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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 -
Immunobiology Sep 2014Macrophages form a heterogeneous cell population displaying multiple functions, and can be polarized into pro- (M1) or anti-inflammatory (M2) macrophages, by...
Macrophages form a heterogeneous cell population displaying multiple functions, and can be polarized into pro- (M1) or anti-inflammatory (M2) macrophages, by environmental factors. Their activation status reflects a beneficial or detrimental role in various diseases. Currently several in vitro maturation and activation protocols are used to induce an M1 or M2 phenotype. Here, the impact of different maturation factors (NHS, M-CSF, or GM-CSF) and activation methods (IFN-γ/LPS, IL-4, dexamethason, IL-10) on the macrophage phenotype was determined. Regarding macrophage morphology, pro-inflammatory (M1) activation stimulated cell elongation, and anti-inflammatory (M2) activation induced a circular appearance. Activation with pro-inflammatory mediators led to increased CD40 and CD64 expression, whereas activation with anti-inflammatory factors resulted in increased levels of MR and CD163. Production of pro-inflammatory cytokines was induced by activation with IFN-γ/LPS, and TGF-β production was enhanced by the maturation factors M-CSF and GM-CSF. Our data demonstrate that macrophage marker expression and cytokine production in vitro is highly dependent on both maturation and activation methods. In vivo macrophage activation is far more complex, since a plethora of stimuli are present. Hence, defining the macrophage activation status ex vivo on a limited number of markers could be indecisive. From this study we conclude that maturation with M-CSF or GM-CSF induces a moderate anti- or pro-inflammatory state respectively, compared to maturation with NHS. CD40 and CD64 are the most distinctive makers for human M1 and CD163 and MR for M2 macrophage activation and therefore can be helpful in determining the activation status of human macrophages ex vivo.
Topics: Cell Differentiation; Cells, Cultured; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunologic Techniques; In Vitro Techniques; Macrophage Activation; Macrophage Colony-Stimulating Factor; Macrophages; Serum
PubMed: 24916404
DOI: 10.1016/j.imbio.2014.05.002 -
Acta Neuropathologica May 2019Virtually all phases of spinal cord injury pathogenesis, including inflammation, cell proliferation and differentiation, as well as tissue remodeling, are mediated in... (Review)
Review
Virtually all phases of spinal cord injury pathogenesis, including inflammation, cell proliferation and differentiation, as well as tissue remodeling, are mediated in part by infiltrating monocyte-derived macrophages. It is now clear that these infiltrating macrophages have distinct functions from resident microglia and are capable of mediating both harmful and beneficial effects after injury. These divergent effects have been largely attributed to environmental cues, such as specific cytokines, that influence the macrophage polarization state. In this review, we also consider the possibility that different macrophage origins, including the spleen, bone marrow, and local self-renewal, may also affect macrophage fate, and ultimately their function that contribute to the complex pathobiology of spinal cord injury.
Topics: Animals; Humans; Macrophages; Spinal Cord Injuries
PubMed: 30929040
DOI: 10.1007/s00401-019-01992-3 -
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 -
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 -
Frontiers in Immunology 2019Polysaccharides are among the most important members of the biopolymer family. They are natural macromolecules composed of monosaccharides. To date, more than 300 kinds... (Review)
Review
Polysaccharides are among the most important members of the biopolymer family. They are natural macromolecules composed of monosaccharides. To date, more than 300 kinds of natural polysaccharide compounds have been identified. They are present in plants, animals, and microorganisms, and they engage in a variety of physiological functions. In the 1950s, due to the discovery of their immunoregulatory and anti-tumor activities, polysaccharides became a popular topic of research in pharmacology, especially in immunopharmacology. Plants are an important source of natural polysaccharides. Pharmacological and clinical studies have shown that plant polysaccharides have many functions, such as immune regulation, anti-tumor activity, anti-inflammatory activity, anti-viral functions, anti-radiation functions, and a hypoglycaemic effect. The immunomodulatory effects of plant polysaccharides have received much attention. Polysaccharides with these effects are also referred to as biological response modifiers (BRMs), and research on them is one of the most active areas of polysaccharide research. Thus, we summarize immunomodulatory effects of botanical polysaccharides isolated from different species of plants on the macrophage. The primary effect of botanical polysaccharides is to enhance and/or activate macrophage immune responses, including increasing reactive oxygen species (ROS) production, and enhancing secretion of cytokines and chemokines. Therefore, it is believed that botanical polysaccharides have significant therapeutic potential, and represent a new method for discovery and development of novel immunomodulatory medicine.
Topics: Animals; Humans; Immunologic Factors; Macrophages; Plants; Polysaccharides
PubMed: 30804942
DOI: 10.3389/fimmu.2019.00145 -
Circulation Research Apr 2020Macrophage immunometabolism, the changes in intracellular metabolic pathways that alter the function of these highly plastic cells, has been the subject of intense... (Review)
Review
Macrophage immunometabolism, the changes in intracellular metabolic pathways that alter the function of these highly plastic cells, has been the subject of intense interest in the past few years, in part because macrophage immunometabolism plays important roles in atherosclerosis and other inflammatory diseases. In this review article, part of the , we introduce the concepts of (1) intracellular immunometabolism-the canonical pathways of intrinsic cell activation leading to changes in intracellular metabolism, which in turn alter cellular function; and (2) intercellular immunometabolism-conditions in which intermediates of cellular metabolism are transferred from one cell to another, thereby altering the function of the recipient cell. The recent discovery that the metabolite cargo of dead and dying cells ingested through efferocytosis by macrophages can alter metabolic pathways and downstream function of the efferocyte is markedly changing the way we think about macrophage immunometabolism. Metabolic transitions of macrophages contribute to their functions in all stages of atherosclerosis, from lesion initiation to formation of advanced lesions characterized by necrotic cores, to lesion regression following aggressive lipid lowering. This review article discusses recent advances in our understanding of these different aspects of macrophage immunometabolism in atherosclerosis. With the increasing understanding of the roles of macrophage immunometabolism in atherosclerosis, new exciting concepts and potential targets for intervention are emerging.
Topics: Animals; Arteries; Atherosclerosis; Energy Metabolism; Humans; Macrophages; Plaque, Atherosclerotic; Signal Transduction
PubMed: 32324504
DOI: 10.1161/CIRCRESAHA.119.315939 -
Shock (Augusta, Ga.) Aug 2016Monocytes and macrophages are important components of the immune system, specialized in either removing pathogens as part of innate immunity or contributing to adaptive... (Review)
Review
Monocytes and macrophages are important components of the immune system, specialized in either removing pathogens as part of innate immunity or contributing to adaptive immunity through antigen presentation. Essential to such functions is classical activation (M1) and alternative activation (M2) of macrophages. M1 polarization of macrophages is characterized by production of pro-inflammatory cytokines, antimicrobial and tumoricidal activity, whereas M2 polarization of macrophages is linked to immunosuppression, tumorigenesis, wound repair, and elimination of parasites. MiRNAs are small non-coding RNAs with the ability to regulate gene expression and network of cellular processes. A number of studies have determined miRNA expression profiles in M1 and M2 polarized human and murine macrophages using microarray and RT-qPCR arrays techniques. More specifically, miR-9, miR-127, miR-155, and miR-125b have been shown to promote M1 polarization while miR-124, miR-223, miR-34a, let-7c, miR-132, miR-146a, and miR-125a-5p induce M2 polarization in macrophages by targeting various transcription factors and adaptor proteins. Further, M1 and M2 phenotypes play distinctive roles in cell growth and progression of inflammation-related diseases such as sepsis, obesity, cancer, and multiple sclerosis. Hence, miRNAs that modulate macrophage polarization may have therapeutic potential in the treatment of inflammation-related diseases. This review highlights recent findings in miRNA expression profiles in polarized macrophages from murine and human sources, and summarizes how these miRNAs regulate macrophage polarization. Last, therapeutic potential of miRNAs in inflammation-related diseases through modulation of macrophage polarization is also discussed.
Topics: Animals; Cell Polarity; Humans; Inflammation; Macrophage Activation; Macrophages; Mice; MicroRNAs
PubMed: 26954942
DOI: 10.1097/SHK.0000000000000604 -
Annual Review of Immunology Apr 2022Macrophages are first responders for the immune system. In this role, they have both effector functions for neutralizing pathogens and sentinel functions for alerting... (Review)
Review
Macrophages are first responders for the immune system. In this role, they have both effector functions for neutralizing pathogens and sentinel functions for alerting other immune cells of diverse pathologic threats, thereby initiating and coordinating a multipronged immune response. Macrophages are distributed throughout the body-they circulate in the blood, line the mucosal membranes, reside within organs, and survey the connective tissue. Several reviews have summarized their diverse roles in different physiological scenarios and in the initiation or amplification of different pathologies. In this review, we propose that both the effector and the sentinel functions of healthy macrophages rely on three hallmark properties: response specificity, context dependence, and stimulus memory. When these hallmark properties are diminished, the macrophage's biological functions are impaired, which in turn results in increased risk for immune dysregulation, manifested by immune deficiency or autoimmunity. We review the evidence and the molecular mechanisms supporting these functional hallmarks.
Topics: Animals; Humans; Immunity, Innate; Macrophages
PubMed: 35471841
DOI: 10.1146/annurev-immunol-101320-031555