We report the activation of anticancer effector functions of T cells through nanoparticle-induced lipid metabolic reprogramming.Fenofibrate was encapsulated in amphiphilic polygamma glutamic acid-based nanoparticles(F...We report the activation of anticancer effector functions of T cells through nanoparticle-induced lipid metabolic reprogramming.Fenofibrate was encapsulated in amphiphilic polygamma glutamic acid-based nanoparticles(F/ANs),and the surfaces of F/ANs were modified with an anti-CD3e f(ab′)2 fragment,yielding aCD3/F/ANs.An in vitro study reveals enhanced delivery of aCD3/F/ANs to T cells compared with plain F/ANs.aCD3/F/AN-treated T cells exhibited clear mitochondrial cristae,a higher membrane potential,and a greater mitochondrial oxygen consumption rate under glucose-deficient conditions compared with T cells treated with other nanoparticle preparations.Peroxisome proliferatoractivated receptor-αand downstream fatty acid metabolismrelated genes are expressed to a greater extent in aCD3/F/AN-treated T cells.Activation of fatty acid metabolism by aCD3/F/ANs supports the proliferation of T cells in a glucose-deficient environment mimicking the tumor microenvironment.Real-time video recordings show that aCD3/F/AN-treated T cells exerted an effector killing effect against B16F10 melanoma cells.In vivo administration of aCD3/F/ANs can increase infiltration of T cells into tumor tissues.The treatment of tumor-bearing mice with aCD3/F/ANs enhances production of various cytokines in tumor tissues and prevented tumor growth.Our findings suggest the potential of nanotechnology-enabled reprogramming of lipid metabolism in T cells as a new modality of immunometabolic therapy.展开更多
Background:Chronic endometritis(CE)is an important pathological factor contributing to female infertility and recurrent pregnancy loss.Although antibiotics are the primary clinical treatment for CE,they do not effecti...Background:Chronic endometritis(CE)is an important pathological factor contributing to female infertility and recurrent pregnancy loss.Although antibiotics are the primary clinical treatment for CE,they do not effectively improve pregnancy outcomes.Wen Yang Hua Zhuo(WYHZ)is a clinically employed classical formula known for its effects in warming yang,tonifying the spleen and kidneys,and resolving dampness.However,its underlying mechanisms remain unclear.This study aimed to elucidate how WYHZ modulates the immunometabolic microenvironment at the maternal-fetal interface in CE by targeting the MCT/HIF-1α/LDHA pathway to promote embryo implantation.Methods:In vivo,the model of CE was established by intrauterine injection of lipopolysaccharide(LPS)(1 mg/mL)into female C57/BL mice,followed by WYHZ treatment for 3 weeks to evaluate its effects on embryo implantation.Mechanistic studies were further conducted using the MCT-1 inhibitor AZD3965 and adeno-associated virus-mediated HIF-1αknockdown.In vitro,an in vitro CE model consisting of M1 macrophages and Ishikawa,as well as an in vitro embryo implantation model mediated by JAR cells,were constructed using Transwell,and the therapeutic mechanisms of WYHZ was validated using AZD3965 and lentiviral sh HIF-1αintervention.Metabolic enzyme activity assays,protein antibody microarrays,immunofluorescence,Western blotting,Seahorse analysis,and ELISA were employed.Results:WYHZ improved the immune-inflammatory microenvironment at the maternal-fetal interface by reducing pro-inflammatory cytokines and increasing anti-inflammatory factors.In parallel,WYHZ reprogrammed endometrial metabolism by enhancing glycolysis and suppressing mitochondrial oxidative phosphorylation,thereby improving endometrial receptivity and embryo implantation.Mechanistically,WYHZ activated the MCT/HIF-1α/LDHA pathway in endometrial epithelial cells,alleviating inflammatory stress and restoring receptivity.Both AZD3965 intervention and HIF-1αknockdown impaired endometrial receptivity and implantation,effects that were reversed by WYHZ.Conclusion:WYHZ modulates the immunometabolic microenvironment of the endometrium in the context of CE by targeting the activation of the MCT/HIF-1α/LDHA pathway,which improves endometrial receptivity and promotes embryo implantation.展开更多
The core principle of diagnosis and treatment in traditional Chinese medicine(TCM) is the identification of different syndromes.Cold and hot syndromes are important elements in TCM theory.Identifying the biological ba...The core principle of diagnosis and treatment in traditional Chinese medicine(TCM) is the identification of different syndromes.Cold and hot syndromes are important elements in TCM theory.Identifying the biological basis of cold and hot syndromes in TCM will help elucidate TCM theories scientifically,thus promoting precise treatment in TCM.Although the biological basis of cold/hot syndromes in TCM remains poorly understood,growing evide nce suggests that immunometab olic interactions play an important role in balancing cold and hot syndromes.Immuno metabolism involve s complex interactions between the immune and metabolic systems.Multilevel mechanisms of interaction between the immune and metabolic systems may underlie many inflammatory diseases and offer substantial therapeutic promise.Therefore,dissecting the relationship between immunometabolism and the biological network of cold/hot syndromes has become a priority.This article reviews the progress of cold/hot syndrome research from the perspective of immunometabolic homeostasis,thus further clarifying cold/hot syndromes in TCM.展开更多
Drug resistance continues to be the principal limiting factor in achieving a cure for patients with cancer,significantly hindering the long-term efficacy of novel cancer drugs.Accumulating evidence has shown that meta...Drug resistance continues to be the principal limiting factor in achieving a cure for patients with cancer,significantly hindering the long-term efficacy of novel cancer drugs.Accumulating evidence has shown that metabolites derived from tumor cells regulate immune cell metabolism via tumor microenvironment crosstalk.However,as immunometabolic research has deepened,the leading role played by the intrinsic metabolic regulation of immune cells in the drug resistance of tumor cells has been discovered.Immune metabolites have been shown to cause immune resistance,target therapy resistance,and chemotherapy resistance,and drugs that target immune metabolism have great potential.To date,researchers have not fully explored the impact of immune-derived metabolites on tumor cells and their influence on the responsiveness to cancer drugs.In this review,we focus on the lactate,fatty acid,glucose,and nucleotide metabolic alterations that take place in T cells and macrophages and how these changes can impair anti-tumor immunity,ultimately promoting tumor cell survival and decreasing responsiveness to the corresponding therapeutic approaches.We present the current developments in drugs targeting immunometabolic pathways and propose constructive suggestions,such as precise delivery to immune cell targets to enhance efficacy and safety,offering novel perspectives for cancer drug development.展开更多
Alzheimer’s disease(AD)represents a prototypical neurodegenerative disorder with a multifactorial pathogenesis encompassing amyloid-β(Aβ)deposition,tau protein hyperphosphorylation,and chronic neuroinflammation.Rec...Alzheimer’s disease(AD)represents a prototypical neurodegenerative disorder with a multifactorial pathogenesis encompassing amyloid-β(Aβ)deposition,tau protein hyperphosphorylation,and chronic neuroinflammation.Recent advances in proteomic profiling have identified significant dysregulation in astrocytic and microglial metabolic pathways in AD pathogenesis,establishing mechanistic links between metabolic dyshomeostasis and neuroimmune crosstalk.Accumulating evidence indicates that acupuncture has gained prominence as a non-pharmacological therapeutic modality for AD management,owing to its multimodal regulatory effects on neuroinflammatory cascades,metabolic recalibration,and immune network stabilization.This study aims to elucidate the molecular mechanisms through which acupuncture exerts its neuroprotective effects,focusing on three interconnected axes:immunometabolic reprogramming in glial cells(particularly microglial bioenergetic adaptation),gut microbiota-derived metabolite signaling(including short-chain fatty acid-mediated pathways),and neuro‐immune‐metabolic interplay.We present a novel therapeutic framework highlighting acupuncture-mediated immunometabolic modulation,thereby providing a mechanistic foundation for developing targeted therapeutic strategies in AD management.展开更多
The gut microbiota is of growing interest to clinicians and researchers due to its elucidating extensive role in metabolic and immune mechanisms,not only in the gut but also in other organs.The liver shares a close bi...The gut microbiota is of growing interest to clinicians and researchers due to its elucidating extensive role in metabolic and immune mechanisms,not only in the gut but also in other organs.The liver shares a close bidirectional relationship with the intestine and the gut microbiota.Disturbances in the composition of the gut microbiota can affect the immune systems of both the intestine and liver.In turn,bile composition also influences the gut microbiota.Disruption of this balance can arise from various causes and may significantly impact intestinal and liver health.Therefore,the aim of the current review is to discuss the biological relationships between the gut microbiota and liver function as well as the clinical significance of their disturbances.展开更多
Liver diseases are of growing interest to clinicians and researchers due to their high prevalence,difficulty in early diagnosis,and limited treatment options.The liver is an important organ at the intersection of many...Liver diseases are of growing interest to clinicians and researchers due to their high prevalence,difficulty in early diagnosis,and limited treatment options.The liver is an important organ at the intersection of many metabolic and immune pathways.To this end,it contains a large number of immune cells of both the innate and adaptive immune system that perform multiple functions,detecting and destroying pathogens that enter the body through the intestine,as well as recognizing endogenous antigens.Immune cells in the liver have a complex regulation that can be impaired in various diseases such as metabolic dysfunctionassociated steatotic liver disease(MASLD),liver cancer,and biliary diseases.A growing body of evidence reinforces the realization that not only impaired metabolism but also many immune mechanisms underlie MASLD.The liver has complex bilateral immune and metabolic links with the gut microbiota,and disruptions of these links underlie the development and progression of both gastrointestinal and other organ diseases.In this regard,acting on immune mechanisms is a promising therapeutic target for liver diseases.展开更多
The transition period of dairy cattle is characterized by a number of metabolic, endocrine, physiologic, and immune adaptations, including the occurrence of negative energy balance, hypocalcemia, liver dysfunction, ov...The transition period of dairy cattle is characterized by a number of metabolic, endocrine, physiologic, and immune adaptations, including the occurrence of negative energy balance, hypocalcemia, liver dysfunction, overt systemic inflammatory response, and oxidative stress status. The degree and length of time during which these systems remain out of balance could render cows more susceptible to disease, poor reproductive outcomes, and less efficient for milk production and quality. Studies on both monogastrics and ruminants have reported the health benefits of nutraceuticals(e.g. probiotics, prebiotics, dietary lipids, functional peptides, phytoextracts) beyond nutritional value, interacting at different levels of the animal's physiology. From a physiological standpoint, it seems unrealistic to disregard any systemic inflammatory processes. However, an alternate approach is to modulate the inflammatory process per se and to resolve the systemic response as quickly as possible.To this aim, a growing body of literature underscores the efficacy of nutraceuticals(active compounds) during the critical phase of the transition period. Supplementation of essential fatty acids throughout a 2-month period(i.e. a month before and a month after calving) successfully attenuates the inflammatory status with a quicker resolution of phenomenon. In this context, the inflammatory and immune response scenario has been recognized to be targeted by the beneficial effect of methyl donors, such as methionine and choline, directly and indirectly modulating such response with the increase of antioxidants GSH and taurine. Indirectly by the establishment of a healthy gastrointestinal tract, yeast and yeast-based products showed to modulate the immune response, mitigating negative effects associated with parturition stress and consequent disorders.The use of phytoproducts has garnered high interest because of their wide range of actions on multiple tissue targets encompassing a series of antimicrobial, antiviral, antioxidant, immune-stimulating, rumen fermentation, and microbial modulation effects. In this review, we provide perspectives on investigations of regulating the immune responses and metabolism using several nutraceuticals in the periparturient cow.展开更多
The tumor microenvironment is an ecosystem composed of multiple types of cells, such as tumor cells, immune cells, and cancerassociated fibroblasts. Cancer cells grow faster than non-cancerous cells and consume larger...The tumor microenvironment is an ecosystem composed of multiple types of cells, such as tumor cells, immune cells, and cancerassociated fibroblasts. Cancer cells grow faster than non-cancerous cells and consume larger amounts of nutrients. The rapid growth characteristic of cancer cells fundamentally alters nutrient availability in the tumor microenvironment and results in reprogramming of immune cell metabolic pathways. Accumulating evidence suggests that cellular metabolism of nutrients, such as lipids and amino acids, beyond being essential to meet the bioenergetic and biosynthetic demands of immune cells, also regulates a broad spectrum of cellular signal transduction, and influences immune cell survival, differentiation, and anti-tumor effector function. The cancer immunometabolism research field is rapidly evolving, and exciting new discoveries are reported in high-profile journals nearly weekly. Therefore, all new findings in this field cannot be summarized within this short review. Instead, this review is intended to provide a brief introduction to this rapidly developing research field, with a focus on the metabolism of two classes of important nutrients-lipids and amino acids-in immune cells. We highlight recent research on the roles of lipids and amino acids in regulating the metabolic fitness and immunological functions of T cells, macrophages, and natural killer cells in the tumor microenvironment. Furthermore, we discuss the possibility of “editing” metabolic pathways in immune cells to act synergistically with currently available immunotherapies in enhancing anti-tumor immune responses.展开更多
Cancer immunotherapy using immune-checkpoint inhibitors(ICIs)has revolutionized the field of cancer treatment;however,ICI efficacy is constrained by progressive dysfunction of CD8+tumor-infiltrating lymphocytes(TILs),...Cancer immunotherapy using immune-checkpoint inhibitors(ICIs)has revolutionized the field of cancer treatment;however,ICI efficacy is constrained by progressive dysfunction of CD8+tumor-infiltrating lymphocytes(TILs),which is termed T cell exhaustion.This process is driven by diverse extrinsic factors across heterogeneous tumor immune microenvironment(TIME).Simultaneously,tumorigenesis entails robust reshaping of the epigenetic landscape,potentially instigating T cell exhaustion.In this review,we summarize the epigenetic mechanisms governing tumor microenvironmental cues leading to T cell exhaustion,and discuss therapeutic potential of targeting epigenetic regulators for immunotherapies.Finally,we outline conceptual and technical advances in developing potential treatment paradigms involving immunostimulatory agents and epigenetic therapies.展开更多
Vital pulp therapy(VPT)is considered a conservative means of preserving the vitality and function of the dental pulp after injury.However,current VPT has unfavorable effects on inflamed pulp.Mesenchymal stem cell(MSC)...Vital pulp therapy(VPT)is considered a conservative means of preserving the vitality and function of the dental pulp after injury.However,current VPT has unfavorable effects on inflamed pulp.Mesenchymal stem cell(MSC)-derived small extracellular vesicles(MSC-sEVs)show powerful immunomodulatory capacities and exert thera-peutic effects on a variety of inflammatory diseases.However,whether MSC-sEVs ameliorate the inflammatory response and promote inflammatory pulp repair in pulpitis is largely unknown.In this study,we show that sEVs derived from dental follicle stem cells(typical dental MSCs,DFSC-sEVs)alleviate lipopolysaccharide-induced pulpitis in rats and enhance pulp repair by inducing M2 macrophage polarization.Mechanistically,heat shock protein 70(HSP70)within DFSC-sEVs can be supplemented into lysosomes to directly protect lysosomal function and induce mitophagy to promote the degradation of depolarized mitochondria,thereby preprogramming in-flammatory macrophages to commit to oxidative phosphorylation,which fuels M2 polarization.Furthermore,DFSC-sEVs also transfer antioxidant miRNAs,including miR-24-3p and let-7c-5p,to inhibit mitochondrial reactive oxygen species production,thereby indirectly stabilizing lysosomes to induce M2 macrophage generation.Our study reveals a promising immunotherapeutic potential of DFSC-sEVs for VPT in inflamed pulp and a novel role for DFSC-sEVs in inhibiting the macrophage inflammatory response by protecting lysosomes and inducing mitophagy-mediated metabolic shifts toward oxidative phosphorylation.展开更多
Hepatocellular carcinoma(HCC)is one of the most aggressive human malignancies with a dismal survival rate.Few strategies can effectively prevent the occurrence of HCC.Although immunotherapy has significantly improved ...Hepatocellular carcinoma(HCC)is one of the most aggressive human malignancies with a dismal survival rate.Few strategies can effectively prevent the occurrence of HCC.Although immunotherapy has significantly improved HCC-related survival in recent years,this systemic therapy is very expensive and lays a heavy burden on most HCC patients.Aspirin,which is currently one of the most widely used medications in analgesic and cardiovascular diseases,is reported to have anti-tumor effects on HCC.Most importantly,long-term administration of low-dose aspirin does not significantly increase the risk of gastrointestinal bleeding.Owing to its costeffectiveness and wide use,aspirin can be easily applied as an HCC treatment and is affordable for a wide range of patients.Therefore,deeper understanding and more attention are needed to extend the frontline of aspirin's preventive and therapeutic potential into cancer research and management.In this review,we discuss the preventive effect of aspirin on HCC in the context of different etiological factors,including hepatitis B or hepatitis C virus infection,non-alcoholic fatty liver disease,and alcohol-associated liver disease.The therapeutic role of aspirin in resectable or unresectable HCC management is also discussed.Furthermore,the mechanisms underlying the anti-cancer effects of aspirin on HCC are fully reviewed and discussed in the following two aspects:the effect of aspirin on multi-oncogenic signaling pathways in HCC(e.g.,AMPK,Wnt/β-catenin,NF-κB)and aspirinmediated immunometabolic responses in liver diseases.These findings indicate aspirin is a promising agent for populations at risk and HCC patients to prevent or treat HCC.展开更多
CD4^(+)T helper cells are key regulators of host health and disease.In the original model,specialized subsets of T helper cells are generated following activation through lineage-specifying cytokines and transcription...CD4^(+)T helper cells are key regulators of host health and disease.In the original model,specialized subsets of T helper cells are generated following activation through lineage-specifying cytokines and transcriptional programs,but recent studies have revealed increasing complexities for CD4^(+)T-cell differentiation.Here,we first discuss CD4^(+)T-cell differentiation from a historical perspective by highlighting the major studies that defined the distinct subsets of T helper cells.We next describe the mechanisms underlying CD4^(+)T-cell differentiation,including cytokine-induced signaling and transcriptional networks.We then review current and emerging topics of differentiation,including the plasticity and heterogeneity of T cells,the tissue-specific effects,and the influence of cellular metabolism on cell fate decisions.Importantly,recent advances in cutting-edge approaches,especially systems biology tools,have contributed to new concepts and mechanisms underlying T-cell differentiation and will likely continue to advance this important research area of adaptive immunity.展开更多
Cardiometabolic disease(CMD), characterized with metabolic disorder triggered cardiovascular events, is a leading cause of death and disability. Metabolic disorders trigger chronic low-grade inflammation, and actually...Cardiometabolic disease(CMD), characterized with metabolic disorder triggered cardiovascular events, is a leading cause of death and disability. Metabolic disorders trigger chronic low-grade inflammation, and actually, a new concept of metaflammation has been proposed to define the state of metabolism connected with immunological adaptations. Amongst the continuously increased list of systemic metabolites in regulation of immune system, bile acids(BAs) represent a distinct class of metabolites implicated in the whole process of CMD development because of its multifaceted roles in shaping systemic immunometabolism. BAs can directly modulate the immune system by either boosting or inhibiting inflammatory responses via diverse mechanisms. Moreover, BAs are key determinants in maintaining the dynamic communication between the host and microbiota. Importantly, BAs via targeting Farnesoid X receptor(FXR) and diverse other nuclear receptors play key roles in regulating metabolic homeostasis of lipids, glucose, and amino acids. Moreover, BAs axis per se is susceptible to inflammatory and metabolic intervention, and thereby BAs axis may constitute a reciprocal regulatory loop in metaflammation. We thus propose that BAs axis represents a core coordinator in integrating systemic immunometabolism implicated in the process of CMD. We provide an updated summary and an intensive discussion about how BAs shape both the innate and adaptive immune system, and how BAs axis function as a core coordinator in integrating metabolic disorder to chronic inflammation in conditions of CMD.展开更多
Immunometabolism,which is the metabolic reprogramming of anaerobic glycolysis,oxidative phosphorylation,and metabolite synthesis upon immune cell activation,has gained importance as a regulator of the homeostasis,acti...Immunometabolism,which is the metabolic reprogramming of anaerobic glycolysis,oxidative phosphorylation,and metabolite synthesis upon immune cell activation,has gained importance as a regulator of the homeostasis,activation,proliferation,and differentiation of innate and adaptive immune cell subsets that function as key factors in immunity.Metabolic changes in epithelial and other stromal cells in response to different stimulatory signals are also crucial in infection,inflammation,cancer,autoimmune diseases,and metabolic disorders.The crosstalk between the PI3K-AKT-mTOR and LKB1-AMPK signaling pathways is critical for modulating both immune and nonimmune cell metabolism.The bidirectional interaction between immune cells and metabolism is a topic of intense study.Toll-like receptors(TLRs),cytokine receptors,and T and B cell receptors have been shown to activate multiple downstream metabolic pathways.However,how intracellular innate immune sensors/receptors intersect with metabolic pathways is less well understood.The goal of this review is to examine the link between immunometabolism and the functions of several intracellular innate immune sensors or receptors,such as nucleotide-binding and leucine-rich repeat-containing receptors(NLRs,or NOD-like receptors),absent in melanoma 2(AIM2)-like receptors(ALRs),and the cyclic dinucleotide receptor stimulator of interferon genes(STING).We will focus on recent advances and describe the impact of these intracellular innate immune receptors on multiple metabolic pathways.Whenever appropriate,this review will provide a brief contextual connection to pathogenic infections,autoimmune diseases,cancers,metabolic disorders,and/or inflammatory bowel diseases.展开更多
Obesity and associated metabolic diseases are characterized by a chronic low-grade inflammatory state with the infiltration of many inflammatory cells,especially macrophages.Immune molecules,including some cytokines,h...Obesity and associated metabolic diseases are characterized by a chronic low-grade inflammatory state with the infiltration of many inflammatory cells,especially macrophages.Immune molecules,including some cytokines,have a close relationship with metabolism.Interleukin(IL)-25 is a member of the IL-17 cytokine family that can regulate macrophages and alleviate some metabolic dysfunction;however,its role and mechanisms in lipid metabolism remain to be extensively clarified.Human serum and liver biopsy specimens,high-fat diet-induced obesity mice and DB/DB(Lepr−/−)animal models were used to examine IL-25 expression in obesity and nonalcoholic fatty liver diseases(NAFLD).To observe the role of IL-25 in lipid metabolism,model mice were administered with IL-25 or adoptively transferred with IL-25-educated macrophages in vivo,whereas bone marrow-derived macrophages,the macrophage cell line RAW264.7 and adipocytes differentiated from 3T3-L1 were used in vitro.IL-25 was decreased in NAFLD patients and obese mice.In addition,IL-25 reduced body weight gain and lipid accumulation,enhanced lipid uptake by macrophages and increased the expression of lipolysis andβ-oxidation enzymes via alternatively activating macrophages.IL-25 also promoted lipolysis and suppressed lipogenesis in adipocytes co-cultured with the IL-25-educated macrophages.Furthermore,IL-25 improved the mitochondrial respiratory capacity and oxygen consumption rate of macrophages and produced more NAD+/NADH and ATP.In conclusion,IL-25 can stimulate M2 macrophage polarization and thereby promote lipolysis and mitochondrial respiratory capacity,highlighting the potential for IL-25 to be used as a therapeutic agent against obesity and associated metabolic syndromes.展开更多
T cell metabolism is dynamic and highly regulated.While the intrinsic metabolic programs of T cell subsets are integral to their distinct differentiation and functional patterns,the ability of cells to acquire nutrien...T cell metabolism is dynamic and highly regulated.While the intrinsic metabolic programs of T cell subsets are integral to their distinct differentiation and functional patterns,the ability of cells to acquire nutrients and cope with hostile microenvironments can limit these pathways.T cells must function in a wide variety of tissue settings,and how T cells interpret these signals to maintain an appropriate metabolic program for their demands or if metabolic mechanisms of immune suppression restrain immunity is an area of growing importance.Both in inflamed and cancer tissues,a wide range of changes in physical conditions and nutrient availability are now acknowledged to shape immunity.These include fever and increased temperatures,depletion of critical micro and macro-nutrients,and accumulation of inhibitory waste products.Here we review several of these factors and how the tissue microenvironment both shapes and constrains immunity.展开更多
It is being increasingly acknowledged that immune cells depend on certain metabolic traits to perform their functions and that the extracellular environment can influence cell metabolism and vice versa.Dendritic cell(...It is being increasingly acknowledged that immune cells depend on certain metabolic traits to perform their functions and that the extracellular environment can influence cell metabolism and vice versa.Dendritic cell(DC)subsets traffic through highly diverse environments from the bone marrow,where they develop,to the various peripheral tissues,where they differentiate and capture antigens,before they migrate to the lymph node to present antigens and prime T cells.It is plausible that DC subsets modulate their stimulatory abilities in response to unique metabolic programming.The metabolic requirements of DCs are just recently being discovered,and subset-and context-specific metabolic phenotypes in DCs are highly intertwined with DC functions.In this review,we present the current knowledge on the intrinsic and extrinsic determinants of DC metabolism,how they regulate DC function with examples from tumor biology and in interaction with the microbiota,and discuss how this can be applied therapeutically.展开更多
Rheumatoid arthritis(RA),the most common inflammatory arthropathy word wild,is a systemic autoimmune disease that mainly affects the synovium of joints with a high disability rate.Metabolic misregulation has emerged a...Rheumatoid arthritis(RA),the most common inflammatory arthropathy word wild,is a systemic autoimmune disease that mainly affects the synovium of joints with a high disability rate.Metabolic misregulation has emerged as a fundamental pathogenesis of RA linked to immune cell dysfunction,while targeting immunometabolism provides a new and effective approach to regulate the immune responses and thus alleviate the symptom of RA.Recently,natural active compounds from traditional Chinese medicines(TCMs)have potential therapeutic effects on RA and regulating immunometabolism.In this review,in addition to updating the connection between cellular metabolism and cell function in immune cells of RA,we summarized that the anti-inflammatory mechanisms of the potential natural compounds from TCM by targeting metabolic reprogramming of immune cells,and discusses them as a rich resource for providing the new potential paradigm for the treatment of RA.展开更多
A novel rheumatoid arthritis(RA)synovial fluid protein,Syntenin-1,and its receptor,Syndecan-1(SDC-1),are colocalized on RA synovial tissue endothelial cells and fibroblast-like synoviocytes(FLS).Syntenin-1 exacerbates...A novel rheumatoid arthritis(RA)synovial fluid protein,Syntenin-1,and its receptor,Syndecan-1(SDC-1),are colocalized on RA synovial tissue endothelial cells and fibroblast-like synoviocytes(FLS).Syntenin-1 exacerbates the inflammatory landscape of endothelial cells and RA FLS by upregulating transcription of IRF1/5/7/9,IL-1β,IL-6,and CCL2 through SDC-1 ligation and HIF1α,or mTOR activation.Mechanistically,Syntenin-1 orchestrates RA FLS and endothelial cell invasion via SDC-1 and/or mTOR signaling.In Syntenin-1 reprogrammed endothelial cells,the dynamic expression of metabolic intermediates coincides with escalated glycolysis along with unchanged oxidative factors,AMPK,PGC-1α,citrate,and inactive oxidative phosphorylation.Conversely,RA FLS rewired by Syntenin-1 displayed a modest glycolytic-ATP accompanied by a robust mitochondrial-ATP capacity.The enriched mitochondrial-ATP detected in Syntenin-1 reprogrammed RA FLS was coupled with mitochondrial fusion and fission recapitulated by escalated Mitofusin-2 and DRP1 expression.We found that VEGFR1/2 and Notch1 networks are responsible for the crosstalk between Syntenin-1 rewired endothelial cells and RA FLS,which are also represented in RA explants.Similar to RA explants,morphological and transcriptome studies authenticated the importance of VEGFR1/2,Notch1,RAPTOR,and HIF1αpathways in Syntenin-1 arthritic mice and their obstruction in SDC-1 deficient animals.Consistently,dysregulation of SDC-1,mTOR,and HIF1αnegated Syntenin-1 inflammatory phenotype in RA explants,while inhibition of HIF1αimpaired synovial angiogenic imprint amplified by Syntenin-1.In conclusion,since the current therapies are ineffective on Syntenin-1 and SDC-1 expression in RA synovial tissue and blood,targeting this pathway and its interconnected metabolic intermediates may provide a novel therapeutic strategy.展开更多
基金supported by grants from the Ministry of Science and ICT,Republic of Korea(NRF-2018R1A2A1A05019203,NRF-2018R1A5A2024425)the Korean Health Technology R&D Project(No.HI15C2842,HI18C2177,HI19C0664),Ministry of Health&Welfare,Republic of Korea.
文摘We report the activation of anticancer effector functions of T cells through nanoparticle-induced lipid metabolic reprogramming.Fenofibrate was encapsulated in amphiphilic polygamma glutamic acid-based nanoparticles(F/ANs),and the surfaces of F/ANs were modified with an anti-CD3e f(ab′)2 fragment,yielding aCD3/F/ANs.An in vitro study reveals enhanced delivery of aCD3/F/ANs to T cells compared with plain F/ANs.aCD3/F/AN-treated T cells exhibited clear mitochondrial cristae,a higher membrane potential,and a greater mitochondrial oxygen consumption rate under glucose-deficient conditions compared with T cells treated with other nanoparticle preparations.Peroxisome proliferatoractivated receptor-αand downstream fatty acid metabolismrelated genes are expressed to a greater extent in aCD3/F/AN-treated T cells.Activation of fatty acid metabolism by aCD3/F/ANs supports the proliferation of T cells in a glucose-deficient environment mimicking the tumor microenvironment.Real-time video recordings show that aCD3/F/AN-treated T cells exerted an effector killing effect against B16F10 melanoma cells.In vivo administration of aCD3/F/ANs can increase infiltration of T cells into tumor tissues.The treatment of tumor-bearing mice with aCD3/F/ANs enhances production of various cytokines in tumor tissues and prevented tumor growth.Our findings suggest the potential of nanotechnology-enabled reprogramming of lipid metabolism in T cells as a new modality of immunometabolic therapy.
基金supported by the National Natural Science Foundation of China(grant number:82205172,82274570).
文摘Background:Chronic endometritis(CE)is an important pathological factor contributing to female infertility and recurrent pregnancy loss.Although antibiotics are the primary clinical treatment for CE,they do not effectively improve pregnancy outcomes.Wen Yang Hua Zhuo(WYHZ)is a clinically employed classical formula known for its effects in warming yang,tonifying the spleen and kidneys,and resolving dampness.However,its underlying mechanisms remain unclear.This study aimed to elucidate how WYHZ modulates the immunometabolic microenvironment at the maternal-fetal interface in CE by targeting the MCT/HIF-1α/LDHA pathway to promote embryo implantation.Methods:In vivo,the model of CE was established by intrauterine injection of lipopolysaccharide(LPS)(1 mg/mL)into female C57/BL mice,followed by WYHZ treatment for 3 weeks to evaluate its effects on embryo implantation.Mechanistic studies were further conducted using the MCT-1 inhibitor AZD3965 and adeno-associated virus-mediated HIF-1αknockdown.In vitro,an in vitro CE model consisting of M1 macrophages and Ishikawa,as well as an in vitro embryo implantation model mediated by JAR cells,were constructed using Transwell,and the therapeutic mechanisms of WYHZ was validated using AZD3965 and lentiviral sh HIF-1αintervention.Metabolic enzyme activity assays,protein antibody microarrays,immunofluorescence,Western blotting,Seahorse analysis,and ELISA were employed.Results:WYHZ improved the immune-inflammatory microenvironment at the maternal-fetal interface by reducing pro-inflammatory cytokines and increasing anti-inflammatory factors.In parallel,WYHZ reprogrammed endometrial metabolism by enhancing glycolysis and suppressing mitochondrial oxidative phosphorylation,thereby improving endometrial receptivity and embryo implantation.Mechanistically,WYHZ activated the MCT/HIF-1α/LDHA pathway in endometrial epithelial cells,alleviating inflammatory stress and restoring receptivity.Both AZD3965 intervention and HIF-1αknockdown impaired endometrial receptivity and implantation,effects that were reversed by WYHZ.Conclusion:WYHZ modulates the immunometabolic microenvironment of the endometrium in the context of CE by targeting the activation of the MCT/HIF-1α/LDHA pathway,which improves endometrial receptivity and promotes embryo implantation.
基金sponsored by Tsinghua-Toyota Joint Research Fundsupported by the Anhui Province TraditionalChinese Medicine Science and Technology Research Project(202303a07020001)the National Natural Science Foundation of China (T2341008)
文摘The core principle of diagnosis and treatment in traditional Chinese medicine(TCM) is the identification of different syndromes.Cold and hot syndromes are important elements in TCM theory.Identifying the biological basis of cold and hot syndromes in TCM will help elucidate TCM theories scientifically,thus promoting precise treatment in TCM.Although the biological basis of cold/hot syndromes in TCM remains poorly understood,growing evide nce suggests that immunometab olic interactions play an important role in balancing cold and hot syndromes.Immuno metabolism involve s complex interactions between the immune and metabolic systems.Multilevel mechanisms of interaction between the immune and metabolic systems may underlie many inflammatory diseases and offer substantial therapeutic promise.Therefore,dissecting the relationship between immunometabolism and the biological network of cold/hot syndromes has become a priority.This article reviews the progress of cold/hot syndrome research from the perspective of immunometabolic homeostasis,thus further clarifying cold/hot syndromes in TCM.
基金supported by the National Key Research and Development Program of China(No.2023YFC2508500)National Natural Science Foundation of China(No.82272951)National Natural Science Foundation of China(No.82272953)。
文摘Drug resistance continues to be the principal limiting factor in achieving a cure for patients with cancer,significantly hindering the long-term efficacy of novel cancer drugs.Accumulating evidence has shown that metabolites derived from tumor cells regulate immune cell metabolism via tumor microenvironment crosstalk.However,as immunometabolic research has deepened,the leading role played by the intrinsic metabolic regulation of immune cells in the drug resistance of tumor cells has been discovered.Immune metabolites have been shown to cause immune resistance,target therapy resistance,and chemotherapy resistance,and drugs that target immune metabolism have great potential.To date,researchers have not fully explored the impact of immune-derived metabolites on tumor cells and their influence on the responsiveness to cancer drugs.In this review,we focus on the lactate,fatty acid,glucose,and nucleotide metabolic alterations that take place in T cells and macrophages and how these changes can impair anti-tumor immunity,ultimately promoting tumor cell survival and decreasing responsiveness to the corresponding therapeutic approaches.We present the current developments in drugs targeting immunometabolic pathways and propose constructive suggestions,such as precise delivery to immune cell targets to enhance efficacy and safety,offering novel perspectives for cancer drug development.
基金Supported by the National Key Research and Development Program of China(2023YFC3503704)the Harbin Municipal Science and Technology Program(Self-funded Project,022ZCZJNS070).
文摘Alzheimer’s disease(AD)represents a prototypical neurodegenerative disorder with a multifactorial pathogenesis encompassing amyloid-β(Aβ)deposition,tau protein hyperphosphorylation,and chronic neuroinflammation.Recent advances in proteomic profiling have identified significant dysregulation in astrocytic and microglial metabolic pathways in AD pathogenesis,establishing mechanistic links between metabolic dyshomeostasis and neuroimmune crosstalk.Accumulating evidence indicates that acupuncture has gained prominence as a non-pharmacological therapeutic modality for AD management,owing to its multimodal regulatory effects on neuroinflammatory cascades,metabolic recalibration,and immune network stabilization.This study aims to elucidate the molecular mechanisms through which acupuncture exerts its neuroprotective effects,focusing on three interconnected axes:immunometabolic reprogramming in glial cells(particularly microglial bioenergetic adaptation),gut microbiota-derived metabolite signaling(including short-chain fatty acid-mediated pathways),and neuro‐immune‐metabolic interplay.We present a novel therapeutic framework highlighting acupuncture-mediated immunometabolic modulation,thereby providing a mechanistic foundation for developing targeted therapeutic strategies in AD management.
文摘The gut microbiota is of growing interest to clinicians and researchers due to its elucidating extensive role in metabolic and immune mechanisms,not only in the gut but also in other organs.The liver shares a close bidirectional relationship with the intestine and the gut microbiota.Disturbances in the composition of the gut microbiota can affect the immune systems of both the intestine and liver.In turn,bile composition also influences the gut microbiota.Disruption of this balance can arise from various causes and may significantly impact intestinal and liver health.Therefore,the aim of the current review is to discuss the biological relationships between the gut microbiota and liver function as well as the clinical significance of their disturbances.
文摘Liver diseases are of growing interest to clinicians and researchers due to their high prevalence,difficulty in early diagnosis,and limited treatment options.The liver is an important organ at the intersection of many metabolic and immune pathways.To this end,it contains a large number of immune cells of both the innate and adaptive immune system that perform multiple functions,detecting and destroying pathogens that enter the body through the intestine,as well as recognizing endogenous antigens.Immune cells in the liver have a complex regulation that can be impaired in various diseases such as metabolic dysfunctionassociated steatotic liver disease(MASLD),liver cancer,and biliary diseases.A growing body of evidence reinforces the realization that not only impaired metabolism but also many immune mechanisms underlie MASLD.The liver has complex bilateral immune and metabolic links with the gut microbiota,and disruptions of these links underlie the development and progression of both gastrointestinal and other organ diseases.In this regard,acting on immune mechanisms is a promising therapeutic target for liver diseases.
基金support from the “Romeo and Enrica Invernizzi Foundation” (Milan, Italy)Università Cattolica del Sacro Cuore (Piacenza, Italy)。
文摘The transition period of dairy cattle is characterized by a number of metabolic, endocrine, physiologic, and immune adaptations, including the occurrence of negative energy balance, hypocalcemia, liver dysfunction, overt systemic inflammatory response, and oxidative stress status. The degree and length of time during which these systems remain out of balance could render cows more susceptible to disease, poor reproductive outcomes, and less efficient for milk production and quality. Studies on both monogastrics and ruminants have reported the health benefits of nutraceuticals(e.g. probiotics, prebiotics, dietary lipids, functional peptides, phytoextracts) beyond nutritional value, interacting at different levels of the animal's physiology. From a physiological standpoint, it seems unrealistic to disregard any systemic inflammatory processes. However, an alternate approach is to modulate the inflammatory process per se and to resolve the systemic response as quickly as possible.To this aim, a growing body of literature underscores the efficacy of nutraceuticals(active compounds) during the critical phase of the transition period. Supplementation of essential fatty acids throughout a 2-month period(i.e. a month before and a month after calving) successfully attenuates the inflammatory status with a quicker resolution of phenomenon. In this context, the inflammatory and immune response scenario has been recognized to be targeted by the beneficial effect of methyl donors, such as methionine and choline, directly and indirectly modulating such response with the increase of antioxidants GSH and taurine. Indirectly by the establishment of a healthy gastrointestinal tract, yeast and yeast-based products showed to modulate the immune response, mitigating negative effects associated with parturition stress and consequent disorders.The use of phytoproducts has garnered high interest because of their wide range of actions on multiple tissue targets encompassing a series of antimicrobial, antiviral, antioxidant, immune-stimulating, rumen fermentation, and microbial modulation effects. In this review, we provide perspectives on investigations of regulating the immune responses and metabolism using several nutraceuticals in the periparturient cow.
基金supported by a CRI Lloyd J. Old STAR Award(Grant No. 3914)a Helmholtz Young Investigator Award(Grant No. VH-NG-1113)+7 种基金an EMBO Young Investigator Awardan Exploration Grant of the Boehringer Ingelheim Foundation (BIS)the German Research Foundation (DFG,Grant Nos. CU375/5-1, CU375/5-2, CU375/7-1, CU375/9-1, and 259332240/RTG2099)the German Cancer Aid Foundation (DKH, Grant Nos. 70113343 and 70114224)the Helmholtz Zukunftsthema Ageing and Metabolic Programming (AMPro, Grant No. ZT0026)HI-TRON KickStart Seed Funding (Grant No. HITR-2021-08)the Hector Foundation (Grant No. M20102)an ERC Consolidator Award (Grant No. 101045416)
文摘The tumor microenvironment is an ecosystem composed of multiple types of cells, such as tumor cells, immune cells, and cancerassociated fibroblasts. Cancer cells grow faster than non-cancerous cells and consume larger amounts of nutrients. The rapid growth characteristic of cancer cells fundamentally alters nutrient availability in the tumor microenvironment and results in reprogramming of immune cell metabolic pathways. Accumulating evidence suggests that cellular metabolism of nutrients, such as lipids and amino acids, beyond being essential to meet the bioenergetic and biosynthetic demands of immune cells, also regulates a broad spectrum of cellular signal transduction, and influences immune cell survival, differentiation, and anti-tumor effector function. The cancer immunometabolism research field is rapidly evolving, and exciting new discoveries are reported in high-profile journals nearly weekly. Therefore, all new findings in this field cannot be summarized within this short review. Instead, this review is intended to provide a brief introduction to this rapidly developing research field, with a focus on the metabolism of two classes of important nutrients-lipids and amino acids-in immune cells. We highlight recent research on the roles of lipids and amino acids in regulating the metabolic fitness and immunological functions of T cells, macrophages, and natural killer cells in the tumor microenvironment. Furthermore, we discuss the possibility of “editing” metabolic pathways in immune cells to act synergistically with currently available immunotherapies in enhancing anti-tumor immune responses.
基金supported by the National Natural Science Foundation of China(82273202,82370948,82072996,82170941)the Fundamental Research Funds for the Central Universities(2042022dx0003)+1 种基金the Hubei Province International Science and Technology Cooperation Project(2021EHB027)the National Key Research and Development Program(2022YFC2504200).
文摘Cancer immunotherapy using immune-checkpoint inhibitors(ICIs)has revolutionized the field of cancer treatment;however,ICI efficacy is constrained by progressive dysfunction of CD8+tumor-infiltrating lymphocytes(TILs),which is termed T cell exhaustion.This process is driven by diverse extrinsic factors across heterogeneous tumor immune microenvironment(TIME).Simultaneously,tumorigenesis entails robust reshaping of the epigenetic landscape,potentially instigating T cell exhaustion.In this review,we summarize the epigenetic mechanisms governing tumor microenvironmental cues leading to T cell exhaustion,and discuss therapeutic potential of targeting epigenetic regulators for immunotherapies.Finally,we outline conceptual and technical advances in developing potential treatment paradigms involving immunostimulatory agents and epigenetic therapies.
基金supported by the National Natural Science Foundation of China(No.82201037 and 82370943)the Young Elite Scientists Sponsorship Program by Guangzhou(QT-2023-030).
文摘Vital pulp therapy(VPT)is considered a conservative means of preserving the vitality and function of the dental pulp after injury.However,current VPT has unfavorable effects on inflamed pulp.Mesenchymal stem cell(MSC)-derived small extracellular vesicles(MSC-sEVs)show powerful immunomodulatory capacities and exert thera-peutic effects on a variety of inflammatory diseases.However,whether MSC-sEVs ameliorate the inflammatory response and promote inflammatory pulp repair in pulpitis is largely unknown.In this study,we show that sEVs derived from dental follicle stem cells(typical dental MSCs,DFSC-sEVs)alleviate lipopolysaccharide-induced pulpitis in rats and enhance pulp repair by inducing M2 macrophage polarization.Mechanistically,heat shock protein 70(HSP70)within DFSC-sEVs can be supplemented into lysosomes to directly protect lysosomal function and induce mitophagy to promote the degradation of depolarized mitochondria,thereby preprogramming in-flammatory macrophages to commit to oxidative phosphorylation,which fuels M2 polarization.Furthermore,DFSC-sEVs also transfer antioxidant miRNAs,including miR-24-3p and let-7c-5p,to inhibit mitochondrial reactive oxygen species production,thereby indirectly stabilizing lysosomes to induce M2 macrophage generation.Our study reveals a promising immunotherapeutic potential of DFSC-sEVs for VPT in inflamed pulp and a novel role for DFSC-sEVs in inhibiting the macrophage inflammatory response by protecting lysosomes and inducing mitophagy-mediated metabolic shifts toward oxidative phosphorylation.
基金This work was supported by the Key Research&Development Plan of Zhejiang Province(No.2019C03050)Youth Program of National Natural Science Foundation of China(82003248).
文摘Hepatocellular carcinoma(HCC)is one of the most aggressive human malignancies with a dismal survival rate.Few strategies can effectively prevent the occurrence of HCC.Although immunotherapy has significantly improved HCC-related survival in recent years,this systemic therapy is very expensive and lays a heavy burden on most HCC patients.Aspirin,which is currently one of the most widely used medications in analgesic and cardiovascular diseases,is reported to have anti-tumor effects on HCC.Most importantly,long-term administration of low-dose aspirin does not significantly increase the risk of gastrointestinal bleeding.Owing to its costeffectiveness and wide use,aspirin can be easily applied as an HCC treatment and is affordable for a wide range of patients.Therefore,deeper understanding and more attention are needed to extend the frontline of aspirin's preventive and therapeutic potential into cancer research and management.In this review,we discuss the preventive effect of aspirin on HCC in the context of different etiological factors,including hepatitis B or hepatitis C virus infection,non-alcoholic fatty liver disease,and alcohol-associated liver disease.The therapeutic role of aspirin in resectable or unresectable HCC management is also discussed.Furthermore,the mechanisms underlying the anti-cancer effects of aspirin on HCC are fully reviewed and discussed in the following two aspects:the effect of aspirin on multi-oncogenic signaling pathways in HCC(e.g.,AMPK,Wnt/β-catenin,NF-κB)and aspirinmediated immunometabolic responses in liver diseases.These findings indicate aspirin is a promising agent for populations at risk and HCC patients to prevent or treat HCC.
基金the National Institutes of Health and the National Multiple Sclerosis Society.
文摘CD4^(+)T helper cells are key regulators of host health and disease.In the original model,specialized subsets of T helper cells are generated following activation through lineage-specifying cytokines and transcriptional programs,but recent studies have revealed increasing complexities for CD4^(+)T-cell differentiation.Here,we first discuss CD4^(+)T-cell differentiation from a historical perspective by highlighting the major studies that defined the distinct subsets of T helper cells.We next describe the mechanisms underlying CD4^(+)T-cell differentiation,including cytokine-induced signaling and transcriptional networks.We then review current and emerging topics of differentiation,including the plasticity and heterogeneity of T cells,the tissue-specific effects,and the influence of cellular metabolism on cell fate decisions.Importantly,recent advances in cutting-edge approaches,especially systems biology tools,have contributed to new concepts and mechanisms underlying T-cell differentiation and will likely continue to advance this important research area of adaptive immunity.
基金The Fundamental Research Funds for the Central public welfare research institutes (Nos.ZZ13-YQ-014-C1 and ZZ13-YQ-014,China)the National Natural Science Foundation of China (No.82004194)Beijing Natural Science Foundation of China (No.7192185)。
文摘Cardiometabolic disease(CMD), characterized with metabolic disorder triggered cardiovascular events, is a leading cause of death and disability. Metabolic disorders trigger chronic low-grade inflammation, and actually, a new concept of metaflammation has been proposed to define the state of metabolism connected with immunological adaptations. Amongst the continuously increased list of systemic metabolites in regulation of immune system, bile acids(BAs) represent a distinct class of metabolites implicated in the whole process of CMD development because of its multifaceted roles in shaping systemic immunometabolism. BAs can directly modulate the immune system by either boosting or inhibiting inflammatory responses via diverse mechanisms. Moreover, BAs are key determinants in maintaining the dynamic communication between the host and microbiota. Importantly, BAs via targeting Farnesoid X receptor(FXR) and diverse other nuclear receptors play key roles in regulating metabolic homeostasis of lipids, glucose, and amino acids. Moreover, BAs axis per se is susceptible to inflammatory and metabolic intervention, and thereby BAs axis may constitute a reciprocal regulatory loop in metaflammation. We thus propose that BAs axis represents a core coordinator in integrating systemic immunometabolism implicated in the process of CMD. We provide an updated summary and an intensive discussion about how BAs shape both the innate and adaptive immune system, and how BAs axis function as a core coordinator in integrating metabolic disorder to chronic inflammation in conditions of CMD.
基金The following funding supports are acknowledged:NIH(R35 CA232109,PO1 DK094779,U19 AI067798,R01 AI141333,and R01 AI029564).
文摘Immunometabolism,which is the metabolic reprogramming of anaerobic glycolysis,oxidative phosphorylation,and metabolite synthesis upon immune cell activation,has gained importance as a regulator of the homeostasis,activation,proliferation,and differentiation of innate and adaptive immune cell subsets that function as key factors in immunity.Metabolic changes in epithelial and other stromal cells in response to different stimulatory signals are also crucial in infection,inflammation,cancer,autoimmune diseases,and metabolic disorders.The crosstalk between the PI3K-AKT-mTOR and LKB1-AMPK signaling pathways is critical for modulating both immune and nonimmune cell metabolism.The bidirectional interaction between immune cells and metabolism is a topic of intense study.Toll-like receptors(TLRs),cytokine receptors,and T and B cell receptors have been shown to activate multiple downstream metabolic pathways.However,how intracellular innate immune sensors/receptors intersect with metabolic pathways is less well understood.The goal of this review is to examine the link between immunometabolism and the functions of several intracellular innate immune sensors or receptors,such as nucleotide-binding and leucine-rich repeat-containing receptors(NLRs,or NOD-like receptors),absent in melanoma 2(AIM2)-like receptors(ALRs),and the cyclic dinucleotide receptor stimulator of interferon genes(STING).We will focus on recent advances and describe the impact of these intracellular innate immune receptors on multiple metabolic pathways.Whenever appropriate,this review will provide a brief contextual connection to pathogenic infections,autoimmune diseases,cancers,metabolic disorders,and/or inflammatory bowel diseases.
基金supported by the National Nature Science Foundation of China:81272338,81272515,81370945,81471033,81570871,81570764 and 81600641the National Key Sci-Tech Special Project of China:2013ZX09102-053,2015GKS-355+7 种基金the Program for Doctoral Station in University:20130171110053the Key Project of the Nature Science Foundation of Guangdong Province,China:2015A030311043,2016A030311035the Guangdong Natural Science Fund:2014A020212023,2014A030313073,2015A030313103 and 2015A030313029the Guandong Science and Technology Project(2014A020212023,2015B090903063 and 2016A020214001)the Guangzhou Science and Technology Project:2014J4100162,201508020033 and 201510010052the Pearl River Nova Program of Guangzhou Municipality,China,Grant Number:201610010186the Chang jiang Scholars and Innovative Research Team in University:985 project PCSIRT 0947the Fundamental Research Funds for the Central Universities of China(Youth Program 13ykpy06,16ykpy24 and 31610046).
文摘Obesity and associated metabolic diseases are characterized by a chronic low-grade inflammatory state with the infiltration of many inflammatory cells,especially macrophages.Immune molecules,including some cytokines,have a close relationship with metabolism.Interleukin(IL)-25 is a member of the IL-17 cytokine family that can regulate macrophages and alleviate some metabolic dysfunction;however,its role and mechanisms in lipid metabolism remain to be extensively clarified.Human serum and liver biopsy specimens,high-fat diet-induced obesity mice and DB/DB(Lepr−/−)animal models were used to examine IL-25 expression in obesity and nonalcoholic fatty liver diseases(NAFLD).To observe the role of IL-25 in lipid metabolism,model mice were administered with IL-25 or adoptively transferred with IL-25-educated macrophages in vivo,whereas bone marrow-derived macrophages,the macrophage cell line RAW264.7 and adipocytes differentiated from 3T3-L1 were used in vitro.IL-25 was decreased in NAFLD patients and obese mice.In addition,IL-25 reduced body weight gain and lipid accumulation,enhanced lipid uptake by macrophages and increased the expression of lipolysis andβ-oxidation enzymes via alternatively activating macrophages.IL-25 also promoted lipolysis and suppressed lipogenesis in adipocytes co-cultured with the IL-25-educated macrophages.Furthermore,IL-25 improved the mitochondrial respiratory capacity and oxygen consumption rate of macrophages and produced more NAD+/NADH and ATP.In conclusion,IL-25 can stimulate M2 macrophage polarization and thereby promote lipolysis and mitochondrial respiratory capacity,highlighting the potential for IL-25 to be used as a therapeutic agent against obesity and associated metabolic syndromes.
文摘T cell metabolism is dynamic and highly regulated.While the intrinsic metabolic programs of T cell subsets are integral to their distinct differentiation and functional patterns,the ability of cells to acquire nutrients and cope with hostile microenvironments can limit these pathways.T cells must function in a wide variety of tissue settings,and how T cells interpret these signals to maintain an appropriate metabolic program for their demands or if metabolic mechanisms of immune suppression restrain immunity is an area of growing importance.Both in inflamed and cancer tissues,a wide range of changes in physical conditions and nutrient availability are now acknowledged to shape immunity.These include fever and increased temperatures,depletion of critical micro and macro-nutrients,and accumulation of inhibitory waste products.Here we review several of these factors and how the tissue microenvironment both shapes and constrains immunity.
基金P-CH was supported in part by SNSF project grants(31003A_182470)the European Research Council Staring Grant(802773-MitoGuide),the Swiss Cancer League(KFS-3949-08-2016),the Cancer Research Institute(Lloyd J.Old Star award and CLIP Investigator award),the Melanoma Research Alliance Established Investigator Award,and EMBO Young Investigator award.
文摘It is being increasingly acknowledged that immune cells depend on certain metabolic traits to perform their functions and that the extracellular environment can influence cell metabolism and vice versa.Dendritic cell(DC)subsets traffic through highly diverse environments from the bone marrow,where they develop,to the various peripheral tissues,where they differentiate and capture antigens,before they migrate to the lymph node to present antigens and prime T cells.It is plausible that DC subsets modulate their stimulatory abilities in response to unique metabolic programming.The metabolic requirements of DCs are just recently being discovered,and subset-and context-specific metabolic phenotypes in DCs are highly intertwined with DC functions.In this review,we present the current knowledge on the intrinsic and extrinsic determinants of DC metabolism,how they regulate DC function with examples from tumor biology and in interaction with the microbiota,and discuss how this can be applied therapeutically.
文摘Rheumatoid arthritis(RA),the most common inflammatory arthropathy word wild,is a systemic autoimmune disease that mainly affects the synovium of joints with a high disability rate.Metabolic misregulation has emerged as a fundamental pathogenesis of RA linked to immune cell dysfunction,while targeting immunometabolism provides a new and effective approach to regulate the immune responses and thus alleviate the symptom of RA.Recently,natural active compounds from traditional Chinese medicines(TCMs)have potential therapeutic effects on RA and regulating immunometabolism.In this review,in addition to updating the connection between cellular metabolism and cell function in immune cells of RA,we summarized that the anti-inflammatory mechanisms of the potential natural compounds from TCM by targeting metabolic reprogramming of immune cells,and discusses them as a rich resource for providing the new potential paradigm for the treatment of RA.
基金supported in part by awards from the Department of Veteran’s Affairs MERIT Award BX002286,CX002565,IK6BX006474the National Institutes of Health NIH R01 AI167155,NIH R41 AI147697the Innovative Research Award from the Rheumatology Research Foundation(RRF,no number assigned).
文摘A novel rheumatoid arthritis(RA)synovial fluid protein,Syntenin-1,and its receptor,Syndecan-1(SDC-1),are colocalized on RA synovial tissue endothelial cells and fibroblast-like synoviocytes(FLS).Syntenin-1 exacerbates the inflammatory landscape of endothelial cells and RA FLS by upregulating transcription of IRF1/5/7/9,IL-1β,IL-6,and CCL2 through SDC-1 ligation and HIF1α,or mTOR activation.Mechanistically,Syntenin-1 orchestrates RA FLS and endothelial cell invasion via SDC-1 and/or mTOR signaling.In Syntenin-1 reprogrammed endothelial cells,the dynamic expression of metabolic intermediates coincides with escalated glycolysis along with unchanged oxidative factors,AMPK,PGC-1α,citrate,and inactive oxidative phosphorylation.Conversely,RA FLS rewired by Syntenin-1 displayed a modest glycolytic-ATP accompanied by a robust mitochondrial-ATP capacity.The enriched mitochondrial-ATP detected in Syntenin-1 reprogrammed RA FLS was coupled with mitochondrial fusion and fission recapitulated by escalated Mitofusin-2 and DRP1 expression.We found that VEGFR1/2 and Notch1 networks are responsible for the crosstalk between Syntenin-1 rewired endothelial cells and RA FLS,which are also represented in RA explants.Similar to RA explants,morphological and transcriptome studies authenticated the importance of VEGFR1/2,Notch1,RAPTOR,and HIF1αpathways in Syntenin-1 arthritic mice and their obstruction in SDC-1 deficient animals.Consistently,dysregulation of SDC-1,mTOR,and HIF1αnegated Syntenin-1 inflammatory phenotype in RA explants,while inhibition of HIF1αimpaired synovial angiogenic imprint amplified by Syntenin-1.In conclusion,since the current therapies are ineffective on Syntenin-1 and SDC-1 expression in RA synovial tissue and blood,targeting this pathway and its interconnected metabolic intermediates may provide a novel therapeutic strategy.
