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Annual Review of Immunology Apr 2020A striking change has happened in the field of immunology whereby specific metabolic processes have been shown to be a critical determinant of immune cell activation.... (Review)
Review
A striking change has happened in the field of immunology whereby specific metabolic processes have been shown to be a critical determinant of immune cell activation. Multiple immune receptor types rewire metabolic pathways as a key part of how they promote effector functions. Perhaps surprisingly for immunologists, the Krebs cycle has emerged as the central immunometabolic hub of the macrophage. During proinflammatory macrophage activation, there is an accumulation of the Krebs cycle intermediates succinate and citrate, and the Krebs cycle-derived metabolite itaconate. These metabolites have distinct nonmetabolic signaling roles that influence inflammatory gene expression. A key bioenergetic target for the Krebs cycle, the electron transport chain, also becomes altered, generating reactive oxygen species from Complexes I and III. Similarly, alternatively activated macrophages require α-ketoglutarate-dependent epigenetic reprogramming to elicit anti-inflammatory gene expression. In this review, we discuss these advances and speculate on the possibility of targeting these events therapeutically for inflammatory diseases.
Topics: Animals; Citric Acid Cycle; Disease Susceptibility; Energy Metabolism; Humans; Immunity; Immunomodulation; Macrophage Activation; Macrophages; Signal Transduction
PubMed: 31986069
DOI: 10.1146/annurev-immunol-081619-104850 -
Blood Jul 2020The diversity of the human microbiome heralds the difference of the impact that gut microbial metabolites exert on allogenic graft-versus-host (GVH) disease (GVHD), even...
The diversity of the human microbiome heralds the difference of the impact that gut microbial metabolites exert on allogenic graft-versus-host (GVH) disease (GVHD), even though short-chain fatty acids and indole were demonstrated to reduce its severity. In this study, we dissected the role of choline-metabolized trimethylamine N-oxide (TMAO) in the GVHD process. Either TMAO or a high-choline diet enhanced the allogenic GVH reaction, whereas the analog of choline, 3,3-dimethyl-1-butanol reversed TMAO-induced GVHD severity. Interestingly, TMAO-induced alloreactive T-cell proliferation and differentiation into T-helper (Th) subtypes was seen in GVHD mice but not in in vitro cultures. We thus investigated the role of macrophage polarization, which was absent from the in vitro culture system. F4/80+CD11b+CD16/32+ M1 macrophage and signature genes, IL-1β, IL-6, TNF-α, CXCL9, and CXCL10, were increased in TMAO-induced GVHD tissues and in TMAO-cultured bone marrow-derived macrophages (BMDMs). Inhibition of the NLRP3 inflammasome reversed TMAO-stimulated M1 features, indicating that NLRP3 is the key proteolytic activator involved in the macrophage's response to TMAO stimulation. Consistently, mitochondrial reactive oxygen species and enhanced NF-κB nuclear relocalization were investigated in TMAO-stimulated BMDMs. In vivo depletion of NLRP3 in GVHD recipients not only blocked M1 polarization but also reversed GVHD severity in the presence of TMAO treatment. In conclusion, our data revealed that TMAO-induced GVHD progression resulted from Th1 and Th17 differentiation, which is mediated by the polarized M1 macrophage requiring NLRP3 inflammasome activation. It provides the link among the host choline diet, microbial metabolites, and GVH reaction, shedding light on alleviating GVHD by controlling choline intake.
Topics: Animals; Choline; Cytokines; Dietary Fats; Gastrointestinal Microbiome; Graft vs Host Disease; Inflammasomes; Macrophages; Methylamines; Mice; Mice, Inbred BALB C; Mice, Knockout; T-Lymphocytes, Helper-Inducer
PubMed: 32291445
DOI: 10.1182/blood.2019003990 -
Nature Reviews. Cardiology Apr 2020Monocytes and macrophages provide defence against pathogens and danger signals. These cells respond to stimulation in a fast and stimulus-specific manner by utilizing... (Review)
Review
Monocytes and macrophages provide defence against pathogens and danger signals. These cells respond to stimulation in a fast and stimulus-specific manner by utilizing complex cascaded activation by lineage-determining and signal-dependent transcription factors. The complexity of the functional response is determined by interactions between triggered transcription factors and depends on the microenvironment and interdependent signalling cascades. Dysregulation of macrophage phenotypes is a major driver of various diseases such as atherosclerosis, rheumatoid arthritis and type 2 diabetes mellitus. Furthermore, exposure of monocytes, which are macrophage precursor cells, to certain stimuli can lead to a hypo-inflammatory tolerized phenotype or a hyper-inflammatory trained phenotype in a macrophage. In atherosclerosis, macrophages and monocytes are exposed to inflammatory cytokines, oxidized lipids, cholesterol crystals and other factors. All these stimuli induce not only a specific transcriptional response but also interact extensively, leading to transcriptional and epigenetic heterogeneity of macrophages in atherosclerotic plaques. Targeting the epigenetic landscape of plaque macrophages can be a powerful therapeutic tool to modulate pro-atherogenic phenotypes and reduce the rate of plaque formation. In this Review, we discuss the emerging role of transcription factors and epigenetic remodelling in macrophages in the context of atherosclerosis and inflammation, and provide a comprehensive overview of epigenetic enzymes and transcription factors that are involved in macrophage activation.
Topics: Atherosclerosis; Epigenesis, Genetic; Macrophage Activation; Macrophages; Transcription, Genetic
PubMed: 31578516
DOI: 10.1038/s41569-019-0265-3 -
STAR Protocols Mar 2021The assessment of macrophage function has been a topic of intense discussion due to multiple subtypes. This protocol describes the collection of bone marrow cells from...
The assessment of macrophage function has been a topic of intense discussion due to multiple subtypes. This protocol describes the collection of bone marrow cells from the femur and tibia of mice, differentiation into bone marrow-derived macrophages (BMDM cells), and sampling from cultures. This protocol focuses on the efficient preparation of BMDM cells, providing a way to assess the function of macrophages. For complete details on the use and execution of this protocol, please refer to Toda et al. (2020).
Topics: Animals; Bone Marrow Cells; Cell Culture Techniques; Cell Separation; Cells, Cultured; Macrophages; Mice
PubMed: 33458708
DOI: 10.1016/j.xpro.2020.100246 -
Theranostics 2021Macrophages are specialized cells that control tissue homeostasis. They include non-resident and tissue-resident macrophage populations which are characterized by the... (Review)
Review
Macrophages are specialized cells that control tissue homeostasis. They include non-resident and tissue-resident macrophage populations which are characterized by the expression of particular cell surface markers and the secretion of molecules with a wide range of biological functions. The differentiation and polarization of macrophages relies on specific growth factors and their receptors. Macrophage-colony stimulating factor (CSF-1) and interleukine-34 (IL-34), also known as "twin" cytokines, are part of this regluatory landscape. CSF-1 and IL-34 share a common receptor, the macrophage-colony stimulating factor receptor (CSF-1R), which is activated in a similar way by both factors and turns on identical signaling pathways. However, there is some discrete differential activation leading to specific activities. In this review, we disscuss recent progress in understanding of the role of the twin cytokines in macrophage differentiation, from their interaction with CSF-1R and the activation of signaling pathways, to their implication in macrophage polarization of non-resident and tissue-resident macrophages. A special focus on IL-34, its involvement in pathophsyiological contexts, and its potential as a theranostic target for macrophage therapy will be proposed.
Topics: Animals; Homeostasis; Humans; Interleukins; Macrophage Activation; Macrophage Colony-Stimulating Factor; Macrophages; Signal Transduction
PubMed: 33408768
DOI: 10.7150/thno.50683 -
Frontiers in Immunology 2022Cardiovascular diseases, the notorious killer, are mainly caused by atherosclerosis (AS) characterized by lipids, cholesterol, and iron overload in plaques. Macrophages...
Cardiovascular diseases, the notorious killer, are mainly caused by atherosclerosis (AS) characterized by lipids, cholesterol, and iron overload in plaques. Macrophages are effector cells and accumulate to the damaged and inflamed sites of arteries to internalize native and chemically modified lipoproteins to transform them into cholesterol-loaded foam cells. Foam cell formation is determined by the capacity of phagocytosis, migration, scavenging, and the features of phenotypes. Macrophages are diverse, and the subsets and functions are controlled by their surrounding microenvironment. Generally, macrophages are divided into classically activated (M1) and alternatively activated (M2). Recently, intraplaque macrophage phenotypes are recognized by the stimulation of CXCL4 (M4), oxidized phospholipids (Mox), hemoglobin/haptoglobin complexes [HA-mac/M(Hb)], and heme (Mhem). The pro-atherogenic or anti-atherosclerotic phenotypes of macrophages decide the progression of AS. Besides, apoptosis, necrosis, ferroptosis, autophagy and pyrotopsis determine plaque formation and cardiovascular vulnerability, which may be associated with macrophage polarization phenotypes. In this review, we first summarize the three most popular hypotheses for AS and find the common key factors for further discussion. Secondly, we discuss the factors affecting macrophage polarization and five types of macrophage death in AS progression, especially ferroptosis. A comprehensive understanding of the cellular and molecular mechanisms of plaque formation is conducive to disentangling the candidate targets of macrophage-targeting therapies for clinical intervention at various stages of AS.
Topics: Atherosclerosis; Foam Cells; Humans; Macrophage Activation; Macrophages; Plaque, Atherosclerotic
PubMed: 35432323
DOI: 10.3389/fimmu.2022.843712 -
Inflammation Feb 2020Luteolin is a natural flavonoid compound derived from vegetables, fruits, and herbs with potent anti-inflammatory activity. Macrophage polarization is important in the...
Luteolin is a natural flavonoid compound derived from vegetables, fruits, and herbs with potent anti-inflammatory activity. Macrophage polarization is important in the development and progression of inflammation. However, whether luteolin can inhibit inflammation by regulating the polarized phenotypes of macrophages remains unknown. The aim of this study was to investigate the effects of luteolin on the inflammatory polarization of macrophages and the underlying mechanisms. RAW264.7 macrophages were induced to M1 polarization by stimulation with lipopolysaccharide plus interferon-γ or to M2 polarization with interleukin 4 (IL-4), simultaneously, accompanied with different concentrations of luteolin. Laser confocal microscopy was used to observe cell morphology; flow cytometry was employed to detect the expression of membrane surface molecule CD86 and CD206; qPCR was performed to examine the mRNA expression of M1 markers (iNOS, IL-1β, IL-6) and M2 markers (Arg1, CD206, CD163, IL-10, and IL-13), respectively; ELISA was used to examine the levels of IL-6, TNF-α, and IL-10; and Western blotting was used to evaluate the p-STAT3 and p-STAT6 protein pathway. The morphology of activated M1 macrophages changed significantly, developing dendritic characteristics. After luteolin treatment, the expression of M1-type proinflammatory mediators and the surface marker CD86 were decreased evidently, but those of M2-related anti-inflammatory factors and CD206 were increased markedly. Moreover, p-STAT3 was downregulated and p-STAT6 was upregulated in a dose-dependent manner. Conclusion, luteolin can alter the M1/M2 polarization of macrophages, thereby playing an anti-inflammatory role via downregulation of p-STAT3 and upregulation of p-STAT6. Therefore, luteolin may be potentially valuable to inhibit inflammation.
Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Cytokines; Inflammation; Inflammation Mediators; Luteolin; Macrophage Activation; Macrophages; Mice; Phenotype; Phosphorylation; RAW 264.7 Cells; STAT3 Transcription Factor; STAT6 Transcription Factor; Signal Transduction
PubMed: 31673976
DOI: 10.1007/s10753-019-01099-7 -
Cells Dec 2022(1) Background: the miR-301a is well known involving the proliferation and migration of tumor cells. However, the role of miR-301a in the migration and phagocytosis of...
(1) Background: the miR-301a is well known involving the proliferation and migration of tumor cells. However, the role of miR-301a in the migration and phagocytosis of macrophages is still unclear. (2) Methods: sciatic nerve injury, liver injury models, as well as primary macrophage cultures were prepared from the miR-301a knockout (KO) and wild type (WT) mice to assess the macrophage's migration and phagocytosis capabilities. Targetscan database analysis, Western blotting, siRNA transfection, and CXCR4 inhibition or activation were performed to reveal miR301a's potential mechanism. (3) Results: the macrophage's migration and phagocytosis were significantly attenuated by the miR-301a KO both in vivo and in vitro. MiR-301a can target Yin-Yang 1 (YY1), and miR-301a KO resulted in YY1 up-regulation and CXCR4 (YY1's down-stream molecule) down-regulation. siYY1 increased the expression of CXCR4 and enhanced migration and phagocytosis in KO macrophages. Meanwhile, a CXCR4 inhibitor or agonist could attenuate or accelerate, respectively, the macrophage migration and phagocytosis. (4) Conclusions: current findings indicated that miR-301a plays important roles in a macrophage's capabilities of migration and phagocytosis through the YY1/CXCR4 pathway. Hence, miR-301a might be a promising therapeutic candidate for inflammatory diseases by adjusting macrophage bio-functions.
Topics: Animals; Mice; Macrophages; MicroRNAs; Phagocytosis; RNA, Small Interfering; Signal Transduction; Cell Movement
PubMed: 36552718
DOI: 10.3390/cells11243952 -
Frontiers in Immunology 2020is a member of the human commensal microflora that exists, apparently benignly, at multiple sites on the host. However, as an opportunist pathogen it can also cause a... (Review)
Review
is a member of the human commensal microflora that exists, apparently benignly, at multiple sites on the host. However, as an opportunist pathogen it can also cause a range of serious diseases. This requires an ability to circumvent the innate immune system to establish an infection. Professional phagocytes, primarily macrophages and neutrophils, are key innate immune cells which interact with , acting as gatekeepers to contain and resolve infection. Recent studies have highlighted the important roles of macrophages during infections, using a wide array of killing mechanisms. In defense, has evolved multiple strategies to survive within, manipulate and escape from macrophages, allowing them to not only subvert but also exploit this key element of our immune system. Macrophage- interactions are multifaceted and have direct roles in infection outcome. In depth understanding of these host-pathogen interactions may be useful for future therapeutic developments. This review examines macrophage interactions with throughout all stages of infection, with special emphasis on mechanisms that determine infection outcome.
Topics: Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Bacterial Vaccines; Cations; Cell Death; Chemotaxis; Cytokines; Extracellular Vesicles; Host-Pathogen Interactions; Humans; Hydrogen-Ion Concentration; Immune Evasion; Macrophages; Mice; Nutrients; Phagocytosis; Phagosomes; Reactive Nitrogen Species; Reactive Oxygen Species; Receptors, Complement; Receptors, Fc; Receptors, Scavenger; Staphylococcal Infections; Staphylococcus aureus
PubMed: 33542723
DOI: 10.3389/fimmu.2020.620339 -
Molecular Cancer Sep 2022Given that hypoxia is a persistent physiological feature of many different solid tumors and a key driver for cancer malignancy, it is thought to be a major target in... (Review)
Review
Given that hypoxia is a persistent physiological feature of many different solid tumors and a key driver for cancer malignancy, it is thought to be a major target in cancer treatment recently. Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME), which have a large impact on tumor development and immunotherapy. TAMs massively accumulate within hypoxic tumor regions. TAMs and hypoxia represent a deadly combination because hypoxia has been suggested to induce a pro-tumorigenic macrophage phenotype. Hypoxia not only directly affects macrophage polarization, but it also has an indirect effect by altering the communication between tumor cells and macrophages. For example, hypoxia can influence the expression of chemokines and exosomes, both of which have profound impacts on the recipient cells. Recently, it has been demonstrated that the intricate interaction between cancer cells and TAMs in the hypoxic TME is relevant to poor prognosis and increased tumor malignancy. However, there are no comprehensive literature reviews on the molecular mechanisms underlying the hypoxia-mediated communication between tumor cells and TAMs. Therefore, this review has the aim to collect all recently available data on this topic and provide insights for developing novel therapeutic strategies for reducing the effects of hypoxia.
Topics: Humans; Hypoxia; Macrophages; Neoplasms; Tumor Microenvironment; Tumor-Associated Macrophages
PubMed: 36071472
DOI: 10.1186/s12943-022-01645-2