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Biomaterials Jun 2020Macrophages are among the first cells to interact with biomaterials and ultimately determine their integrative fate. Biomaterial surface characteristics like roughness...
Macrophages are among the first cells to interact with biomaterials and ultimately determine their integrative fate. Biomaterial surface characteristics like roughness and hydrophilicity can activate macrophages to an anti-inflammatory phenotype. Wnt signaling, a key cell proliferation and differentiation pathway, has been associated with dysregulated macrophage activity in disease. However, the role Wnt signaling plays in macrophage activation and response to biomaterials is unknown. The aim of this study was to characterize the regulation of Wnt signaling in macrophages during classical pro- and anti-inflammatory polarization and in their response to smooth, rough, and rough-hydrophilic titanium (Ti) surfaces. Peri-implant Wnt signaling in macrophage-ablated (MaFIA) mice instrumented with intramedullary Ti rods was significantly attenuated compared to untreated controls. Wnt ligand mRNA were upregulated in a surface modification-dependent manner in macrophages isolated from the surface of Ti implanted in C57Bl/6 mice. In vitro, Wnt mRNAs were regulated in primary murine bone-marrow-derived macrophages cultured on Ti in a surface modification-dependent manner. When macrophageal Wnt secretion was inhibited, macrophage sensitivity to both physical and biological stimuli was abrogated. Loss of macrophage-derived Wnts also impaired recruitment of mesenchymal stem cells and T-cells to Ti implants in vivo. Finally, inhibition of integrin signaling decreased surface-dependent upregulation of Wnt genes. These results suggest that Wnt signaling regulates macrophage response to biomaterials and that macrophages are an important source of Wnt ligands during inflammation and healing.
Topics: Animals; Biocompatible Materials; Macrophage Activation; Macrophages; Mice; Surface Properties; Titanium; Wnt Signaling Pathway
PubMed: 32179303
DOI: 10.1016/j.biomaterials.2020.119920 -
Frontiers in Immunology 2023Lung macrophages constitute the first line of defense against airborne particles and microbes and are key to maintaining pulmonary immune homeostasis. There is... (Review)
Review
Lung macrophages constitute the first line of defense against airborne particles and microbes and are key to maintaining pulmonary immune homeostasis. There is increasing evidence suggesting that macrophages also participate in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), including the modulation of inflammatory responses and the repair of damaged lung tissues. The diversity of their functions may be attributed to their polarized states. Classically activated or inflammatory (M1) macrophages and alternatively activated or anti-inflammatory (M2) macrophages are the two main polarized macrophage phenotypes. The precise regulatory mechanism of macrophage polarization is a complex process that is not completely understood. A growing body of literature on immunometabolism has demonstrated the essential role of immunometabolism and its metabolic intermediates in macrophage polarization. In this review, we summarize macrophage polarization phenotypes, the role of immunometabolism, and its metabolic intermediates in macrophage polarization and ALI/ARDS, which may represent a new target and therapeutic direction.
Topics: Humans; Macrophages, Alveolar; Lung; Macrophages; Respiratory Distress Syndrome; Acute Lung Injury
PubMed: 37020557
DOI: 10.3389/fimmu.2023.1117548 -
International Journal of Biological... 2022Heart failure with preserved ejection fraction (HFpEF) can arise from hypertension-induced cardiac remodeling. Monocyte/macrophage accumulation and inflammation are...
Heart failure with preserved ejection fraction (HFpEF) can arise from hypertension-induced cardiac remodeling. Monocyte/macrophage accumulation and inflammation are crucial elements in the pathogenesis of hypertension-induced cardiac remodeling. The C-X-C chemokine receptor 4 (CXCR4) is a critical regulator of the macrophage-mediated immune response. Nevertheless, the contribution of CXCR4 to macrophage phenotype and function during the progression of HFpEF remains unclear. Herein, we aimed to determine the role of macrophagic CXCR4 in heart failure with preserved ejection fraction (HFpEF). As a HFpEF model, wild type mice and myeloid-specific CXCR4 deficiency mice were subjected to pressure overload for 30 days to assess the function of macrophagic CXCR4 on cardiac function. Medium from macrophages was used to treat cardiac fibroblasts to study macrophage-to-fibroblast signaling. We found circulatory CXCR4+ immune cells, mainly monocytes, markedly increased in HFpEF patients with hypertension. In the experimental HFpEF mice model, macrophages but not neutrophils represent the main infiltrating inflammatory cells in the heart, abundantly expressing CXCR4. Myeloid-specific CXCR4 deficient impeded macrophage infiltration and inflammatory response in the heart of HFpEF mice, thus ameliorating cardiac fibrosis and improving cardiac diastolic function. Furthermore, transcriptomic profiling data revealed that CXCR4 loss in macrophages exhibited a decreased transcriptional signature associated with the regulation of inflammatory response. Notably, CXCR4 significantly augmented chemokine (C‑X‑C) motif ligand (CXCL3) expression, which at least partly contributed to fibrosis by promoting myofibroblast differentiation. Mechanistically, the increased production of pro-inflammatory cytokines in CXCR4 expressed macrophages could be attributed to the suppression of the peroxisome proliferator-activated receptor γ (PPARγ) activity. Collectively, our data supported that the infiltration of CXCR4+ macrophages in the heart exacerbates hypertension-induced diastolic function by promoting pro-inflammatory cytokines production and thus may serve as a potential therapeutic target for hypertension-induced HFpEF.
Topics: Animals; Cardiomyopathies; Cytokines; Fibroblasts; Heart Failure; Hypertension; Macrophages; Mice; Receptors, CXCR4; Stroke Volume; Ventricular Function, Left; Ventricular Remodeling
PubMed: 35173552
DOI: 10.7150/ijbs.65802 -
Journal of the American College of... Dec 2019Macrophages and fibroblasts are 2 major cell types involved in healing after myocardial infarction (MI), contributing to myocardial remodeling and fibrosis. Post-MI...
BACKGROUND
Macrophages and fibroblasts are 2 major cell types involved in healing after myocardial infarction (MI), contributing to myocardial remodeling and fibrosis. Post-MI fibrosis progression is characterized by a decrease in cardiac macrophage content.
OBJECTIVES
This study explores the potential of macrophages to express fibroblast genes and the direct role of these cells in post-MI cardiac fibrosis.
METHODS
Prolonged in vitro culture of human macrophages was used to evaluate the capacity to express fibroblast markers. Infiltrating cardiac macrophages was tracked in vivo after experimental MI of LysM(Cre);ROSA26(EYFP) transgenic mice. The expression of Yellow Fluorescent Protein (YFP) in these animals is restricted to myeloid lineage allowing the identification of macrophage-derived fibroblasts. The expression in YFP-positive cells of fibroblast markers was determined in myocardial tissue sections of hearts from these mice after MI.
RESULTS
Expression of the fibroblast markers type I collagen, prolyl-4-hydroxylase, fibroblast specific protein-1, and fibroblast activation protein was evidenced in YFP-positive cells in the heart after MI. The presence of fibroblasts after MI was evaluated in the hearts of animals after depletion of macrophages with clodronate liposomes. This macrophage depletion significantly reduced the number of Mac3Col1A1 cells in the heart after MI.
CONCLUSIONS
The data provide both in vitro and in vivo evidence for the ability of macrophages to transition and adopt a fibroblast-like phenotype. Therapeutic manipulation of this macrophage-fibroblast transition may hold promise for favorably modulating the fibrotic response after MI and after other cardiovascular pathological processes.
Topics: Animals; Biomarkers; Cell Transdifferentiation; Fibroblasts; Humans; Macrophages; Mice, Transgenic; Myocardial Infarction
PubMed: 31856969
DOI: 10.1016/j.jacc.2019.10.036 -
Biochemistry. Biokhimiia Mar 2018Studies of the role of macrophages in phagocytosis are of great theoretical and practical importance for understanding how these cells are involved in the organism's...
Studies of the role of macrophages in phagocytosis are of great theoretical and practical importance for understanding how these cells are involved in the organism's defense response and in the development of various pathologies. Here we investigated phagocytic plasticity of THP-1 (acute monocytic human leukemia) cells at different stages (days 1, 3, and 7) of phorbol ester (PMA)-induced macrophage differentiation. Analysis of cytokine profiles showed that PMA at a concentration of 100 nM induced development of the proinflammatory macrophage population. The functional activity of macrophages was assessed on days 3 and 7 of differentiation using unlabeled latex beads and latex beads conjugated with ligands (gelatin, mannan, and IgG Fc fragment) that bind to the corresponding specific receptors. The general phagocytic activity increased significantly (1.5-2.0-fold) in the course of differentiation; phagocytosis occurred mostly through the Fc receptors, as shown previously for M1 macrophages. On day 7, the levels of phagocytosis of gelatin- and Fc-covered beads were high; however, the intensity of ingestion of mannan-conjugated beads via mannose receptors increased 2.5-3.0-fold as well, which indicated formation of cells with an alternative phenotype similar to that of M2 macrophages. Thus, the type and the plasticity of phagocytic activity at certain stages of macrophage differentiation can be associated with the formation of functionally mature morphological phenotype. This allows macrophages to exhibit their phagocytic potential in response to specific ligands. These data are of fundamental importance and can be used to develop therapeutic methods for correcting the M1/M2 macrophage ratio in an organism.
Topics: Cell Differentiation; Humans; Ligands; Macrophages; Phagocytes; Phagocytosis; Phenotype; THP-1 Cells; Tumor Cells, Cultured
PubMed: 29625541
DOI: 10.1134/S0006297918030021 -
Experimental Cell Research Nov 2017Macrophages are versatile and multifunctional cell types present in most vertebrate tissues. They are the first line of defense against pathogens through phagocytosis of... (Review)
Review
Macrophages are versatile and multifunctional cell types present in most vertebrate tissues. They are the first line of defense against pathogens through phagocytosis of microbial infections, particles and dead cells. Macrophages harbor additional functions besides immune protection by participating in essential homeostatic and tissue development functions. The immune response requires a concomitant and coordinated regulation of the energetic metabolism. In this review, we will discuss how macrophages influence metabolic tissues and in turn how metabolic pathways, particularly glucose and lipid metabolism, affect macrophage phenotypes.
Topics: Animals; Energy Metabolism; Homeostasis; Humans; Macrophages
PubMed: 28341447
DOI: 10.1016/j.yexcr.2017.03.043 -
Seminars in Immunology Oct 2016Macrophages are heterogeneous cells that play a key role in inflammatory and tissue reparative responses. Over the past decade it has become clear that shifts in... (Review)
Review
Macrophages are heterogeneous cells that play a key role in inflammatory and tissue reparative responses. Over the past decade it has become clear that shifts in cellular metabolism are important determinants of macrophage function and phenotype. At the same time, our appreciation of macrophage diversity in vivo has also been increasing. Factors such as cell origin and tissue localization are now recognized as important variables that influence macrophage biology. Whether different macrophage populations also have unique metabolic phenotypes has not been extensively explored. In this article, we will discuss the importance of understanding how macrophage origin can modulate metabolic programming and influence inflammatory responses.
Topics: Animals; Energy Metabolism; Gene Expression Regulation; Humans; Immunomodulation; Macrophage Activation; Macrophages; Metabolic Networks and Pathways; Organ Specificity; Phenotype
PubMed: 27771140
DOI: 10.1016/j.smim.2016.10.004 -
European Journal of Immunology Aug 2021The term 'macrophage' encompasses tissue cells that typically share dependence on the same transcriptional regulatory pathways (e.g. the transcription factor PU.1) and... (Review)
Review
The term 'macrophage' encompasses tissue cells that typically share dependence on the same transcriptional regulatory pathways (e.g. the transcription factor PU.1) and growth factors (e.g. CSF1/IL-34). They share a core set of functions that largely arise from a uniquely high phagocytic capacity manifest in their ability to clear dying cells, pathogens and scavenge damaged, toxic or modified host molecules. However, macrophages demonstrate a remarkable degree of tissue-specific functionality and have diverse origins that vary by tissue site and inflammation status. With our understanding of this diversity has come an appreciation of the longevity and replicative capacity of tissue-resident macrophages and thus the realisation that macrophages may persist through tissue perturbations and inflammatory events with important consequences for cell function. Here, we discuss our current understanding of the parameters that regulate macrophage survival and function, focusing on the relative importance of the tissue environment versus cell-intrinsic factors, such as origin, how long a cell has been resident within a tissue and prior history of activation. Thus, we reconsider the view of macrophages as wholly plastic cells and raise many unanswered questions about the relative importance of cell life-history versus environment in macrophage programming and function.
Topics: Animals; Humans; Macrophages
PubMed: 34107057
DOI: 10.1002/eji.202048881 -
Advances in Experimental Medicine and... 2020Macrophages represent one of the most diverse immunocyte populations, constantly shifting between various phenotypes/functional states. In addition to execution of vital... (Review)
Review
Macrophages represent one of the most diverse immunocyte populations, constantly shifting between various phenotypes/functional states. In addition to execution of vital functions in normal physiological conditions, macrophages represent a key contributing factor in the pathogenesis of some of the most challenging diseases, such as chronic inflammatory disorders, diabetes and its complications, and cancer. Macrophage polarization studies focus primarily on cytokine-mediated mechanisms. However, to explore the full spectrum of macrophage action, additional, non-cytokine pathways responsible for altering macrophage phenotype have to be taken into consideration as well. Heparanase, the only known mammalian endoglycosidase that cleaves heparan sulfate glycosaminoglycans, has been shown to contribute to the altered macrophage phenotypes in vitro and in numerous animal models of inflammatory conditions, occurring either in the presence of microbial products or in the setting of non-infectious "aseptic" inflammation. Here we discuss the involvement of heparanase in shaping macrophage responses and provide information that may help to establish the rationale for heparanase-targeting interventions aimed at preventing abnormal macrophage activation in various disorders.
Topics: Animals; Glucuronidase; Heparitin Sulfate; Humans; Macrophage Activation; Macrophages
PubMed: 32274721
DOI: 10.1007/978-3-030-34521-1_17 -
Journal of Neuroinflammation Mar 2017Dysregulation of the immune system in endometriotic milieus has been considered to play a pivotal role in the pathogenesis of endometriosis. Macrophage recruitment and... (Review)
Review
Dysregulation of the immune system in endometriotic milieus has been considered to play a pivotal role in the pathogenesis of endometriosis. Macrophage recruitment and nerve fiber infiltration are the two major characteristics of this aberrant immune environment. First, the recruitment of macrophages and their polarization phenotype within the endometriotic lesion have been demonstrated to facilitate the development and maintenance of endometriosis. M1 phenotype of macrophages has the capacity to secrete multiple cytokines for inflammatory response, while M2 macrophage possesses an opposite property that can mediate the process of immunosuppression and neuroangiogenesis. Upon secretion of multiple abnormal signal molecules by the endometriotic lesion, macrophages could alter their location and phenotype. These changes facilitate the accommodation of the aberrant microenvironment and the exacerbation of disease progression. Second, the infiltration of nerve fibers and their abnormal distribution are proved to be involved in the generation of endometriosis-associated pain and inflammatory response. An imbalance in sensory and sympathetic innervation and the abnormal secretion of different cytokines could mediate neurogenesis and subsequent peripheral neuroinflammation in endometriosis. Although endometriosis creates an inflammatory milieu promoting macrophage infiltration and an imbalanced innervation, interaction between macrophages and nerve fibers in this process remains unknown. The aim of this review is to highlight the role of macrophage and nerve interaction in endometriosis, where macrophage recruitment and neurogenesis can be the underlying mechanism of neuroinflammation and pathogenesis of endometriosis.
Topics: Animals; Endometriosis; Female; Humans; Macrophages; Nerve Fibers
PubMed: 28288663
DOI: 10.1186/s12974-017-0828-3