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Frontiers in Immunology 2023Lactate, traditionally regarded as a metabolic waste product at the terminal of the glycolysis process, has recently been found to have multifaceted functional roles in... (Review)
Review
Lactate, traditionally regarded as a metabolic waste product at the terminal of the glycolysis process, has recently been found to have multifaceted functional roles in metabolism and beyond. A metabolic reprogramming phenomenon commonly seen in tumor cells, known as the "Warburg effect," sees high levels of aerobic glycolysis result in an excessive production of lactate. This lactate serves as a substrate that sustains not only the survival of cancer cells but also immune cells. However, it also inhibits the function of tumor-associated macrophages (TAMs), a group of innate immune cells ubiquitously present in solid tumors, thereby facilitating the immune evasion of malignant tumor cells. Characterized by their high plasticity, TAMs are generally divided into the pro-inflammatory M1 phenotype and the pro-tumour M2 phenotype. Through a process of 'education' by lactate, TAMs tend to adopt an immunosuppressive phenotype and collaborate with tumor cells to promote angiogenesis. Additionally, there is growing evidence linking metabolic reprogramming with epigenetic modifications, suggesting the participation of histone modification in diverse cellular events within the tumor microenvironment (TME). In this review, we delve into recent discoveries concerning lactate metabolism in tumors, with a particular focus on the impact of lactate on the function of TAMs. We aim to consolidate the molecular mechanisms underlying lactate-induced TAM polarization and angiogenesis and explore the lactate-mediated crosstalk between TAMs and tumor cells. Finally, we also touch upon the latest progress in immunometabolic therapies and drug delivery strategies targeting glycolysis and lactate production, offering new perspectives for future therapeutic approaches.
Topics: Humans; Tumor-Associated Macrophages; Macrophages; Lactic Acid; Neoplasms; Glycolysis; Tumor Microenvironment
PubMed: 37564659
DOI: 10.3389/fimmu.2023.1208870 -
European Journal of Pharmacology Oct 2023Acute kidney injury (AKI) is a clinically serious disorder associated with high mortality rates and an increased risk of progression to end-stage renal disease. As an...
Acute kidney injury (AKI) is a clinically serious disorder associated with high mortality rates and an increased risk of progression to end-stage renal disease. As an essential supportive treatment for patients with respiratory failure, mechanical ventilation not only save many critically ill patients, but also affect glomerular filtration function by changing renal hemodynamics, neurohumoral and positive end-expiratory pressure, eventually leading to AKI. AMP-activated protein kinase (AMPK), a crucial energy homeostasis regulator, could enhance macrophage phagocytic ability and inhibit inflammation, but whether it can engulf neutrophil extracellular traps (NETs) and alleviate mechanical ventilation-associated AKI is still unclear. In this study, we found that geniposide significantly ameliorated histopathological damage, reduced serum Cre and BUN levels. Besides, geniposide can also induce AMPK activation and enhance macrophage phagocytic ability toward NETs. Moreover, geniposide can markedly reduce the levels of high mobility group box 1 (HMGB1), and these effects were dependent on AMPK-PI3K/Akt signaling. Altogether, these results indicated that geniposide promoted macrophage efferocytosis by inducing AMPK-PI3K/Akt signaling activation, clearing NETs and ameliorating AKI.
Topics: Humans; Extracellular Traps; AMP-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Macrophages; Acute Kidney Injury
PubMed: 37634840
DOI: 10.1016/j.ejphar.2023.176018 -
Nanoscale Apr 2024Tumor-associated macrophages (TAMs) play crucial roles in the immunosuppressive solid tumor microenvironment (TME). Despite their tumor-promoting functions, TAMs can... (Review)
Review
Tumor-associated macrophages (TAMs) play crucial roles in the immunosuppressive solid tumor microenvironment (TME). Despite their tumor-promoting functions, TAMs can also be therapeutically modulated to exhibit tumor-killing properties, making them attractive targets for tumor immunotherapy. This review highlights the recent advances in nanomedicine-based strategies centered around macrophages for enhanced cancer immunotherapy. Emerging nanomedicine-based strategies to modulate TAMs in cancer treatment include repolarization of the TAM phenotype, inhibition of monocyte recruitment, depletion of TAMs, and blockage of immune checkpoints. These strategies have shown great promise in significantly improving the efficacy of cancer immunotherapy. Moreover, macrophage-inspired drug delivery systems have demonstrated significant promise in inducing immunotherapeutic effects and enhancing therapeutic efficacy by facilitating evasion from the reticuloendothelial system and promoting accumulation at the tumor site. Finally, we also discuss the challenges and propose future opportunities associated with macrophage-modulating nanomedicine to enhance cancer immunotherapy.
Topics: Humans; Nanomedicine; Macrophages; Mononuclear Phagocyte System; Neoplasms; Immunotherapy; Tumor Microenvironment
PubMed: 38511468
DOI: 10.1039/d3nr06333j -
Immunity, Inflammation and Disease Aug 2023This study endeavored to investigate the role of DOCK8 in modulating the immune function triggered by sepsis.
INTRODUCTION
This study endeavored to investigate the role of DOCK8 in modulating the immune function triggered by sepsis.
METHODS
Expression of DOCK8 in the whole blood of sepsis patients and its enrichment pathways were assayed by bioinformatics. Pearson analysis was used to predict the relationship between glycolytic signaling pathway and its relevance to neutrophil function in sepsis. A sepsis mouse model was then built by performing cecal ligation and puncture treatment on male mice. Neutrophils were isolated, and their purity was tested by flow cytometry. Neutrophils were then stimulated by lipopolysaccharide to build a sepsis cell model. Next, quantitative reverse transcription polymerase chain reaction and CCK-8 were applied to test the expression of DOCK8 and cell viability, western blot to assay the expression of HK-2, PKM2, and LDHA proteins, ELISA to measure the concentrations of TNF-α, IL-1β, and IL-6, Transwell to detect the chemotaxis of neutrophils and flow cytometry to detect the phagocytic activity of neutrophils. Finally, in different treatment groups, we used Seahorse XF 96 to analyze the extracellular acidification rate (ECAR) of sepsis cells and used enzyme-linked immunosorbent assay to detect the contents of pyruvic acid, lactic acid, and ATP in sepsis cells.
RESULTS
DOCK8 was downregulated in sepsis blood and activated neutrophils. Aerobic glycolysis was positively correlated with sepsis. Activated neutrophils promoted the expression of inflammatory factors TNF-α, IL-1β, and IL-6. Low expression of DOCK8 facilitated the proliferation, chemotaxis, and phagocytic activity of sepsis cells and promoted the expression of inflammatory factors. Bioinformatics analysis revealed that DOCK8 was enriched in the glycolytic signaling pathway. Low expression of DOCK8 induced ECAR, promoted the protein expression of HK-2, PKM2 and LDHA, and favored the increase of pyruvate, lactate, and ATP contents. While 2-DG treatment could restore these effects.
CONCLUSION
DOCK8 may inhibit sepsis-induced neutrophil immune function by regulating aerobic glycolysis and causing excessive inflammation, which helps to explore potential therapeutic targets.
Topics: Male; Animals; Mice; Neutrophils; Interleukin-6; Tumor Necrosis Factor-alpha; Sepsis; Immunity; Glycolysis; Adenosine Triphosphate
PubMed: 37647440
DOI: 10.1002/iid3.965 -
Mini Reviews in Medicinal Chemistry 2024Efferocytosis is the physiological process of phagocytic clearance of apoptotic cells by both professional phagocytic cells, such as macrophages, and non-professional... (Review)
Review
Efferocytosis is the physiological process of phagocytic clearance of apoptotic cells by both professional phagocytic cells, such as macrophages, and non-professional phagocytic cells, such as epithelial cells. This process is crucial for maintaining tissue homeostasis in normal physiology. Any defects in efferocytosis can lead to pathological consequences and result in inflammatory diseases. Extracellular vesicles (EVs), including exosomes, microvesicles (MVs), and apoptotic vesicles (ApoVs), play a crucial role in proper efferocytosis. These EVs can significantly impact efferocytosis by affecting the polarization of macrophages and impacting calreticulin (CRT), TAM receptors, and MFG-E8. With further knowledge of these effects, new treatment strategies can be proposed for many inflammatory diseases caused by efferocytosis disorders. This review article aims to investigate the role of EVs during efferocytosis and its potential clinical applications in inflammatory diseases.
Topics: Humans; Extracellular Vesicles; Phagocytosis; Animals; Inflammation; Macrophages; Apoptosis; Efferocytosis
PubMed: 37859308
DOI: 10.2174/0113895575247690230926113455 -
Clinical Science (London, England :... Aug 2023Macrophages represent heterogeneous cell population with important roles in defence mechanisms and in homoeostasis. Tissue macrophages from diverse anatomical locations...
Macrophages represent heterogeneous cell population with important roles in defence mechanisms and in homoeostasis. Tissue macrophages from diverse anatomical locations adopt distinct activation states. M1 and M2 macrophages are two polarized forms of mononuclear phagocyte in vitro differentiation with distinct phenotypic patterns and functional properties, but in vivo, there is a wide range of different macrophage phenotypes in between depending on the microenvironment and natural signals they receive. In human infections, pathogens use different strategies to combat macrophages and these strategies include shaping the macrophage polarization towards one or another phenotype. Macrophages infiltrating the tumours can affect the patient's prognosis. M2 macrophages have been shown to promote tumour growth, while M1 macrophages provide both tumour-promoting and anti-tumour properties. In autoimmune diseases, both prolonged M1 activation, as well as altered M2 function can contribute to their onset and activity. In human atherosclerotic lesions, macrophages expressing both M1 and M2 profiles have been detected as one of the potential factors affecting occurrence of cardiovascular diseases. In allergic inflammation, T2 cytokines drive macrophage polarization towards M2 profiles, which promote airway inflammation and remodelling. M1 macrophages in transplantations seem to contribute to acute rejection, while M2 macrophages promote the fibrosis of the graft. The view of pro-inflammatory M1 macrophages and M2 macrophages suppressing inflammation seems to be an oversimplification because these cells exploit very high level of plasticity and represent a large scale of different immunophenotypes with overlapping properties. In this respect, it would be more precise to describe macrophages as M1-like and M2-like.
Topics: Humans; Macrophages; Cytokines; Phenotype; Inflammation; Cell Differentiation
PubMed: 37530555
DOI: 10.1042/CS20220531 -
Science Translational Medicine Dec 2023Vaccination has substantially reduced the morbidity and mortality of bacterial diseases, but mechanisms of vaccine-elicited pathogen clearance remain largely undefined....
Vaccination has substantially reduced the morbidity and mortality of bacterial diseases, but mechanisms of vaccine-elicited pathogen clearance remain largely undefined. We report that vaccine-elicited immunity against invasive bacteria mainly operates in the liver. In contrast to the current paradigm that migrating phagocytes execute vaccine-elicited immunity against blood-borne pathogens, we found that invasive bacteria are captured and killed in the liver of vaccinated host via various immune mechanisms that depend on the protective potency of the vaccine. Vaccines with relatively lower degrees of protection only activated liver-resident macrophage Kupffer cells (KCs) by inducing pathogen-binding immunoglobulin M (IgM) or low amounts of IgG. IgG-coated pathogens were directly captured by KCs via multiple IgG receptors FcγRs, whereas IgM-opsonized bacteria were indirectly bound to KCs via complement receptors of immunoglobulin superfamily (CRIg) and complement receptor 3 (CR3) after complement C3 activation at the bacterial surface. Conversely, the more potent vaccines engaged both KCs and liver sinusoidal endothelial cells by inducing higher titers of functional IgG antibodies. Endothelial cells (ECs) captured densely IgG-opsonized pathogens by the low-affinity IgG receptor FcγRIIB in a "zipper-like" manner and achieved bacterial killing predominantly in the extracellular milieu via an undefined mechanism. KC- and endothelial cell-based capture of antibody-opsonized bacteria also occurred in FcγR-humanized mice. These vaccine protection mechanisms in the liver not only provide a comprehensive explanation for vaccine-/antibody-boosted immunity against invasive bacteria but also may serve as in vivo functional readouts of vaccine efficacy.
Topics: Animals; Mice; Kupffer Cells; Endothelial Cells; Macrophages; Vaccines; Immunoglobulin G; Liver; Antibodies, Viral; Immunoglobulin M; Receptors, IgG; Bacteria
PubMed: 38117903
DOI: 10.1126/scitranslmed.ade0054 -
Advanced Materials (Deerfield Beach,... Mar 2024Nanodiamonds (ND) hold great potential for diverse applications due to their biocompatibility, non-toxicity, and versatile functionalization. Direct visualization of ND...
Nanodiamonds (ND) hold great potential for diverse applications due to their biocompatibility, non-toxicity, and versatile functionalization. Direct visualization of ND by means of non-invasive imaging techniques will open new venues for labeling and tracking, offering unprecedented and unambiguous detection of labeled cells or nanodiamond-based drug carrier systems. The structural defects in diamonds, such as vacancies, can have paramagnetic properties and potentially act as contrast agents in magnetic resonance imaging (MRI). The smallest nanoscale diamond particles, detonation ND, are reported to effectively reduce longitudinal relaxation time T and provide signal enhancement in MRI. Using in vivo, chicken embryos, direct visualization of ND is demonstrated as a bright signal with high contrast to noise ratio. At 24 h following intravascular application marked signal enhancement is noticed in the liver and the kidneys, suggesting uptake by the phagocytic cells of the reticuloendothelial system (RES), and in vivo labeling of these cells. This is confirmed by visualization of nanodiamond-labeled macrophages as positive (bright) signal, in vitro. Macrophage cell labeling is not associated with significant increase in pro-inflammatory cytokines or marked cytotoxicity. These results indicate nanodiamond as a novel gadolinium-free contrast-enhancing agent with potential for cell labeling and tracking and over periods of time.
Topics: Chick Embryo; Animals; Nanodiamonds; Magnetic Resonance Imaging; Liver; Macrophages; Drug Carriers
PubMed: 38037437
DOI: 10.1002/adma.202310109 -
Aging Oct 2023B-cell lymphoma 2-related protein A1 (BCL2A1) is a member of the BCL-2 family. Previous studies have shown that BCL2A1 is closely related to the tumorigenesis and...
B-cell lymphoma 2-related protein A1 (BCL2A1) is a member of the BCL-2 family. Previous studies have shown that BCL2A1 is closely related to the tumorigenesis and resistance to chemotherapy of multiple solid tumors, such as breast cancer. However, the expression pattern and potential biological function of BCL2A1 in glioma remain unknown. For the first time, we found that the expression of BCL2A1 was higher in human glioma tissues than in normal brain tissues (NBTs) in both public datasets and an in-house cohort. High BCL2A1 expression was associated with advanced WHO grade, IDH 1/2 wild type and the mesenchymal (ME) subtype, and its overexpression in glioma predicted resistance to temozolomide (TMZ) chemotherapy and unfavorable prognosis. In addition, Gene set enrichment analysis (GSEA), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that BCL2A1 was significantly correlated with the immune response and immune-related pathways, and BCL2A1 expression was positively correlated with microenvironmental parameters (immune, stromal, and ESTIMATE scores) and macrophage infiltration. Interestingly, bioinformatic prediction and immunohistochemical/immunofluorescence staining analysis revealed that BCL2A1 expression was obviously associated with the tumor-associated macrophages (TAMs) markers CD68 and CCL2. Notably, knockdown of BCL2A1 significantly inhibited cell proliferation of U87 and U251 , induced smaller tumor size and prolonged survival time of mice . Co-culture experiments of macrophages and GBM cells showed that BCL2A1 knockdown inhibited macrophage migration. Meanwhile, knockdown of BCL2A1 was associated with low expression of CD68 and CCL2 in intracranial xenograft model. This may suggest that BCL2A1 promotes the progression of glioma and influences the prognosis of patients by participating in TAMs infiltration. In conclusion, these findings suggest that BCL2A1 could serve as a promising prognostic indicator and immunotherapy target in gliomas.
Topics: Animals; Female; Humans; Mice; Breast Neoplasms; Glioma; Macrophages; Prognosis; Tumor-Associated Macrophages
PubMed: 37889551
DOI: 10.18632/aging.205149 -
Respiratory Research Mar 2024Inflammation and immune processes underlie pulmonary hypertension progression. Two main different activated phenotypes of macrophages, classically activated M1... (Review)
Review
Inflammation and immune processes underlie pulmonary hypertension progression. Two main different activated phenotypes of macrophages, classically activated M1 macrophages and alternatively activated M2 macrophages, are both involved in inflammatory processes related to pulmonary hypertension. Recent advances suggest that macrophages coordinate interactions among different proinflammatory and anti-inflammatory mediators, and other cellular components such as smooth muscle cells and fibroblasts. In this review, we summarize the current literature on the role of macrophages in the pathogenesis of pulmonary hypertension, including the origin of pulmonary macrophages and their response to triggers of pulmonary hypertension. We then discuss the interactions among macrophages, cytokines, and vascular adventitial fibroblasts in pulmonary hypertension, as well as the potential therapeutic benefits of macrophages in this disease. Identifying the critical role of macrophages in pulmonary hypertension will contribute to a comprehensive understanding of this pathophysiological abnormality, and may provide new perspectives for pulmonary hypertension management.
Topics: Humans; Hypertension, Pulmonary; Macrophages; Macrophages, Alveolar; Inflammation; Cytokines
PubMed: 38555425
DOI: 10.1186/s12931-024-02772-8