT1 pathway and mediated the M1 macrophage polarization.Moreover,catRAPID prediction,RNA-pull down,and mass spectrometry were used to identify and screen the protein kinase RNA-activated(PKR),then catRAPID and RPIseq were used to predict the binding ability of lnc_000048 to PKR.Immunofluorescence(IF)-RNA fluorescence in situ hybridization(FISH)double labeling was performed to verify the subcellular colocalization of lnc_000048 and PKR in the cytoplasm of M1 macrophage.We speculate that lnc_000048 may form stem-loop structure-specific binding and activate PKR by inducing its phosphorylation,leading to activation of STAT1 phosphorylation and thereby enhancing STAT1 pathway-mediated polarization of THP-1 macrophages to M1 and inflammatory factor expression.Taken together,these results reveal that the lnc_000048/PKR/STAT1 axis plays a crucial role in the polarization of M1 macrophages and may be a novel therapeutic target for atherosclerosis alleviation in stroke.展开更多
The repair of bone tissue damage is a complex process that is well-orchestrated in time and space,a focus and difficulty in orthopedic treatment.In recent years,the success of mesenchymal stem cells(MSCs)-mediated bon...The repair of bone tissue damage is a complex process that is well-orchestrated in time and space,a focus and difficulty in orthopedic treatment.In recent years,the success of mesenchymal stem cells(MSCs)-mediated bone repair in clinical trials of large-area bone defects and bone necrosis has made it a candidate in bone tissue repair engineering and regenerative medicine.MSCs are closely related to macrophages.On one hand,MSCs regulate the immune regulatory function by influencing macrophages proliferation,infiltration,and phenotype polarization,while also affecting the osteoclasts differentiation of macrophages.On the other hand,macrophages activate MSCs and mediate the multilineage differentiation of MSCs by regulating the immune microenvironment.The cross-talk between MSCs and macrophages plays a crucial role in regulating the immune system and in promoting tissue regeneration.Making full use of the relationship between MSCs and macrophages will enhance the efficacy of MSCs therapy in bone tissue repair,and will also provide a reference for further application of MSCs in other diseases.展开更多
BACKGROUND Alveolar bone defects caused by inflammation are an urgent issue in oral implant surgery that must be solved.Regulating the various phenotypes of macrophages to enhance the inflammatory environment can sign...BACKGROUND Alveolar bone defects caused by inflammation are an urgent issue in oral implant surgery that must be solved.Regulating the various phenotypes of macrophages to enhance the inflammatory environment can significantly affect the progression of diseases and tissue engineering repair process.AIM To assess the influence of interleukin-10(IL-10)on the osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs)following their interaction with macrophages in an inflammatory environment.METHODS IL-10 modulates the differentiation of peritoneal macrophages in Wistar rats in an inflammatory environment.In this study,we investigated its impact on the proliferation,migration,and osteogenesis of BMSCs.The expression levels of signal transducer and activator of transcription 3(STAT3)and its activated form,phos-phorylated-STAT3,were examined in IL-10-stimulated macrophages.Subsequently,a specific STAT3 signaling inhibitor was used to impede STAT3 signal activation to further investigate the role of STAT3 signaling.RESULTS IL-10-stimulated macrophages underwent polarization to the M2 type through substitution,and these M2 macrophages actively facilitated the osteogenic differentiation of BMSCs.Mechanistically,STAT3 signaling plays a crucial role in the process by which IL-10 influences macrophages.Specifically,IL-10 stimulated the activation of the STAT3 signaling pathway and reduced the macrophage inflammatory response,as evidenced by its diminished impact on the osteogenic differentiation of BMSCs.CONCLUSION Stimulating macrophages with IL-10 proved effective in improving the inflammatory environment and promoting the osteogenic differentiation of BMSCs.The IL-10/STAT3 signaling pathway has emerged as a key regulator in the macrophage-mediated control of BMSCs’osteogenic differentiation.展开更多
Macrophages play an important role in peripheral nerve regeneration,but the specific mechanism of regeneration is still unclear.Our preliminary findings indicated that neutrophil peptide 1 is an innate immune peptide ...Macrophages play an important role in peripheral nerve regeneration,but the specific mechanism of regeneration is still unclear.Our preliminary findings indicated that neutrophil peptide 1 is an innate immune peptide closely involved in peripheral nerve regeneration.However,the mechanism by which neutrophil peptide 1 enhances nerve regeneration remains unclear.This study was designed to investigate the relationship between neutrophil peptide 1 and macrophages in vivo and in vitro in peripheral nerve crush injury.The functions of RAW 264.7 cells we re elucidated by Cell Counting Kit-8 assay,flow cytometry,migration assays,phagocytosis assays,immunohistochemistry and enzyme-linked immunosorbent assay.Axonal debris phagocytosis was observed using the CUBIC(Clear,Unobstructed Brain/Body Imaging Cocktails and Computational analysis)optical clearing technique during Wallerian degeneration.Macrophage inflammatory factor expression in different polarization states was detected using a protein chip.The results showed that neutrophil peptide 1 promoted the prolife ration,migration and phagocytosis of macrophages,and CD206 expression on the surfa ce of macrophages,indicating M2 polarization.The axonal debris clearance rate during Wallerian degeneration was enhanced after neutrophil peptide 1 intervention.Neutrophil peptide 1 also downregulated inflammatory factors interleukin-1α,-6,-12,and tumor necrosis factor-αin invo and in vitro.Thus,the results suggest that neutrophil peptide 1 activates macrophages and accelerates Wallerian degeneration,which may be one mechanism by which neutrophil peptide 1 enhances peripheral nerve regeneration.展开更多
Glioma associated microglia/macrophages (GAMs) constitute the largest proportion of glioma infiltrating cells, par-ticularly in high grade tumors (i.e., glioblastoma). Once inside the tumors, GAMs usually acquire a sp...Glioma associated microglia/macrophages (GAMs) constitute the largest proportion of glioma infiltrating cells, par-ticularly in high grade tumors (i.e., glioblastoma). Once inside the tumors, GAMs usually acquire a specific pheno-type of activation that favors tumor growth, angiogenesis and promotes the invasion of normal brain parenchyma. Therefore, treatments that limit or prevent GAMs' recruitment at the tumor site or modulate their immune activa-tion promoting antitumor activities are expected to exert beneficial effects in glioblastoma. In the present paper, we aim at the revision of pharmacological strategies that interfere with GAMs' function and are currently proposed as an alternative/additional option to current approved cytotoxic regimens.展开更多
Obesity is one of the most serious global health problems,with an incidence that increases yearly and coincides with the development of cancer.Adipose tissue macrophages(ATMs)are particularly important in this context...Obesity is one of the most serious global health problems,with an incidence that increases yearly and coincides with the development of cancer.Adipose tissue macrophages(ATMs)are particularly important in this context and contribute to linking obesity-related inflammation and tumor progression.However,the functions of ATMs on the progression of obesity-associated cancer remain unclear.In this review,we describe the origins,phenotypes,and functions of ATMs.Subsequently,we summarize the potential mechanisms on the reprogramming of ATMs in the obesity-associated microenvironment,including the direct exchange of dysfunctional metabolites,inordinate cytokines and other signaling mediators,transfer of extracellular vesicle cargo,and variations in the gut microbiota and its metabolites.A better understanding of the properties and functions of ATMs under conditions of obesity will lead to the development of new therapeutic interventions for obesity-related cancer.展开更多
Spinal cord injury (SCI) is a devastating type of neurological trauma with limited therapeutic op- portunities. The pathophysiology of SCI involves primary and secondary mechanisms of injury. Among all the secondary...Spinal cord injury (SCI) is a devastating type of neurological trauma with limited therapeutic op- portunities. The pathophysiology of SCI involves primary and secondary mechanisms of injury. Among all the secondary injury mechanisms, the inflammatory response is the major contrib- utor and results in expansion of the lesion and further loss of neurologic function. Meanwhile, the inflammation directly and indirectly dominates the outcomes of SCI, including not only pain and motor dysfunction, but also preventingneuronal regeneration. Microglia and macrophages play very important roles in secondary injury. Microglia reside in spinal parenchyma and survey the microenvironment through the signals of injury or infection. Macrophages are derived from monocytes recruited to injured sites from the peripheral circulation. Activated resident microglia and monocyte-derived macrophages induce and magnify immune and inflammatory responses not only by means of their secretory moleculesand phagocytosis, but also through their influence on astrocytes, oligodendrocytes and demyelination. In this review, we focus on the roles of mi- croglia and macrophages in secondary injury and how they contribute to the sequelae of SCI.展开更多
Inflammation plays an important role in the occurrence and development of many inflammatory diseases.The purpose of this study was to evaluate the anti-inflammatory effect and metabolic behavior of the dual targeting ...Inflammation plays an important role in the occurrence and development of many inflammatory diseases.The purpose of this study was to evaluate the anti-inflammatory effect and metabolic behavior of the dual targeting procyanidins(PC)nanoparticles on lipopolysaccharide(LPS)-stimulated inflammatory macrophages by metabolomics method.The double-targeting PC nanoparticles could specifi cally target both the CD44 receptor and mitochondria,while the single targeting PC-loaded nanoparticles that could target the CD44 receptor on the surface of macrophages.The double-targeting PC nanoparticles had better inhibitory effect than single-targeting PC nanoparticles on the leakage of lactate dehydrogenase and reactive oxygen species overexpression induced by LPS.Amino acid metabolism,energy metabolism and purine metabolism were disordered in LPS-treated group,and metabolic pathway analysis indicated that the double-targeting PC nanoparticles reversed some of LPS impacts.The changes of these potential biomarkers and their corresponding pathways are helpful to further understand the mechanism of PC nanoparticles in alleviating inflammation,and promote their application in nutrition intervention.展开更多
Porcine reproductive and respiratory syndrome(PRRS)is recognized as one of the most infectious viral diseases of swine.Although Cluster of differentiation 163(CD163)is identified as an essential receptor for mediating...Porcine reproductive and respiratory syndrome(PRRS)is recognized as one of the most infectious viral diseases of swine.Although Cluster of differentiation 163(CD163)is identified as an essential receptor for mediating PRRS virus(PRRSV)infection,the important residues involved in infection on CD163 are still unclear.Therefore,it is very important to identify these key residues to study the mechanism of PRRSV infection and to generate anti-PRRSV pigs.In this study,we first generated immortalized porcine alveolar macrophage(IPAM)cell lines harboring 40-residues(residues 523-562,including R561(arginine(R)at position 561))deletion of CD163.PRRSV infection experiments showed that these IPAM cell lines were completely resistant to PRRSV infection.We then generated cloned pigs carrying CD163-R561A(an arginine(R)to alanine(A)substitution at position 561 of CD163).PRRSV challenge experiments in porcine alveolar macrophages(PAMs)isolated from the CD163-R561A pigs showed significantly lower susceptibility to PRRSV than that of CD163-R561 PAMs.Through this study,we show that CD163523-562 contains essential residues for mediating PRRSV infection,and that CD163 R561 significantly contributes to PRRSV infection but is not essential for infection.These functional sites can therefore serve as new targets for understanding the mechanism of PRRSV infection.Furthermore,CD163-R561A pigs can be used as an important model for improving pig germplasm with resistance against PRRSV.展开更多
The process of lymphatic metastasis was proved to be associated with podoplanin-expressing macrophages in breast cancer(BC).This study aimed to investigate the role of the M2 phenotype of tumor-associated macrophages ...The process of lymphatic metastasis was proved to be associated with podoplanin-expressing macrophages in breast cancer(BC).This study aimed to investigate the role of the M2 phenotype of tumor-associated macrophages and mine the key M2 macrophages-related genes for lymph node metastasis in BC.We downloaded the GSE158399 dataset from the Gene Expression Omnibus(GEO)database,which includes transcriptomic profiles of individual cells from primary tumors,negative lymph nodes(NLNs),and positive lymph nodes(PLNs)of breast cancer patients.The cell subsets were identified by clustering analysis after quality control of the scRNA-seq using Seurat.The activation and migration capability of M2 macrophages were evaluated with R package“GSVA”.The key M2 macrophages-related genes were screened from the differential expressed genes(DEGs)and M2 macrophages activation and migration gene sets collected from MSigDB database.Our analysis identified three main cell types in primary tumors,NLNs,and PLNs:basal cells,luminal cells,and immune cell subsets.The further cell type classification of immune cell subsets indicated M2 macrophages accumulation in NLs and PLs.The GSVA enrichment scores for activation and migration capability were increased significantly in M2 macrophages from primary tumors than NLNs and PLNs(pvalue<0.001).Seven M2 macrophages activation-related and 15 M2 macrophages migration-related genes were significantly up-regulated in primary tumors than NLNs and PLNs.The proportion and GSVA enrichment scores for activation and migration of M2 macrophages may be potential markers for lymph node metastasis in breast cancer.Our study demonstrated that twenty-two up-regulated mRNA may be possible therapeutic targets for lymph node metastasis in breast cancer.展开更多
Many digestive system malignant tumors are characterized by high incidence and mortality rate.Increasing evidence has revealed that the tumor microenvironment(TME)is involved in cancer initiation and tumor progression...Many digestive system malignant tumors are characterized by high incidence and mortality rate.Increasing evidence has revealed that the tumor microenvironment(TME)is involved in cancer initiation and tumor progression.Tumor-associated macrophages(TAMs)are a predominant constituent of the TME,and participate in the regulation of various biological behaviors and influence the prognosis of digestive system cancer.TAMs can be mainly classified into the antitumor M1 phenotype and protumor M2 phenotype.The latter especially are crucial drivers of tumor invasion,growth,angiogenesis,metastasis,immunosuppression,and resistance to therapy.TAMs are of importance in the occurrence,development,diagnosis,prognosis,and treatment of common digestive system malignant tumors.In this review,we summarize the role of TAMs in common digestive system malignant tumors,including esophageal,gastric,colorectal,pancreatic and liver cancers.How TAMs promote the development of tumors,and how they act as potential therapeutic targets and their clinical applications are also described.展开更多
In the central nervous system, the formation of fibrotic scar after injury inhibits axon regeneration and promotes repair. However, the mechanism underlying fibrotic scar formation and regulation remains poorly unders...In the central nervous system, the formation of fibrotic scar after injury inhibits axon regeneration and promotes repair. However, the mechanism underlying fibrotic scar formation and regulation remains poorly understood. M2 macrophages regulate fibrotic scar formation after injury to the heart, lung, kidney, and central nervous system. However, it remains to be clarified whether and how M2 macrophages regulate fibrotic scar formation after cerebral ischemia injury. In this study, we found that, in a rat model of cerebral ischemia induced by middle cerebral artery occlusion/reperfusion, fibrosis and macrophage infiltration were apparent in the ischemic core in the early stage of injury(within 14 days of injury). The number of infiltrated macrophages was positively correlated with fibronectin expression. Depletion of circulating monocyte-derived macrophages attenuated fibrotic scar formation. Interleukin 4(IL4) expression was strongly enhanced in the ischemic cerebral tissues, and IL4-induced M2 macrophage polarization promoted fibrotic scar formation in the ischemic core. In addition, macrophage-conditioned medium directly promoted fibroblast proliferation and the production of extracellular matrix proteins in vitro. Further pharmacological and genetic analyses showed that sonic hedgehog secreted by M2 macrophages promoted fibrogenesis in vitro and in vivo, and that this process was mediated by secretion of the key fibrosis-associated regulatory proteins transforming growth factor beta 1 and matrix metalloproteinase 9. Furthermore, IL4-afforded functional restoration on angiogenesis, cell apoptosis, and infarct volume in the ischemic core of cerebral ischemia rats were markedly impaired by treatment with an sonic hedgehog signaling inhibitor, paralleling the extent of fibrosis. Taken together, our findings show that IL4/sonic hedgehog/transforming growth factor beta 1 signaling targeting macrophages regulates the formation of fibrotic scar and is a potential therapeutic target for ischemic stroke.展开更多
Microglia,the tissue resident macrophages of the brain,are increasingly recognized as key players for central nervous system development and homeostasis.They are long-lived cells deriving from a transient wave of yolk...Microglia,the tissue resident macrophages of the brain,are increasingly recognized as key players for central nervous system development and homeostasis.They are long-lived cells deriving from a transient wave of yolk-sac derived erythro-myeloid progenitors early in development.Their unique ontology has prompted the search for specific markers to be used for their selective investigation and manipulation.The first generation of genomewide expression studies has provided a bundle of transcripts(such as Olfml3,Fcrls,Tmem119,P2ry12,Gpr34,and Siglech)useful to distinguish microglia from peripheral macrophages.However,more recent reports have revealed that microglial phenotype is constantly shaped by the microenvironment in a time-,and context-dependent manner.In this article,we review data that provide additional pieces to this complex scenario and show the existence of unexpected phenotypic convergence between microglia and peripheral macrophages at certain developmental stages and under pathological conditions.These observations suggest that the two cell types act synergically boosting their mutual activities depending on the microenvironment.This novel information about the biology of microglia and peripheral macrophages sheds new light about their therapeutic potential for neuroinflammatory and neurodegenerative diseases.展开更多
基金supported by Multiple Sclerosis Research Australia and Trish Multiple Sclerosis Research Foundation Postgraduate Scholarship(to JYL)the National Multiple Sclerosis Society Project Grant#RG4398A1/1+2 种基金International Progressive Multiple Sclerosis Alliance Challenge Award#PA0065Multiple Sclerosis Research Australia and Trish Multiple Sclerosis Research Foundation#15-022Bethlehem Griffiths Research Foundation#BGRF1706(to SP)
文摘Myelin-associated inhibitory factors within the central nervous system(CNS) are considered to be one of the main obstacles for axonal regeneration following disease or injury. The nogo receptor 1(NgR1) has been well documented to play a key role in limiting axonal regrowth in the injured and diseased mammalian CNS. However, the role of nogo receptor in immune cell activation during CNS inflammation is yet to be mechanistically elucidated. Microglia/macrophages are immune cells that are regarded as pathogenic contributors to inflammatory demyelinating lesions in multiple sclerosis(MS). In this study, the animal model of MS, experimental autoimmune encephalomyelitis(EAE) was induced in ngr1^+/+ and ngr1^–/– female mice following injection with the myelin oligodendrocyte glycoprotein(MOG_(35–55)) peptide. A fatemap analysis of microglia/macrophages was performed throughout spinal cord sections of EAE-induced mice at clinical scores of 0, 1, 2 and 3, respectively(increasing locomotor disability) from both genotypes, using the CD11 b and Iba1 cell markers. Western immunoblotting using lysates from isolated spinal cord microglia/macrophages, along with immunohistochemistry and flow cytometric analysis, was performed to demonstrate the expression of nogo receptor and its two homologs during EAE progression. Myelin protein engulfment during EAE progression in ngr1^+/+ and ngr1^–/– mice was demonstrated by western immunblotting of lysates from isolated spinal cord microglia/macrophages, detecting levels of Nogo-A and MOG. The numbers of M1 and M2 microglia/macrophage phenotypes present in the spinal cords of EAE-induced ngr1^+/+ and ngr1^–/– mice, were assessed by flow cytometric analysis using CD38 and Erg-2 markers. A significant difference in microglia/macrophage numbers between ngr1^+/+ and ngr1^–/– mice was identified during the progression of the clinical symptoms of EAE, in the white versus gray matter regions of the spinal cord. This difference was unrelated to the expression of Ng R on these macrophage/microglial cells. We have identified that as EAE progresses, the phagocytic activity of microglia/macrophages with myelin debris, in ngr1^–/– mice, was enhanced. Moreover, we show a modulation from a predominant M1-pathogenic to the M2-neurotrophic cell phenotype in the ngr1^–/– mice during EAE progression. These findings suggest that CNS-specific macrophages and microglia of ngr1^–/– mice may exhibit an enhanced capacity to clear inhibitory molecules that are sequestered in inflammatory lesions.
基金supported by Science and Technology Innovation Enhancement Project of Army Medical University(to LX).
文摘MIcroglia/macrophage-mediated erythrophagocytosis plays a crucial role in hematoma clearance after intracerebral hemorrhage.Dynamic cytoskeletal changes accompany phagocytosis.However,whether and how these changes are associated with microglia/macrophage-mediated erythrophagocytosis remain unclear.In this study,we investigated the function of acetylatedα-tubulin,a stabilized microtubule form,in microglia/macrophage erythrophagocytosis after intracerebral hemorrhage both in vitro and in vivo.We first assessed the function of acetylatedα-tubulin in erythrophagocytosis using primary DiO GFP-labeled red blood cells co-cultured with the BV2 microglia or RAW264.7 macrophage cell lines.Acetylatedα-tubulin expression was significantly decreased in BV2 and RAW264.7 cells during erythrophagocytosis.Moreover,silencingα-tubulin acetyltransferase 1(ATAT1),a newly discoveredα-tubulin acetyltransferase,decreased Ac-α-tub levels and enhanced the erythrophagocytosis by BV2 and RAW264.7 cells.Consistent with these findings,in ATAT1-/-mice,we observed increased ionized calcium binding adapter molecule 1(Iba1)and Perls-positive microglia/macrophage phagocytes of red blood cells in peri-hematoma and reduced hematoma volume in mice with intracerebral hemorrhage.Additionally,knocking out ATAT1 alleviated neuronal apoptosis and pro-inflammatory cytokines and increased anti-inflammatory cytokines around the hematoma,ultimately improving neurological recovery of mice after intracerebral hemorrhage.These findings suggest that ATAT1 deficiency accelerates erythrophagocytosis by microglia/macrophages and hematoma absorption after intracerebral hemorrhage.These results provide novel insights into the mechanisms of hematoma clearance and suggest ATAT1 as a potential target for the treatment of intracerebral hemorrhage.
基金supported by the National Natural Science Foundation of China,No.81971097(to JY)。
文摘Preclinical and clinical studies have shown that microglia and macrophages participate in a multiphasic brain damage repair process following intracerebral hemorrhage.The E26 transformation-specific sequence-related transcription factor Spi1 regulates microglial/macrophage commitment and maturation.However,the effect of Spi1 on intracerebral hemorrhage remains unclear.In this study,we found that Spi1 may regulate recovery from the neuroinflammation and neurofunctional damage caused by intracerebral hemorrhage by modulating the microglial/macrophage transcriptome.We showed that high Spi1expression in microglia/macrophages after intracerebral hemorrhage is associated with the activation of many pathways that promote phagocytosis,glycolysis,and autophagy,as well as debris clearance and sustained remyelination.Notably,microglia with higher levels of Soil expression were chara cterized by activation of pathways associated with a variety of hemorrhage-related cellular processes,such as complement activation,angiogenesis,and coagulation.In conclusion,our results suggest that Spi1 plays a vital role in the microglial/macrophage inflammatory response following intracerebral hemorrhage.This new insight into the regulation of Spi1 and its target genes may advance our understanding of neuroinflammation in intracerebral hemorrhage and provide therapeutic targets for patients with intracerebral hemorrhage.
基金This work was supported by the National Natural Science Foundation of China(82003018).
文摘Tumor-associated macrophages(TAMs)are emerging as targets for tumor therapy because of their primary role in promoting tumor progression.Several studies have been conducted to target TAMs by reducing their infiltration,depleting their numbers,and reversing their phenotypes to suppress tumor progression,leading to the development of drugs in preclinical and clinical trials.However,the heterogeneous characteristics of TAMs,including their ontogenetic and functional heterogeneity,limit their targeting.Therefore,in-depth exploration of the heterogeneity of TAMs,combined with immune checkpoint therapy or other therapeutic modalities could improve the efficiency of tumor treatment.This review focuses on the heterogeneous ontogeny and function of TAMs,as well as the current development of tumor therapies targeting TAMs and combination strategies.
基金supported by Shanghai Sailing Program(22YF1438700)National Key Research and Development Program of China(2021YFA1201303)+5 种基金National Natural Science Foundation of China(82172511,81972121,81972129,82072521,82011530023,and 82111530200)Sanming Project of Medicine in Shenzhen(SZSM201612078)the Introduction Project of Clinical Medicine Expert Team for Suzhou(SZYJTD201714)Shanghai Talent Development Funding Scheme 2020080Shanghai Sailing Program(21YF1404100 and 22YF1405200)Research Project of Shanghai Science and Technology Commission(22DZ2204900)。
文摘Skeletal muscle has a robust regeneration ability that is impaired by severe injury,disease,and aging.resulting in a decline in skeletal muscle function.Therefore,improving skeletal muscle regeneration is a key challenge in treating skeletal muscle-related disorders.Owing to their significant role in tissue regeneration,implantation of M2 macrophages(M2MФ)has great potential for improving skeletal muscle regeneration.Here,we present a short-wave infrared(SWIR)fluorescence imaging technique to obtain more in vivo information for an in-depth evaluation of the skeletal muscle regeneration effect after M2MФtransplantation.SWIR fluorescence imaging was employed to track implanted M2MФin the injured skeletal muscle of mouse models.It is found that the implanted M2MФaccumulated at the injury site for two weeks.Then,SWIR fluorescence imaging of blood vessels showed that M2MФimplantation could improve the relative perfusion ratio on day 5(1.09±0.09 vs 0.85±0.05;p=0.01)and day 9(1.38±0.16 vs 0.95±0.03;p=0.01)post-injury,as well as augment the degree of skeletal muscle regencration on day 13 post-injury.Finally,multiple linear regression analyses determined that post-injury time and relative perfusion ratio could be used as predictive indicators to evaluate skeletal muscle regeneration.These results provide more in vivo details about M2MФin skeletal muscle regeneration and confirm that M2MФcould promote angiogenesis and improve the degree of skeletal muscle repair,which will guide the research and development of M2MФimplantation to improve skeletal muscle regeneration.
基金the financial supports by the National Natural Science Foundation of China(82060594)the Natural Science Foundation of Jiangxi Province,China(20202BAB205006)。
文摘The biological activity of plant polysaccharides can be enhanced by sulfated modification.In this study,the immunomodulatory effect of sulfated Cyclocarya paliurus polysaccharides(SCP3)on macrophages RAW264.7 and its potential molecular mechanism were investigated.Results showed that SCP3 at 25-100μg/m L increased viability and improved phagocytosis of RAW264.7 cells.Meanwhile,SCP3 could activate mitogen-activated protein kinase(MAPK)and nuclear factor kappa B(NF-κB)signaling pathways,which increased the phosphorylation of Erk1/2,JNK,p38 and NF-κB p65,promoting secretion of cytokines tumor necrosis factorα(TNF-α),interleukin 6(IL-6)and nitric oxide(NO)as well as the production of reactive oxygen species(ROS).In addition,Toll-like receptor 4(TLR4)receptor inhibitors were able to block the production of NO and TNF-αby SCP3-stimulated macrophages.Based on Western blot analysis and validation using specific inhibitors against MAPK and NF-κB signaling pathways,the results demonstrated that SCP3 induced macrophages activation and enhanced TNF-αand NO production via TLR4-mediated MAPK and NF-κB pathways.In summary,SCP3 has significant immunomodulatory potential.The underlying molecular mechanism was that SCP3 activates macrophages via TLR4 receptors to promote ROS production,which in turn activates the downstream MAPK/NF-κB signaling pathway and then increases the secretion levels of cytokines and NO.
基金supported by a grant from the Department of Science and Technology of Shanxi Province,China,No.20210302123477(to CL)Datong Bureau of Science and Technology of China,No.2020152(to CL)the Opening Foundation of Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine,No.2022-KF-03(to CL).
文摘Multiple sclerosis is characterized by demyelination and neuronal loss caused by inflammatory cell activation and infiltration into the central nervous system.Macrophage polarization plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis,a traditional experimental model of multiple sclerosis.This study investigated the effect of Fasudil on macrophages and examined the therapeutic potential of Fasudil-modified macrophages in experimental autoimmune encephalomyelitis.We found that Fasudil induced the conversion of macrophages from the pro-inflammatory M1 type to the anti-inflammatory M2 type,as shown by reduced expression of inducible nitric oxide synthase/nitric oxide,interleukin-12,and CD16/32 and increased expression of arginase-1,interleukin-10,CD14,and CD206,which was linked to inhibition of Rho kinase activity,decreased expression of toll-like receptors,nuclear factor-κB,and components of the mitogen-activated protein kinase signaling pathway,and generation of the pro-inflammatory cytokines tumor necrosis factor-α,interleukin-1β,and interleukin-6.Crucially,Fasudil-modified macrophages effectively decreased the impact of experimental autoimmune encephalomyelitis,resulting in later onset of disease,lower symptom scores,less weight loss,and reduced demyelination compared with unmodified macrophages.In addition,Fasudil-modified macrophages decreased interleukin-17 expression on CD4^(+)T cells and CD16/32,inducible nitric oxide synthase,and interleukin-12 expression on F4/80^(+)macrophages,as well as increasing interleukin-10 expression on CD4^(+)T cells and arginase-1,CD206,and interleukin-10 expression on F4/80^(+)macrophages,which improved immune regulation and reduced inflammation.These findings suggest that Fasudil-modified macrophages may help treat experimental autoimmune encephalomyelitis by inducing M2 macrophage polarization and inhibiting the inflammatory response,thereby providing new insight into cell immunotherapy for multiple sclerosis.
基金supported by the Natural Science Foundation of Shandong Province,No.ZR2020MH138(to XZ).
文摘Our previous study has demonstrated that lnc_000048 is upregulated in large-artery atherosclerotic stroke and promotes atherosclerosis in ApoE^(-/-)mice.However,little is known about the role of lnc_000048 in classically activated macrophage(M1)polarization.In this study,we established THP-1-derived testing state macrophages(M0),M1 macrophages,and alternately activated macrophages(M2).Real-time fluorescence quantitative PCR was used to verify the expression of marker genes and the expression of lnc_000048 in macrophages.Flow cytometry was used to detect phenotypic proteins(CD11b,CD38,CD80).We generated cell lines with lentivirus-mediated upregulation or downregulation of lnc_000048.Flow cytometry,western blot,and real-time fluorescence quantitative PCR results showed that down-regulation of lnc_000048 reduced M1 macrophage polarization and the inflammation response,while over-expression of lnc_000048 led to the opposite effect.Western blot results indicated that lnc_000048 enhanced the activation of the STAT1 pathway and mediated the M1 macrophage polarization.Moreover,catRAPID prediction,RNA-pull down,and mass spectrometry were used to identify and screen the protein kinase RNA-activated(PKR),then catRAPID and RPIseq were used to predict the binding ability of lnc_000048 to PKR.Immunofluorescence(IF)-RNA fluorescence in situ hybridization(FISH)double labeling was performed to verify the subcellular colocalization of lnc_000048 and PKR in the cytoplasm of M1 macrophage.We speculate that lnc_000048 may form stem-loop structure-specific binding and activate PKR by inducing its phosphorylation,leading to activation of STAT1 phosphorylation and thereby enhancing STAT1 pathway-mediated polarization of THP-1 macrophages to M1 and inflammatory factor expression.Taken together,these results reveal that the lnc_000048/PKR/STAT1 axis plays a crucial role in the polarization of M1 macrophages and may be a novel therapeutic target for atherosclerosis alleviation in stroke.
基金Supported by the National Key Research and Development Program of China,No.2023YFC2508806Key Research and Development Project in Henan Province,No.231111310500+4 种基金Young Elite Scientists Sponsorship Program by CAST,No.2021-QNRC2-A06Scientific Research Project of Henan Zhongyuan Medical Science and Technology Innovation and Development Foundation,No.ZYYC2023ZDYouth Science Award Project of the Provincial-Level Joint Fund for Science and Technology Research and Development Project in Henan Province,No.225200810084Special Project on Training Top Talents in Traditional Chinese Medicine in Henan Province,No.2022ZYBJ242023 Hunan University of Chinese Medicine Postgraduate Innovation Project,No.2023CX64。
文摘The repair of bone tissue damage is a complex process that is well-orchestrated in time and space,a focus and difficulty in orthopedic treatment.In recent years,the success of mesenchymal stem cells(MSCs)-mediated bone repair in clinical trials of large-area bone defects and bone necrosis has made it a candidate in bone tissue repair engineering and regenerative medicine.MSCs are closely related to macrophages.On one hand,MSCs regulate the immune regulatory function by influencing macrophages proliferation,infiltration,and phenotype polarization,while also affecting the osteoclasts differentiation of macrophages.On the other hand,macrophages activate MSCs and mediate the multilineage differentiation of MSCs by regulating the immune microenvironment.The cross-talk between MSCs and macrophages plays a crucial role in regulating the immune system and in promoting tissue regeneration.Making full use of the relationship between MSCs and macrophages will enhance the efficacy of MSCs therapy in bone tissue repair,and will also provide a reference for further application of MSCs in other diseases.
文摘BACKGROUND Alveolar bone defects caused by inflammation are an urgent issue in oral implant surgery that must be solved.Regulating the various phenotypes of macrophages to enhance the inflammatory environment can significantly affect the progression of diseases and tissue engineering repair process.AIM To assess the influence of interleukin-10(IL-10)on the osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs)following their interaction with macrophages in an inflammatory environment.METHODS IL-10 modulates the differentiation of peritoneal macrophages in Wistar rats in an inflammatory environment.In this study,we investigated its impact on the proliferation,migration,and osteogenesis of BMSCs.The expression levels of signal transducer and activator of transcription 3(STAT3)and its activated form,phos-phorylated-STAT3,were examined in IL-10-stimulated macrophages.Subsequently,a specific STAT3 signaling inhibitor was used to impede STAT3 signal activation to further investigate the role of STAT3 signaling.RESULTS IL-10-stimulated macrophages underwent polarization to the M2 type through substitution,and these M2 macrophages actively facilitated the osteogenic differentiation of BMSCs.Mechanistically,STAT3 signaling plays a crucial role in the process by which IL-10 influences macrophages.Specifically,IL-10 stimulated the activation of the STAT3 signaling pathway and reduced the macrophage inflammatory response,as evidenced by its diminished impact on the osteogenic differentiation of BMSCs.CONCLUSION Stimulating macrophages with IL-10 proved effective in improving the inflammatory environment and promoting the osteogenic differentiation of BMSCs.The IL-10/STAT3 signaling pathway has emerged as a key regulator in the macrophage-mediated control of BMSCs’osteogenic differentiation.
基金supported by the National Natural Science Foundation of China,No.32371048(to YK)the Peking University People’s Hospital Research and Development Funds,No.RDX2021-01(to YK)the Natural Science Foundation of Beijing,No.7222198(to NH)。
文摘Macrophages play an important role in peripheral nerve regeneration,but the specific mechanism of regeneration is still unclear.Our preliminary findings indicated that neutrophil peptide 1 is an innate immune peptide closely involved in peripheral nerve regeneration.However,the mechanism by which neutrophil peptide 1 enhances nerve regeneration remains unclear.This study was designed to investigate the relationship between neutrophil peptide 1 and macrophages in vivo and in vitro in peripheral nerve crush injury.The functions of RAW 264.7 cells we re elucidated by Cell Counting Kit-8 assay,flow cytometry,migration assays,phagocytosis assays,immunohistochemistry and enzyme-linked immunosorbent assay.Axonal debris phagocytosis was observed using the CUBIC(Clear,Unobstructed Brain/Body Imaging Cocktails and Computational analysis)optical clearing technique during Wallerian degeneration.Macrophage inflammatory factor expression in different polarization states was detected using a protein chip.The results showed that neutrophil peptide 1 promoted the prolife ration,migration and phagocytosis of macrophages,and CD206 expression on the surfa ce of macrophages,indicating M2 polarization.The axonal debris clearance rate during Wallerian degeneration was enhanced after neutrophil peptide 1 intervention.Neutrophil peptide 1 also downregulated inflammatory factors interleukin-1α,-6,-12,and tumor necrosis factor-αin invo and in vitro.Thus,the results suggest that neutrophil peptide 1 activates macrophages and accelerates Wallerian degeneration,which may be one mechanism by which neutrophil peptide 1 enhances peripheral nerve regeneration.
文摘Glioma associated microglia/macrophages (GAMs) constitute the largest proportion of glioma infiltrating cells, par-ticularly in high grade tumors (i.e., glioblastoma). Once inside the tumors, GAMs usually acquire a specific pheno-type of activation that favors tumor growth, angiogenesis and promotes the invasion of normal brain parenchyma. Therefore, treatments that limit or prevent GAMs' recruitment at the tumor site or modulate their immune activa-tion promoting antitumor activities are expected to exert beneficial effects in glioblastoma. In the present paper, we aim at the revision of pharmacological strategies that interfere with GAMs' function and are currently proposed as an alternative/additional option to current approved cytotoxic regimens.
基金supported by the Fundamental Research Funds for the Central Universities(2042021kf0102,2042021kf0083)supported by two National Natural Science Foundation of China(NSFC)Grants(81903166,82203629)+1 种基金a Natural Science Foundation of Hubei(2018CKB916)sponsored by Shanghai Pujiang Program(22PJD054).
文摘Obesity is one of the most serious global health problems,with an incidence that increases yearly and coincides with the development of cancer.Adipose tissue macrophages(ATMs)are particularly important in this context and contribute to linking obesity-related inflammation and tumor progression.However,the functions of ATMs on the progression of obesity-associated cancer remain unclear.In this review,we describe the origins,phenotypes,and functions of ATMs.Subsequently,we summarize the potential mechanisms on the reprogramming of ATMs in the obesity-associated microenvironment,including the direct exchange of dysfunctional metabolites,inordinate cytokines and other signaling mediators,transfer of extracellular vesicle cargo,and variations in the gut microbiota and its metabolites.A better understanding of the properties and functions of ATMs under conditions of obesity will lead to the development of new therapeutic interventions for obesity-related cancer.
基金supported by grants from National Institutes of Health(R01GM100474)the New Jersey Commission on Spinal Cord Research(CSCR13IRG006)
文摘Spinal cord injury (SCI) is a devastating type of neurological trauma with limited therapeutic op- portunities. The pathophysiology of SCI involves primary and secondary mechanisms of injury. Among all the secondary injury mechanisms, the inflammatory response is the major contrib- utor and results in expansion of the lesion and further loss of neurologic function. Meanwhile, the inflammation directly and indirectly dominates the outcomes of SCI, including not only pain and motor dysfunction, but also preventingneuronal regeneration. Microglia and macrophages play very important roles in secondary injury. Microglia reside in spinal parenchyma and survey the microenvironment through the signals of injury or infection. Macrophages are derived from monocytes recruited to injured sites from the peripheral circulation. Activated resident microglia and monocyte-derived macrophages induce and magnify immune and inflammatory responses not only by means of their secretory moleculesand phagocytosis, but also through their influence on astrocytes, oligodendrocytes and demyelination. In this review, we focus on the roles of mi- croglia and macrophages in secondary injury and how they contribute to the sequelae of SCI.
基金supported by the National Science Fund for Distinguished Young Scholars of China(31925031).
文摘Inflammation plays an important role in the occurrence and development of many inflammatory diseases.The purpose of this study was to evaluate the anti-inflammatory effect and metabolic behavior of the dual targeting procyanidins(PC)nanoparticles on lipopolysaccharide(LPS)-stimulated inflammatory macrophages by metabolomics method.The double-targeting PC nanoparticles could specifi cally target both the CD44 receptor and mitochondria,while the single targeting PC-loaded nanoparticles that could target the CD44 receptor on the surface of macrophages.The double-targeting PC nanoparticles had better inhibitory effect than single-targeting PC nanoparticles on the leakage of lactate dehydrogenase and reactive oxygen species overexpression induced by LPS.Amino acid metabolism,energy metabolism and purine metabolism were disordered in LPS-treated group,and metabolic pathway analysis indicated that the double-targeting PC nanoparticles reversed some of LPS impacts.The changes of these potential biomarkers and their corresponding pathways are helpful to further understand the mechanism of PC nanoparticles in alleviating inflammation,and promote their application in nutrition intervention.
基金supported by the Major Scientific Research Tasks for Scientific and Technological Innovation Projects of the Chinese Academy of Agricultural Sciences(CAAS-ZDRW202006)the National Transgenic Breeding Project,China(2018ZX08009-26B)+1 种基金the Shenzhen Science and Technology Plan Project,China(CJGJZD20210408092402006)the Shenzhen Key Technology Projects,China(JSGG20180507182028625).
文摘Porcine reproductive and respiratory syndrome(PRRS)is recognized as one of the most infectious viral diseases of swine.Although Cluster of differentiation 163(CD163)is identified as an essential receptor for mediating PRRS virus(PRRSV)infection,the important residues involved in infection on CD163 are still unclear.Therefore,it is very important to identify these key residues to study the mechanism of PRRSV infection and to generate anti-PRRSV pigs.In this study,we first generated immortalized porcine alveolar macrophage(IPAM)cell lines harboring 40-residues(residues 523-562,including R561(arginine(R)at position 561))deletion of CD163.PRRSV infection experiments showed that these IPAM cell lines were completely resistant to PRRSV infection.We then generated cloned pigs carrying CD163-R561A(an arginine(R)to alanine(A)substitution at position 561 of CD163).PRRSV challenge experiments in porcine alveolar macrophages(PAMs)isolated from the CD163-R561A pigs showed significantly lower susceptibility to PRRSV than that of CD163-R561 PAMs.Through this study,we show that CD163523-562 contains essential residues for mediating PRRSV infection,and that CD163 R561 significantly contributes to PRRSV infection but is not essential for infection.These functional sites can therefore serve as new targets for understanding the mechanism of PRRSV infection.Furthermore,CD163-R561A pigs can be used as an important model for improving pig germplasm with resistance against PRRSV.
文摘The process of lymphatic metastasis was proved to be associated with podoplanin-expressing macrophages in breast cancer(BC).This study aimed to investigate the role of the M2 phenotype of tumor-associated macrophages and mine the key M2 macrophages-related genes for lymph node metastasis in BC.We downloaded the GSE158399 dataset from the Gene Expression Omnibus(GEO)database,which includes transcriptomic profiles of individual cells from primary tumors,negative lymph nodes(NLNs),and positive lymph nodes(PLNs)of breast cancer patients.The cell subsets were identified by clustering analysis after quality control of the scRNA-seq using Seurat.The activation and migration capability of M2 macrophages were evaluated with R package“GSVA”.The key M2 macrophages-related genes were screened from the differential expressed genes(DEGs)and M2 macrophages activation and migration gene sets collected from MSigDB database.Our analysis identified three main cell types in primary tumors,NLNs,and PLNs:basal cells,luminal cells,and immune cell subsets.The further cell type classification of immune cell subsets indicated M2 macrophages accumulation in NLs and PLs.The GSVA enrichment scores for activation and migration capability were increased significantly in M2 macrophages from primary tumors than NLNs and PLNs(pvalue<0.001).Seven M2 macrophages activation-related and 15 M2 macrophages migration-related genes were significantly up-regulated in primary tumors than NLNs and PLNs.The proportion and GSVA enrichment scores for activation and migration of M2 macrophages may be potential markers for lymph node metastasis in breast cancer.Our study demonstrated that twenty-two up-regulated mRNA may be possible therapeutic targets for lymph node metastasis in breast cancer.
基金Supported by National Natural Science Foundation of China,No.82272396Suzhou Medical and Health Science and Technology Innovation Project,No.SKY2022057The Youth Medical Talent of Jiangsu Province,No.QNRC2016475.
文摘Many digestive system malignant tumors are characterized by high incidence and mortality rate.Increasing evidence has revealed that the tumor microenvironment(TME)is involved in cancer initiation and tumor progression.Tumor-associated macrophages(TAMs)are a predominant constituent of the TME,and participate in the regulation of various biological behaviors and influence the prognosis of digestive system cancer.TAMs can be mainly classified into the antitumor M1 phenotype and protumor M2 phenotype.The latter especially are crucial drivers of tumor invasion,growth,angiogenesis,metastasis,immunosuppression,and resistance to therapy.TAMs are of importance in the occurrence,development,diagnosis,prognosis,and treatment of common digestive system malignant tumors.In this review,we summarize the role of TAMs in common digestive system malignant tumors,including esophageal,gastric,colorectal,pancreatic and liver cancers.How TAMs promote the development of tumors,and how they act as potential therapeutic targets and their clinical applications are also described.
基金supported by the National Natural Science Foundation of China,Nos.82171456 (to QY),81971229 (to QY)the Natural Science Foundation of Chongqing,No.cstc2021jcyj-msxmX0263 (to QY)the Postgraduate Research and Innovation Project of Chongqing,Nos.CYB20151 (to QY),CYS19182 (to YC)。
文摘In the central nervous system, the formation of fibrotic scar after injury inhibits axon regeneration and promotes repair. However, the mechanism underlying fibrotic scar formation and regulation remains poorly understood. M2 macrophages regulate fibrotic scar formation after injury to the heart, lung, kidney, and central nervous system. However, it remains to be clarified whether and how M2 macrophages regulate fibrotic scar formation after cerebral ischemia injury. In this study, we found that, in a rat model of cerebral ischemia induced by middle cerebral artery occlusion/reperfusion, fibrosis and macrophage infiltration were apparent in the ischemic core in the early stage of injury(within 14 days of injury). The number of infiltrated macrophages was positively correlated with fibronectin expression. Depletion of circulating monocyte-derived macrophages attenuated fibrotic scar formation. Interleukin 4(IL4) expression was strongly enhanced in the ischemic cerebral tissues, and IL4-induced M2 macrophage polarization promoted fibrotic scar formation in the ischemic core. In addition, macrophage-conditioned medium directly promoted fibroblast proliferation and the production of extracellular matrix proteins in vitro. Further pharmacological and genetic analyses showed that sonic hedgehog secreted by M2 macrophages promoted fibrogenesis in vitro and in vivo, and that this process was mediated by secretion of the key fibrosis-associated regulatory proteins transforming growth factor beta 1 and matrix metalloproteinase 9. Furthermore, IL4-afforded functional restoration on angiogenesis, cell apoptosis, and infarct volume in the ischemic core of cerebral ischemia rats were markedly impaired by treatment with an sonic hedgehog signaling inhibitor, paralleling the extent of fibrosis. Taken together, our findings show that IL4/sonic hedgehog/transforming growth factor beta 1 signaling targeting macrophages regulates the formation of fibrotic scar and is a potential therapeutic target for ischemic stroke.
基金This work was supported by Merk-Serono,TargetBrain(EU Framework 7 Project,No.HEALTH-F2–2012-279017 to GM)Fondazione Italiana Sclerosi Multipla(FISM,No.grant 2016/R/14 to CF)cofinanced with the 5 per mille public funding.
文摘Microglia,the tissue resident macrophages of the brain,are increasingly recognized as key players for central nervous system development and homeostasis.They are long-lived cells deriving from a transient wave of yolk-sac derived erythro-myeloid progenitors early in development.Their unique ontology has prompted the search for specific markers to be used for their selective investigation and manipulation.The first generation of genomewide expression studies has provided a bundle of transcripts(such as Olfml3,Fcrls,Tmem119,P2ry12,Gpr34,and Siglech)useful to distinguish microglia from peripheral macrophages.However,more recent reports have revealed that microglial phenotype is constantly shaped by the microenvironment in a time-,and context-dependent manner.In this article,we review data that provide additional pieces to this complex scenario and show the existence of unexpected phenotypic convergence between microglia and peripheral macrophages at certain developmental stages and under pathological conditions.These observations suggest that the two cell types act synergically boosting their mutual activities depending on the microenvironment.This novel information about the biology of microglia and peripheral macrophages sheds new light about their therapeutic potential for neuroinflammatory and neurodegenerative diseases.