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Macrophages in Health and Non-infectious Disease
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Macrophages in Health and Non-infectious Disease

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 70145

Special Issue Editors

Dr. Alexei Gratchev

E-Mail Website
Guest Editor
N.N. Blokhin Cancer Research Center, Institute of Carcinogenesis, 115478 Moscow, Russia
Interests: macrophages; regulation of homeostasis; tumor associated macrophages; chronic inflammation; macrophage plasticity; macrophage molecular markers
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Alexander N. Orekhov

E-Mail Website
Guest Editor
1. Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, 125315 Moscow, Russia
2. Laboratory of Infection Pathology and Molecular Microecology, Institute of Human Morphology, 3 Tsyurupa Street, 117418 Moscow, Russia
Interests: atherosclerosis; mitophagy; atherogenicity; autoantibodies; inflammation; innate immunity; cell test; macrophage; membrane transport; modified low density lipoprotein; monocyte; transcriptome; trans-sialydase; enzymatic test; cytokine; epigenetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Having first been described more than 100 years ago, macrophages are still the focus of biomedical research. For about 50 decades, they were considered solely as part of the defense against pathogens intruding an organism; however, unravelling the mechanisms of inflammatory reaction regulation made it clear that macrophages not only possess effector function but also act as important regulators of inflammation. A new boost was given to macrophage research in the last decade of the 20th century with the essential study made in the lab of Siamon Gordon, which demonstrated alternative macrophage activation. This was a literal milestone in understanding macrophage function. Since that publication, a variety of macrophage markers and functional peculiarities have been described, and it has become clear that in a healthy organism, macrophages are the ones that actively contribute to homeostasis and regulate processes of tolerance. Apart from infectious diseases, it has been demonstrated that macrophages are actively involved in the pathogenesis of socially important non-infectious diseases, such as atherosclerosis, cancer, and diabetes. These findings have expectedly led to identification of macrophages as potential and highly attractive therapeutic targets. In this Special Issue, we want to collect the most recent publications on the mechanisms that macrophages use to regulate homeostasis and their involvement in pathogenesis of non-infectious diseases. We also welcome research describing novel macrophage markers that reflect their functional state or are involved in macrophage tolerance and training.

Dr. Alexei Gratchev
Guest Editor

Manuscript Submission Information

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Keywords

  • homeostasis
  • macrophage training and tolerance
  • tumor-associated macrophages
  • chronic inflammation
  • non-infectious diseases

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Published Papers (20 papers)

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Editorial

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5 pages, 523 KiB  
Editorial
Macrophages in Health and Non-Infectious Disease
by Evgeny E. Bezsonov, Alexei Gratchev and Alexander N. Orekhov
Biomedicines 2021, 9(5), 460; https://doi.org/10.3390/biomedicines9050460 - 23 Apr 2021
Cited by 4 | Viewed by 1920
Abstract
In this Special Issue of Biomedicines, we have many insightful reviews and research papers on the subject “Macrophages in Health and Non-infectious Disease”, but first; we should discuss briefly the current situation in the field [...] Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease)
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Research

Jump to: Editorial, Review

20 pages, 3666 KiB  
Article
Absence of Cold-Inducible RNA-Binding Protein (CIRP) Promotes Angiogenesis and Regeneration of Ischemic Tissue by Inducing M2-Like Macrophage Polarization
by Matthias Kübler, Sebastian Beck, Silvia Fischer, Philipp Götz, Konda Kumaraswami, Hellen Ishikawa-Ankerhold, Manuel Lasch and Elisabeth Deindl
Biomedicines 2021, 9(4), 395; https://doi.org/10.3390/biomedicines9040395 - 07 Apr 2021
Cited by 13 | Viewed by 4217
Abstract
Cold-inducible RNA-binding protein (CIRP) is an intracellular RNA-chaperone and extracellular promoter of inflammation, which is increasingly expressed and released under conditions of hypoxia and cold stress. The functional relevance of CIRP for angiogenesis and regeneration of ischemic muscle tissue has never been investigated [...] Read more.
Cold-inducible RNA-binding protein (CIRP) is an intracellular RNA-chaperone and extracellular promoter of inflammation, which is increasingly expressed and released under conditions of hypoxia and cold stress. The functional relevance of CIRP for angiogenesis and regeneration of ischemic muscle tissue has never been investigated and is the topic of the present study. We investigated the role of CIRP employing CIRP deficient mice along with a hindlimb model of ischemia-induced angiogenesis. 1 and 7 days after femoral artery ligation or sham operation, gastrocnemius muscles of CIRP-deficient and wildtype mice were isolated and processed for (immuno-) histological analyses. CIRP deficient mice showed decreased ischemic tissue damage as evidenced by Hematoxylin and Eosin staining, whereas angiogenesis was enhanced as demonstrated by increased capillary/muscle fiber ratio and number of proliferating endothelial (CD31+/BrdU+) cells on day 7 after surgery. Moreover, CIRP deficiency resulted in a reduction of total leukocyte count (CD45+), neutrophils (myeloperoxidase, MPO+), neutrophil extracellular traps (NETs) (MPO+/CitH3+), and inflammatory M1-like polarized macrophages (CD68+/MRC1-), whereas the number of tissue regenerating M2-like polarized macrophages (CD68+/MRC1-) was increased in ischemic tissue samples. In summary, we show that the absence of CIRP ameliorates angiogenesis and regeneration of ischemic muscle tissue, most likely by influencing macrophage polarization in direction to regenerative M2-like macrophages. Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease)
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13 pages, 2436 KiB  
Article
Statins Directly Influence the Polarization of Adipose Tissue Macrophages: A Role in Chronic Inflammation
by Sona Kauerova, Hana Bartuskova, Barbora Muffova, Libor Janousek, Jiri Fronek, Marek Petras, Rudolf Poledne and Ivana Kralova Lesna
Biomedicines 2021, 9(2), 211; https://doi.org/10.3390/biomedicines9020211 - 19 Feb 2021
Cited by 8 | Viewed by 2672
Abstract
Statins represent one of the most widely used classes of drugs in current medicine. In addition to a substantial decrease in atherogenic low density lipoprotein (LDL) particle concentrations, several large trials have documented their potent anti-inflammatory activity. Based on our preliminary data, we [...] Read more.
Statins represent one of the most widely used classes of drugs in current medicine. In addition to a substantial decrease in atherogenic low density lipoprotein (LDL) particle concentrations, several large trials have documented their potent anti-inflammatory activity. Based on our preliminary data, we showed that statins are able to decrease the proportion of pro-inflammatory macrophages (CD14+16+CD36high) in visceral adipose tissue in humans. In the present study including 118 healthy individuals (living kidney donors), a very close relationship between the pro-inflammatory macrophage proportion and LDL cholesterol levels was found. This was confirmed after adjustment for the most important risk factors. The effect of statins on the proportion of pro-inflammatory macrophages was also confirmed in an experimental model of the Prague hereditary hypercholesterolemia rat. A direct anti-inflammatory effect of fluvastatin on human macrophage polarization in vitro was documented. Based on modifying the LDL cholesterol concentrations, statins are suggested to decrease the cholesterol inflow through the lipid raft of macrophages in adipose tissue and hypercholesterolemia to enhance the pro-inflammatory macrophage phenotype polarization. On the contrary, due to their opposite effect, statins respond with anti-inflammatory activity, affecting the whole organism. Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease)
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13 pages, 2582 KiB  
Article
Expression of Estrogen Receptor α by Decidual Macrophages in Preeclampsia
by Polina Vishnyakova, Anastasiya Poltavets, Maria Nikitina, Konstantin Midiber, Liudmila Mikhaleva, Kamilla Muminova, Alena Potapova, Zulfiya Khodzhaeva, Alexey Pyregov, Andrey Elchaninov, Timur Fatkhudinov and Gennady Sukhikh
Biomedicines 2021, 9(2), 191; https://doi.org/10.3390/biomedicines9020191 - 14 Feb 2021
Cited by 7 | Viewed by 2376
Abstract
Preeclampsia is a gestation-associated hypertensive syndrome that threatens the life and health of the mother and the child. The condition is presumably caused by systemic failure with a strong involvement of innate immunity. In particular, it has been associated with flexible phenotypes of [...] Read more.
Preeclampsia is a gestation-associated hypertensive syndrome that threatens the life and health of the mother and the child. The condition is presumably caused by systemic failure with a strong involvement of innate immunity. In particular, it has been associated with flexible phenotypes of macrophages, which depend on the molecules circulating in the blood and tissue fluid, such as cytokines and hormones. This study aimed at a comparative evaluation of pro-inflammatory (TNFα) and anti-inflammatory (CD206, MMP9, HGF) markers, as well as the levels of estrogen receptor α, expressed by decidual macrophages in normal pregnancy and in patients with early- and late-onset preeclampsia. The tissue samples of decidua basalis were examined by immunohistochemistry and Western blotting. Isolation of decidual macrophages and their characterization were performed using cultural methods, flow cytometry and real-time PCR. Over 50% of the isolated decidual macrophages were positive for the pan-macrophage marker CD68. In the early-onset preeclampsia group, the levels of estrogen receptor α in decidua were significantly decreased. Furthermore, significantly decreased levels of HGF and CD206 were observed in both preeclampsia groups compared with the control group. The observed downregulation of estrogen receptor α, HGF and CD206 may contribute to the balance of pro- and anti-inflammatory macrophages and thereby to pathogenesis of preeclampsia. Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease)
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11 pages, 1315 KiB  
Article
Netrin-1 in Atherosclerosis: Relationship between Human Macrophage Intracellular Levels and In Vivo Plaque Morphology
by Susanna Fiorelli, Nicola Cosentino, Benedetta Porro, Franco Fabbiocchi, Giampaolo Niccoli, Francesco Fracassi, Nicolò Capra, Simone Barbieri, Filippo Crea, Giancarlo Marenzi, Viviana Cavalca, Elena Tremoli and Sonia Eligini
Biomedicines 2021, 9(2), 168; https://doi.org/10.3390/biomedicines9020168 - 08 Feb 2021
Cited by 8 | Viewed by 1904
Abstract
Netrin-1 is a laminin-like protein that plays a pivotal role in cell migration and, according to the site of its release, exerts both pro and anti-atherosclerotic functions. Macrophages, key cells in atherosclerosis, are heterogeneous in morphology and function and different subpopulations may support [...] Read more.
Netrin-1 is a laminin-like protein that plays a pivotal role in cell migration and, according to the site of its release, exerts both pro and anti-atherosclerotic functions. Macrophages, key cells in atherosclerosis, are heterogeneous in morphology and function and different subpopulations may support plaque progression, stabilization, and/or regression. Netrin-1 was evaluated in plasma and, together with its receptor UNC5b, in both spindle and round monocyte-derived macrophages (MDMs) morphotypes from coronary artery disease (CAD) patients and control subjects. In CAD patients, plaque features were detected in vivo by optical coherence tomography. CAD patients had lower plasma Netrin-1 levels and a higher MDMs expression of both protein and its receptor compared to controls. Specifically, a progressive increase in Netrin-1 and UNC5b was evidenced going from controls to stable angina (SA) and acute myocardial infarction (AMI) patients. Of note, spindle MDMs of AMI showed a marked increase of both Netrin-1 and its receptor compared to spindle MDMs of controls. UNC5b expression is always higher in spindle compared to round MDMs, regardless of the subgroup. Finally, CAD patients with higher intracellular Netrin-1 levels showed greater intraplaque macrophage accumulation in vivo. Our findings support the role of Netrin-1 and UNC5b in the atherosclerotic process. Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease)
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13 pages, 1689 KiB  
Article
M2 Monocyte Polarization in Dialyzed Patients Is Associated with Increased Levels of M-CSF and Myeloperoxidase-Associated Oxidative Stress: Preliminary Results
by Valérie Pireaux, Cédric Delporte, Alexandre Rousseau, Jean-Marc Desmet, Pierre Van Antwerpen, Martine Raes and Karim Zouaoui Boudjeltia
Biomedicines 2021, 9(1), 84; https://doi.org/10.3390/biomedicines9010084 - 16 Jan 2021
Cited by 5 | Viewed by 2024
Abstract
Cardiovascular diseases represent a major issue in terms of morbidity and mortality for dialysis patients. This morbidity is due to the accelerated atherosclerosis observed in these patients. Atherosclerosis is a chronic inflammatory disease characterized by key players such as monocytes, macrophages, or oxidized [...] Read more.
Cardiovascular diseases represent a major issue in terms of morbidity and mortality for dialysis patients. This morbidity is due to the accelerated atherosclerosis observed in these patients. Atherosclerosis is a chronic inflammatory disease characterized by key players such as monocytes, macrophages, or oxidized LDLs. Monocytes-macrophages are classified into subsets of polarized cells, with M1 and M2 macrophages considered, respectively, as pro- and anti-inflammatory. (1) Methods: The monocyte subsets and phenotypes were analyzed by flow cytometry. These data were completed by the quantification of plasma M-CSF, IL-8, CRP, Mox-LDLs, Apo-B, Apo-AI, chloro-tyrosine, and homocitrulline concentrations. The statistical differences and associations between two continuous variables were assessed using the Mann–Whitney U test and Spearman’s correlation coefficient, respectively. (2) Results: Hemodialyzed patients showed a significant increase in their concentrations of CRP, M-CSF, and IL-8 (inflammation biomarkers), as well as chloro-tyrosine and homocitrulline (myeloperoxidase-associated oxidative stress biomarkers). Moreover, we observed a higher percentage of M2 monocytes in the plasma of hemodialysis patients as compared to the controls. (3) Conclusions: Our data suggest that oxidative stress and an inflammatory environment, which is amplified in hemodialysis patients, seems to favor an increase in the concentration of circulating M-CSF, therefore leading to an increase in M2 polarization among circulating monocytes. Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease)
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18 pages, 3373 KiB  
Article
Comparative Analysis of the Transcriptome, Proteome, and miRNA Profile of Kupffer Cells and Monocytes
by Andrey Elchaninov, Anastasia Lokhonina, Maria Nikitina, Polina Vishnyakova, Andrey Makarov, Irina Arutyunyan, Anastasiya Poltavets, Evgenia Kananykhina, Sergey Kovalchuk, Evgeny Karpulevich, Galina Bolshakova, Gennady Sukhikh and Timur Fatkhudinov
Biomedicines 2020, 8(12), 627; https://doi.org/10.3390/biomedicines8120627 - 18 Dec 2020
Cited by 10 | Viewed by 3550
Abstract
Macrophage populations in most mammalian organs consist of cells of different origin. Resident macrophages originate from erythromyeloid precursors of the yolk sac wall; maintenance of the numbers of such macrophages in postnatal ontogenesis is practically independent of bone marrow haematopoiesis. The largest populations [...] Read more.
Macrophage populations in most mammalian organs consist of cells of different origin. Resident macrophages originate from erythromyeloid precursors of the yolk sac wall; maintenance of the numbers of such macrophages in postnatal ontogenesis is practically independent of bone marrow haematopoiesis. The largest populations of the resident macrophages of embryonic origin are found in the central nervous system (microglia) and liver (Kupffer cells). In contrast, skin dermis and mucous membranes become predominantly colonized by bone marrow-derived monocytes that show pronounced functional and phenotypic plasticity. In the present study, we compared Kupffer cells and monocytes using the immunophenotype, gene expression profile, proteome, and pool of microRNA. The observed differences did not consider the resident liver macrophages as purely M2 macrophages or state that monocytes have purely M1 features. Monocytes show signs of high plasticity and sensitivity to pathogen-associated molecular patterns (e.g., high levels of transcription for Tlr 2, 4, 7, and 8). In contrast, the resident liver macrophages were clearly involved in the regulation of specific organ functions (nitrogen metabolism, complement system protein synthesis). Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease)
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12 pages, 1966 KiB  
Article
Influence of Obesity and Exercise on β2-Adrenergic-Mediated Anti-Inflammatory Effects in Peritoneal Murine Macrophages
by Leticia Martín-Cordero, Isabel Gálvez, María Dolores Hinchado and Eduardo Ortega
Biomedicines 2020, 8(12), 556; https://doi.org/10.3390/biomedicines8120556 - 30 Nov 2020
Cited by 6 | Viewed by 1800
Abstract
Obesity is a chronic low-grade inflammatory condition, and β2-adrenergic agonists as well as exercise have been proposed as anti-inflammatory strategies in obesity, so it is critical to accurately determine the effects of β2-adrenergic stimulation, especially when combined with other non-pharmacological therapies. The aim [...] Read more.
Obesity is a chronic low-grade inflammatory condition, and β2-adrenergic agonists as well as exercise have been proposed as anti-inflammatory strategies in obesity, so it is critical to accurately determine the effects of β2-adrenergic stimulation, especially when combined with other non-pharmacological therapies. The aim of this investigation was to determine the effect of β2-adrenergic activation on the inflammatory profile and phenotype of macrophages, and whether these effects could be affected by obesity and exercise in this condition. High-fat diet-induced obese and lean C57BL/6J mice were allocated to sedentary or exercised groups. The inflammatory profiles and phenotypes of their peritoneal macrophages were assessed by flow cytometry in the presence or absence of the selective β2-adrenergic receptor agonist terbutaline. β2-adrenergic activation caused global phenotypic anti-inflammatory effects in lean and obese sedentary mice, which were more drastic (also including anti-inflammatory effects on the cytokine profile) in obese animals. In exercised lean and obese animals, this anti-inflammatory effect is weaker and only evident by decreased iNOS and IL-8 expression, without changes in the anti-inflammatory markers. Therefore, β2-adrenergic activation leads to anti-inflammatory effects, but these effects are modulated by obesity in sedentary conditions, as well as by regular exercise; but not by obesity in trained conditions. Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease)
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12 pages, 2948 KiB  
Article
CRP Is Transported by Monocytes and Monocyte-Derived Exosomes in the Blood of Patients with Coronary Artery Disease
by Ivan Melnikov, Sergey Kozlov, Olga Saburova, Ekaterina Zubkova, Olga Guseva, Sergey Domogatsky, Tatiana Arefieva, Natalia Radyukhina, Maria Zvereva, Yuliya Avtaeva, Lyudmila Buryachkovskaya and Zufar Gabbasov
Biomedicines 2020, 8(10), 435; https://doi.org/10.3390/biomedicines8100435 - 19 Oct 2020
Cited by 14 | Viewed by 2747
Abstract
The objective of this work was to study the ability of blood cells and their microparticles to transport monomeric and pentameric forms of C-reactive protein (mCRP and pCRP) in the blood of patients with coronary artery disease (CAD). Blood was obtained from 14 [...] Read more.
The objective of this work was to study the ability of blood cells and their microparticles to transport monomeric and pentameric forms of C-reactive protein (mCRP and pCRP) in the blood of patients with coronary artery disease (CAD). Blood was obtained from 14 patients with CAD 46 ± 13 years old and 8 healthy volunteers 49 ± 13.6 years old. Blood cells and microparticles with mCRP and pCRP on their surface were detected by flow cytometry. Messenger RNA (mRNA) of CRP was extracted from peripheral blood monocytes stimulated with lipopolysaccharide (LPS) and granulocyte-macrophage colony-stimulating factor (GM-CSF). mRNA of CRP in monocytes was detected with PCR. Monocytes were predominantly pCRP-positive (92.9 ± 6.8%). mCRP was present on 22.0 ± 9.6% of monocyte-derived exosomes. mCRP-positive leukocyte-derived microparticle counts were significantly higher (8764 ± 2876/µL) in the blood of patients with CAD than in healthy volunteers (1472 ± 307/µL). LPS and GM-CSF stimulated monocytes expressed CRP mRNA transcripts levels (0.79 ± 0.73-fold), slightly lower relative to unstimulated hepatocytes of the HepG2 cell line (1.0 ± 0.6-fold), but still detectable. The ability of monocytes to transport pCRP in blood flow, and monocyte-derived exosomes to transmit mCRP, may contribute to the maintenance of chronic inflammation in CAD. Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease)
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16 pages, 3708 KiB  
Article
Stearic Acid and TNF-α Co-Operatively Potentiate MIP-1α Production in Monocytic Cells via MyD88 Independent TLR4/TBK/IRF3 Signaling Pathway
by Shihab Kochumon, Hossein Arefanian, Rafaat Azim, Steve Shenouda, Texy Jacob, Nermeen Abu Khalaf, Fatema Al-Rashed, Amal Hasan, Sardar Sindhu, Fahd Al-Mulla and Rasheed Ahmad
Biomedicines 2020, 8(10), 403; https://doi.org/10.3390/biomedicines8100403 - 09 Oct 2020
Cited by 16 | Viewed by 3409
Abstract
Increased circulatory and adipose tissue expression of macrophage inflammatory protein (MIP)-1α (CC motif chemokine ligand-3/CCL3) and its association with inflammation in the state of obesity is well documented. Since obesity is associated with increases in both stearic acid and tumor necrosis factor α [...] Read more.
Increased circulatory and adipose tissue expression of macrophage inflammatory protein (MIP)-1α (CC motif chemokine ligand-3/CCL3) and its association with inflammation in the state of obesity is well documented. Since obesity is associated with increases in both stearic acid and tumor necrosis factor α (TNF-α) in circulation, we investigated whether stearic acid and TNF-α together could regulate MIP-1α/CCL3 expression in human monocytic cells, and if so, which signaling pathways were involved in MIP-1α/CCL3 modulation. Monocytic cells were treated with stearic acid and TNF-α resulted in enhanced production of MIP-1α/CCL3 compared to stearic acid or TNF-α alone. To explore the underlying mechanisms, cooperative effect of stearic acid for MIP-α/CCL3 expression was reduced by TLR4 blocking, and unexpectedly we found that the synergistic production of MIP-α/CCL3 in MyD88 knockout (KO) cells was not suppressed. In contrast, this MIP-α/CCL3 expression was attenuated by inhibiting TBK1/IRF3 activity. Cells deficient in IRF3 did not show cooperative effect of stearate/TNF-α on MIP-1α/CCL3 production. Furthermore, activation of IRF3 by polyinosinic-polycytidylic acid (poly I:C) produced a cooperative effect with TNF-α for MIP-1α/CCL3 production that was comparable to stearic acid. Individuals with obesity show high IRF3 expression in monocytes as compared to lean individuals. Furthermore, elevated levels of MIP-1α/CCL3 positively correlate with TNF-α and CD163 in fat tissues from individuals with obesity. Taken together, this study provides a novel model for the pathologic role of stearic acid to produce MIP-1α/CCL3 in the presence of TNF-α associated with obesity settings. Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease)
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16 pages, 1661 KiB  
Article
Abundance of Non-Polarized Lung Macrophages with Poor Phagocytic Function in Chronic Obstructive Pulmonary Disease (COPD)
by Kentaro Akata, Kei Yamasaki, Fernando Sergio Leitao Filho, Chen Xi Yang, Hiroto Takiguchi, Basak Sahin, Beth A. Whalen, Cheng Wei Tony Yang, Janice M. Leung, Don D. Sin and Stephan F. van Eeden
Biomedicines 2020, 8(10), 398; https://doi.org/10.3390/biomedicines8100398 - 08 Oct 2020
Cited by 13 | Viewed by 3014
Abstract
Lung macrophages are the key immune effector cells in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Several studies have shown an increase in their numbers in bronchoalveolar lavage fluid (BAL) of subjects with COPD compared to controls, suggesting a pathogenic role in [...] Read more.
Lung macrophages are the key immune effector cells in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Several studies have shown an increase in their numbers in bronchoalveolar lavage fluid (BAL) of subjects with COPD compared to controls, suggesting a pathogenic role in disease initiation and progression. Although reduced lung macrophage phagocytic ability has been previously shown in COPD, the relationship between lung macrophages’ phenotypic characteristics and functional properties in COPD is still unclear. (1) Methods: Macrophages harvested from bronchoalveolar lavage (BAL) fluid of subjects with and without COPD (GOLD grades, I–III) were immuno-phenotyped, and their function and gene expression profiles were assessed using targeted assays. (2) Results: BAL macrophages from 18 COPD and 10 (non-COPD) control subjects were evaluated. The majority of macrophages from COPD subjects were non-polarized (negative for both M1 and M2 markers; 77.9%) in contrast to controls (23.9%; p < 0.001). The percentages of these non-polarized macrophages strongly correlated with the severity of COPD (p = 0.006) and current smoking status (p = 0.008). Non-polarized macrophages demonstrated poor phagocytic function in both the control (p = 0.02) and COPD (p < 0.001) subjects. Non-polarized macrophages demonstrated impaired ability to phagocytose Staphylococcus aureus (p < 0.001). They also demonstrated reduced gene expression for CD163, CD40, CCL13 and C1QA&B, which are involved in pathogen recognition and processing and showed an increased gene expression for CXCR4, RAF1, amphiregulin and MAP3K5, which are all involved in promoting the inflammatory response. (3) Conclusions: COPD is associated with an abundance of non-polarized airway macrophages that is related to the severity of COPD. These non-polarized macrophages are predominantly responsible for the poor phagocytic capacity of lung macrophages in COPD, having reduced capacity for pathogen recognition and processing. This could be a key risk factor for COPD exacerbation and could contribute to disease progression. Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease)
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14 pages, 2690 KiB  
Article
Macrophage Stimulated by Low Ambient Temperature Hasten Tumor Growth via Glutamine Production
by Eun-Ji Lee, Tae-Wook Chung, Keuk-Jun Kim, Boram Bae, Bo-Sung Kim, Suhkmann Kim, Dongryeol Ryu, Sung-Jin Bae and Ki-Tae Ha
Biomedicines 2020, 8(10), 381; https://doi.org/10.3390/biomedicines8100381 - 26 Sep 2020
Cited by 4 | Viewed by 2484
Abstract
Ambient temperature can regulate the immune response and affect tumor growth. Although thermoneutral caging reduces tumor growth via immune activation, little attention has been paid to the tumorigenic effect of low temperature. In the present study, tumor growth was higher at low ambient [...] Read more.
Ambient temperature can regulate the immune response and affect tumor growth. Although thermoneutral caging reduces tumor growth via immune activation, little attention has been paid to the tumorigenic effect of low temperature. In the present study, tumor growth was higher at low ambient temperature (4 °C for 8 h/d) than at the standard housing temperature (22 °C) in allograft models. Low temperature-stimulated tumor growth in mice was reduced by monocyte depletion using clodronate liposomes. Proliferation was considerably greater in cancer cells treated with 33 °C-cultured RAW264.7 cell-conditioned media (33CM) than in cells treated with 37 °C-cultured RAW264.7 cell-conditioned media (37CM). Additionally, glutamine levels were markedly higher in 33CM-treated cells than in 37CM-treated cells. We further confirmed that the addition of glutamine into 37CM enhanced its effects on cancer cell proliferation and glutamine uptake inhibition ameliorated the accelerated proliferation induced by 33CM. Consistently, the inhibition of glutamine uptake in the allograft model exposed to low temperature, effectively reduced tumor volume and weight. Collectively, these data suggest that the secretion and utilization of glutamine by macrophages and cancer cells, respectively, are key regulators of low temperature-enhanced cancer progression in the tumor microenvironment. Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease)
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17 pages, 3710 KiB  
Article
Lung Microbiome Differentially Impacts Survival of Patients with Non-Small Cell Lung Cancer Depending on Tumor Stroma Phenotype
by Olga Kovaleva, Polina Podlesnaya, Madina Rashidova, Daria Samoilova, Anatoly Petrenko, Irina Zborovskaya, Valeria Mochalnikova, Vladimir Kataev, Yuri Khlopko, Andrey Plotnikov and Alexei Gratchev
Biomedicines 2020, 8(9), 349; https://doi.org/10.3390/biomedicines8090349 - 13 Sep 2020
Cited by 27 | Viewed by 4058
Abstract
The link between a lung tumor and the lung microbiome is a largely unexplored issue. To investigate the relationship between a lung microbiome and the phenotype of an inflammatory stromal infiltrate, we studied a cohort of 89 patients with non-small cell lung cancer. [...] Read more.
The link between a lung tumor and the lung microbiome is a largely unexplored issue. To investigate the relationship between a lung microbiome and the phenotype of an inflammatory stromal infiltrate, we studied a cohort of 89 patients with non-small cell lung cancer. The microbiome was analyzed in tumor and adjacent normal tissue by 16S rRNA amplicon sequencing. Characterization of the tumor stroma was done using immunohistochemistry. We demonstrated that the bacterial load was higher in adjacent normal tissue than in a tumor (p = 0.0325) with similar patterns of taxonomic structure and alpha diversity. Lung adenocarcinomas did not differ in their alpha diversity from squamous cell carcinomas, although the content of Gram-positive bacteria increased significantly in the adenocarcinoma group (p = 0.0419). An analysis of an inflammatory infiltrate of tumor stroma showed a correlation of CD68, iNOS and FOXP3 with a histological type of tumor. For the first time we showed that high bacterial load in the tumor combined with increased iNOS expression is a favorable prognostic factor (HR = 0.1824; p = 0.0123), while high bacterial load combined with the increased number of FOXP3+ cells is a marker of poor prognosis (HR = 4.651; p = 0.0116). Thus, we established that bacterial load of the tumor has an opposite prognostic value depending on the status of local antitumor immunity. Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease)
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10 pages, 1029 KiB  
Article
Low-Grade Inflammation Is Not Present in Former Obese Males but Adipose Tissue Macrophage Infiltration Persists
by Ignacio Ara, Pernille Auerbach, Steen Larsen, Esmeralda Mata, Bente Stallknecht, Thorkil Ploug, Clara Prats and Jørn W. Helge
Biomedicines 2020, 8(5), 123; https://doi.org/10.3390/biomedicines8050123 - 14 May 2020
Cited by 11 | Viewed by 3944
Abstract
Macrophage infiltration in two subcutaneous adipose tissue depots and systemic low-grade inflammation were studied in post-obese (PO), obese (O), and control (C) subjects. Young males were recruited into PO: (n = 10, weight-loss avg. 26%, BMI: 26.6 ± 0.7, mean ±SEM kg/m [...] Read more.
Macrophage infiltration in two subcutaneous adipose tissue depots and systemic low-grade inflammation were studied in post-obese (PO), obese (O), and control (C) subjects. Young males were recruited into PO: (n = 10, weight-loss avg. 26%, BMI: 26.6 ± 0.7, mean ±SEM kg/m2), O: (n = 10, BMI: 33.8 ± 1.0kg/m2) and C: (n = 10, BMI: 26.6 ± 0.6 kg/m2). PO and C were matched by BMI. Blood and abdominal and gluteal subcutaneous adipose tissue were obtained in the overnight fasted state. Plasma concentrations of IL-6 and CRP were higher (p < 0.05) in O than in PO and C, TNF-α was higher (p < 0.05) only in O compared to PO and IL-18 was similar between groups. The number of CD68+ macrophages was higher (p < 0.05) in the gluteal than the abdominal depot, and higher (p < 0.05) in O and PO compared to C in both depots. The content of CD163+ macrophages was similar between depots but was higher (p < 0.05) in PO compared to C and O in the gluteal depot. In post obese men with a long-term sustained weight loss, systemic low-grade inflammation was similar to non-obese controls despite a higher subcutaneous adipose tissue CD68+ macrophage content. Interestingly, the anti-inflammatory CD163+ macrophage adipose tissue content was consistently higher in post obese than obese and controls. Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease)
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Review

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17 pages, 1150 KiB  
Review
Deciphering the Role of Heme Oxygenase-1 (HO-1) Expressing Macrophages in Renal Ischemia-Reperfusion Injury
by Maxime Rossi, Kéziah Korpak, Arnaud Doerfler and Karim Zouaoui Boudjeltia
Biomedicines 2021, 9(3), 306; https://doi.org/10.3390/biomedicines9030306 - 16 Mar 2021
Cited by 11 | Viewed by 2984
Abstract
Ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI), which contributes to the development of chronic kidney disease (CKD). Renal IRI combines major events, including a strong inflammatory immune response leading to extensive cell injuries, necrosis and late interstitial fibrosis. [...] Read more.
Ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI), which contributes to the development of chronic kidney disease (CKD). Renal IRI combines major events, including a strong inflammatory immune response leading to extensive cell injuries, necrosis and late interstitial fibrosis. Macrophages act as key players in IRI-induced AKI by polarizing into proinflammatory M1 and anti-inflammatory M2 phenotypes. Compelling evidence exists that the stress-responsive enzyme, heme oxygenase-1 (HO-1), mediates protection against renal IRI and modulates macrophage polarization by enhancing a M2 subset. Hereafter, we review the dual effect of macrophages in the pathogenesis of IRI-induced AKI and discuss the critical role of HO-1 expressing macrophages. Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease)
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17 pages, 773 KiB  
Review
Macrophage Polarization in Chronic Lymphocytic Leukemia: Nurse-Like Cells Are the Caretakers of Leukemic Cells
by Oana Mesaros, Laura Jimbu, Alexandra Neaga, Cristian Popescu, Iulia Berceanu, Ciprian Tomuleasa, Bogdan Fetica and Mihnea Zdrenghea
Biomedicines 2020, 8(11), 516; https://doi.org/10.3390/biomedicines8110516 - 19 Nov 2020
Cited by 13 | Viewed by 3217
Abstract
Macrophages are terminally differentiated innate immune cells. Through their activation, they can be polarized towards the pro-inflammatory M1 type or the wound healing-associated, anti-inflammatory M2 type macrophages. In the tumor microenvironment (TME), M2 is the dominant phenotype and these cells are referred to [...] Read more.
Macrophages are terminally differentiated innate immune cells. Through their activation, they can be polarized towards the pro-inflammatory M1 type or the wound healing-associated, anti-inflammatory M2 type macrophages. In the tumor microenvironment (TME), M2 is the dominant phenotype and these cells are referred to as tumor-associated macrophages (TAMs). TAMs secrete cytokines and chemokines, exerting an antiapoptotic, proliferative and pro-metastatic effect on the tumor cells. TAMs can be found in many cancers, including chronic lymphocytic leukemia (CLL), where they are called nurse-like cells (NLCs). Despite the generally indolent behavior of CLL, the proportion of treatment-refractory patients is significant. As with the majority of cancers, despite significant recent progress, CLL pathogenesis is poorly understood. The emerging role of the TME in nurturing the neoplastic process warrants the investigation of macrophages as a significant pathogenetic element of tumors. In this paper, we review the current knowledge on the role of stromal macrophages in CLL. Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease)
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23 pages, 5811 KiB  
Review
Interplay between Endoplasmic Reticulum Stress and Large Extracellular Vesicles (Microparticles) in Endothelial Cell Dysfunction
by Aisha Osman, Tarek Benameur, Hesham M. Korashy, Asad Zeidan and Abdelali Agouni
Biomedicines 2020, 8(10), 409; https://doi.org/10.3390/biomedicines8100409 - 12 Oct 2020
Cited by 12 | Viewed by 2945
Abstract
Upon increased demand for protein synthesis, accumulation of misfolded and/or unfolded proteins within the endoplasmic reticulum (ER), a pro-survival response is activated termed unfolded protein response (UPR), aiming at restoring the proper function of the ER. Prolonged activation of the UPR leads, however, [...] Read more.
Upon increased demand for protein synthesis, accumulation of misfolded and/or unfolded proteins within the endoplasmic reticulum (ER), a pro-survival response is activated termed unfolded protein response (UPR), aiming at restoring the proper function of the ER. Prolonged activation of the UPR leads, however, to ER stress, a cellular state that contributes to the pathogenesis of various chronic diseases including obesity and diabetes. ER stress response by itself can result in endothelial dysfunction, a hallmark of cardiovascular disease, through various cellular mechanisms including apoptosis, insulin resistance, inflammation and oxidative stress. Extracellular vesicles (EVs), particularly large EVs (lEVs) commonly referred to as microparticles (MPs), are membrane vesicles. They are considered as a fingerprint of their originating cells, carrying a variety of molecular components of their parent cells. lEVs are emerging as major contributors to endothelial cell dysfunction in various metabolic disease conditions. However, the mechanisms underpinning the role of lEVs in endothelial dysfunction are not fully elucidated. Recently, ER stress emerged as a bridging molecular link between lEVs and endothelial cell dysfunction. Therefore, in the current review, we summarized the roles of lEVs and ER stress in endothelial dysfunction and discussed the molecular crosstalk and relationship between ER stress and lEVs in endothelial dysfunction. Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease)
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23 pages, 1955 KiB  
Review
Tissue-Specific Role of Macrophages in Noninfectious Inflammatory Disorders
by Daria Skuratovskaia, Maria Vulf, Olga Khaziakhmatova, Vladimir Malashchenko, Aleksandra Komar, Egor Shunkin, Valeriya Shupletsova, Andrei Goncharov, Olga Urazova and Larisa Litvinova
Biomedicines 2020, 8(10), 400; https://doi.org/10.3390/biomedicines8100400 - 09 Oct 2020
Cited by 20 | Viewed by 4406
Abstract
Chronic inflammation may not begin with local tissue disorders, such as hypoxia, but with the accumulation of critically activated macrophages in one site. The purpose of this review is to analyze the data reported in the scientific literature on the features of the [...] Read more.
Chronic inflammation may not begin with local tissue disorders, such as hypoxia, but with the accumulation of critically activated macrophages in one site. The purpose of this review is to analyze the data reported in the scientific literature on the features of the functions of macrophages and their contributions to the development of pathology in various tissues during aseptic inflammation in obese subjects. In individuals with obesity, increased migration of monocytes from the peripheral blood to various tissues, the proliferation of resident macrophages and a change in the balance between alternatively activated anti-inflammatory macrophages (M2) and pro-inflammatory classically activated macrophages (M1) towards the latter have been observed. The primary cause of some metabolic pathologies has been precisely identified as the recruitment of macrophages with an altered phenotype, which is probably typical for many other pathologies. Recent studies have identified phenotypes, such as metabolically activated M (MMe), oxidized (Mox), hemoglobin-related macrophages (Mhem and MHb), M4 and neuroimmunological macrophages (NAM, SAM), which directly and indirectly affect energy metabolism. The high heterogeneity of macrophages in tissues contributes to the involvement of these cells in the development of a wide range of immune responses, including pathological ones. The replenishment of tissue-specific macrophages occurs at the expense of infiltrating monocyte-derived macrophages (MoMFs) in the pathological process. The origin of MoMFs from a general precursor retains their common regulatory mechanisms and similar sensitivity to regulatory stimuli. This makes it possible to find universal approaches to the effect on these cells and, as a consequence, universal approaches for the treatment of various pathological conditions. Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease)
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18 pages, 842 KiB  
Review
Endoplasmic Reticulum Stress in Macrophages: The Vicious Circle of Lipid Accumulation and Pro-Inflammatory Response
by Vasily N. Sukhorukov, Victoria A. Khotina, Mariam Bagheri Ekta, Ekaterina A. Ivanova, Igor A. Sobenin and Alexander N. Orekhov
Biomedicines 2020, 8(7), 210; https://doi.org/10.3390/biomedicines8070210 - 13 Jul 2020
Cited by 23 | Viewed by 4955
Abstract
The endoplasmic reticulum (ER) stress is an important event in the pathogenesis of different human disorders, including atherosclerosis. ER stress leads to disturbance of cellular homeostasis, apoptosis, and in the case of macrophages, to foam cell formation and pro-inflammatory cytokines production. In atherosclerosis, [...] Read more.
The endoplasmic reticulum (ER) stress is an important event in the pathogenesis of different human disorders, including atherosclerosis. ER stress leads to disturbance of cellular homeostasis, apoptosis, and in the case of macrophages, to foam cell formation and pro-inflammatory cytokines production. In atherosclerosis, several cell types can be affected by ER stress, including endothelial cells, vascular smooth muscular cells, and macrophages. Modified low-density lipoproteins (LDL) and cytokines, in turn, can provoke ER stress through different processes. The signaling cascades involved in ER stress initiation are complex and linked to other cellular processes, such as lysosomal biogenesis and functioning, autophagy, mitochondrial homeostasis, and energy production. In this review, we discuss the underlying mechanisms of ER stress formation and the interplay of lipid accumulation and pro-inflammatory response. We will specifically focus on macrophages, which are the key players in maintaining chronic inflammatory milieu in atherosclerotic lesions, and also a major source of lipid-accumulating foam cells. Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease)
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14 pages, 975 KiB  
Review
The Link between Chronic Stress and Accelerated Aging
by Yegor E. Yegorov, Anastasia V. Poznyak, Nikita G. Nikiforov, Igor A. Sobenin and Alexander N. Orekhov
Biomedicines 2020, 8(7), 198; https://doi.org/10.3390/biomedicines8070198 - 07 Jul 2020
Cited by 55 | Viewed by 9475
Abstract
People exposed to chronic stress age rapidly. The telomeres in their cells of all types shorten faster. Inflammation is another important feature of stress that, along with aging, accounts for the phenomenon of inflammaging. In addition to aging itself, inflammaging can contribute to [...] Read more.
People exposed to chronic stress age rapidly. The telomeres in their cells of all types shorten faster. Inflammation is another important feature of stress that, along with aging, accounts for the phenomenon of inflammaging. In addition to aging itself, inflammaging can contribute to the development of several pathologies, including atherosclerosis, diabetes, hypertension, and others. Oxidative stress is one of the main mechanisms related to stress. Oxidative stress is caused by the over-production of reactive oxygen species (ROS) that can damage various tissues. The main source of ROS is mitochondria. Being suppressed by mitochondrial mutations, mitophagy can aggravate the situation. In this case, the aging-specific pro-inflammatory changes are amplified. It happens because of the inability of cells to maintain the normal state of mitochondria. Macrophages are the crucial element of the innate immunity associated with the chronic inflammation and, subsequently, with the inflammaging. In this review, we focus on the therapy approaches potentially reducing the deleterious effects of oxidative stress. These include stimulation of mitophagy, activation of mitochondrial uncoupling, induction of the expression of the telomerase catalytic component gene, and use of antioxidants. Any method reducing oxidative stress should improve post-traumatic stress disorder. Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease)
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