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Phenotypic and Functional Heterogeneity of Cells of the Monocytes/Macrophage Lineage

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (15 January 2023) | Viewed by 16578

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Guest Editor
Department of Cell and Molecular Biology, Uppsala University, The Biomedical Center, Uppsala, Sweden
Interests: mast cells; basophilic leukocytes; neutrophilic leukocytes; serine proteases; cleavage specificity; phage display; IgE; evolution; allergy; vaccines; Fc receptors; dermatitis; cytokines; immune regulation
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Special Issue Information

Dear Colleagues, 

Macrophages (MΦs) were probably the first immune cells to appear during eukaryote evolution, and MΦ-like cells have been found in almost all multicellular organisms. They are found in all mammalian organs, represented by microglial cells in the brain, Kupffer cells in the liver, osteoclasts in the bone, alveolar MΦs in the lung, synovial A cells in the joints, kidney MΦs, gingival MΦs surrounding the teeth, peritoneal MΦs, intestinal MΦs, as well as several MΦ types in the lymph nodes and spleen (including marginal zone, metallophilic, and red pulp MΦs.

For many years, MΦs were thought to originate exclusively from blood monocytes, which after entering local tissues and under the influence of the local environment (including cell–cell contacts and different soluble factors) develop into MΦs of different phenotypes. However, it has recently been shown that almost all MΦ subpopulations primarily originate from an early wave of MΦs emanating from the yolk sac, and that these cells can increase in numbers by local proliferation. It is essentially only the monocytes and the intestinal MΦs that seems to primarily originate from the adult bone marrow.

Single cell analyses of different macrophage populations have shown that MΦs of different organs have quite different phenotypes and probably also functions. However, few if any quantitative and functional studies of these subpopulations have been performed. In vitro studies of macrophages are also problematic as they by plastic adherence or the presence of pyrogenic compounds in culture cell media get activated and quickly change phenotype from non-inflammatory tissue MΦs to inflammatory MΦs. For long-term studies, in vitro cell lines originating from transformed MΦs have been extensively used as model systems. The question is therefore based on how similar they are to tissue-resident MΦs or blood monocytes.

In this Special Issue, we invite papers that addresses questions addressing these issues with specific emphasis on quantitative and functional studies on MΦ heterogeneity and on comparative studies of in vitro models for studies of MΦ function, both in vitro cultures of freshly isolated cells and on monocyte/MΦ cell lines.

Prof. Dr. Lars Hellman
Guest Editor

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Published Papers (6 papers)

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Editorial

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5 pages, 1857 KiB  
Editorial
Phenotypic and Functional Heterogeneity of Monocytes and Macrophages
by Lars Hellman
Int. J. Mol. Sci. 2023, 24(19), 14525; https://doi.org/10.3390/ijms241914525 - 25 Sep 2023
Cited by 1 | Viewed by 687
Abstract
Macrophages are likely to be the first immune cells to have appeared during the evolution of multicellular organisms [...] Full article
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Research

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10 pages, 609 KiB  
Communication
Quantitative Analysis of the Transcriptome of Two Commonly Used Human Monocytic Cell Lines—THP-1 and Mono Mac 6—Reveals Their Arrest during Early Monocyte/Neutrophil Differentiation
by Srinivas Akula, Sandra Lara, Anna-Karin Olsson and Lars Hellman
Int. J. Mol. Sci. 2022, 23(10), 5818; https://doi.org/10.3390/ijms23105818 - 22 May 2022
Cited by 3 | Viewed by 2216
Abstract
Cell lines of monocyte/macrophage origin are often used as model systems to study monocyte/macrophage biology. A relevant question is how similar these cell lines are to their in vivo counterparts? To address this issue, we performed a detailed analysis of the transcriptome of [...] Read more.
Cell lines of monocyte/macrophage origin are often used as model systems to study monocyte/macrophage biology. A relevant question is how similar these cell lines are to their in vivo counterparts? To address this issue, we performed a detailed analysis of the transcriptome of two commonly used human monocyte/macrophage cell lines, Mono Mac 6 and THP-1. Both of these cell lines originate from leukemic cells with myelo-monocytic characteristics. We found that both Mono Mac 6 and THP-1 represent cells of very immature origin. Their transcriptomes show more similarities to immature neutrophils than cells of the monocyte/macrophage lineage. They express significant levels of N-elastase, proteinase 3, cathepsin G, and azurocidin but very low levels of CD14, ficolin, and complement factor P. All major MHC class II genes are also expressed at low levels. They show high levels of lysozyme and low levels of one of the immunoglobulin Fc receptors, FCGRIIA, which is characteristic of both neutrophils and monocytes. THP-1, but not Mono Mac 6, also expresses the high-affinity receptor for IgG, FCGRIA. Both cell lines lack the expression of the connective tissue components fibronectin, proteoglycan 4, and syndecan 3, which are characteristics of tissue macrophages but are absent in blood monocytes, indicating that they originate from bone marrow precursors and not yolk sac-derived hematopoietic cells. Both of these cell lines seem, therefore, to represent cells arrested during early myelo-monocytic development, at a branch point between neutrophil and monocyte differentiation. Their very immature phenotype indicates that great care should be taken when using these cell lines as models for normal monocyte/macrophage biology. Full article
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13 pages, 1786 KiB  
Article
The Human Monocyte—A Circulating Sensor of Infection and a Potent and Rapid Inducer of Inflammation
by Sandra Lara, Srinivas Akula, Zhirong Fu, Anna-Karin Olsson, Sandra Kleinau and Lars Hellman
Int. J. Mol. Sci. 2022, 23(7), 3890; https://doi.org/10.3390/ijms23073890 - 31 Mar 2022
Cited by 8 | Viewed by 2080
Abstract
Monocytes were previously thought to be the precursors of all tissue macrophages but have recently been found to represent a unique population of cells, distinct from the majority of tissue macrophages. Monocytes and intestinal macrophages seem now to be the only monocyte/macrophage populations [...] Read more.
Monocytes were previously thought to be the precursors of all tissue macrophages but have recently been found to represent a unique population of cells, distinct from the majority of tissue macrophages. Monocytes and intestinal macrophages seem now to be the only monocyte/macrophage populations that originate primarily from adult bone marrow. To obtain a better view of the biological function of monocytes and how they differ from tissue macrophages, we have performed a quantitative analysis of its transcriptome in vivo and after in vitro stimulation with E. coli LPS. The monocytes rapidly responded to LPS by producing extremely high amounts of mRNA for the classical inflammatory cytokines, IL-1α, IL-1β, IL-6 and TNF-α, but almost undetectable amounts of other cytokines. IL-6 was upregulated 58,000 times, from almost undetectable levels at baseline to become one of the major transcripts already after a few hours of cultivation. The cells also showed very strong upregulation of a number of chemokines, primarily IL-8, Ccl2, Ccl3, Ccl3L3, Ccl20, Cxcl2, Cxcl3 and Cxcl4. IL-8 became the most highly expressed transcript in the monocytes already after four hours of in vitro culture in the presence of LPS. A high baseline level of MHC class II chains and marked upregulation of super oxide dismutase (SOD2), complement factor B, complement factor C3 and coagulation factor 3 (F3; tissue factor) at four hours of in vitro culture were also observed. This indicates a rapid protective response to high production of oxygen radicals, to increase complement activation and possibly also be an inducer of local coagulation. Overall, these findings give strong support for monocytes acting primarily as potent mobile sensors of infection and rapid activators of a strong inflammatory response. Full article
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25 pages, 15936 KiB  
Article
Quantitative In-Depth Transcriptome Analysis Implicates Peritoneal Macrophages as Important Players in the Complement and Coagulation Systems
by Aida Paivandy, Srinivas Akula, Sandra Lara, Zhirong Fu, Anna-Karin Olsson, Sandra Kleinau, Gunnar Pejler and Lars Hellman
Int. J. Mol. Sci. 2022, 23(3), 1185; https://doi.org/10.3390/ijms23031185 - 21 Jan 2022
Cited by 7 | Viewed by 2361
Abstract
To obtain a more detailed picture of macrophage (MΦ) biology, in the current study, we analyzed the transcriptome of mouse peritoneal MΦs by RNA-seq and PCR-based transcriptomics. The results show that peritoneal MΦs, based on mRNA content, under non-inflammatory conditions produce large amounts [...] Read more.
To obtain a more detailed picture of macrophage (MΦ) biology, in the current study, we analyzed the transcriptome of mouse peritoneal MΦs by RNA-seq and PCR-based transcriptomics. The results show that peritoneal MΦs, based on mRNA content, under non-inflammatory conditions produce large amounts of a number of antimicrobial proteins such as lysozyme and several complement components. They were also found to be potent producers of several chemokines, including platelet factor 4 (PF4), Ccl6, Ccl9, Cxcl13, and Ccl24, and to express high levels of both TGF-β1 and TGF-β2. The liver is considered to be the main producer of most complement and coagulation components. However, we can now show that MΦs are also important sources of such compounds including C1qA, C1qB, C1qC, properdin, C4a, factor H, ficolin, and coagulation factor FV. In addition, FX, FVII, and complement factor B were expressed by the MΦs, altogether indicating that MΦs are important local players in both the complement and coagulation systems. For comparison, we analyzed human peripheral blood monocytes. We show that the human monocytes shared many characteristics with the mouse peritoneal MΦs but that there were also many major differences. Similar to the mouse peritoneal MΦs, the most highly expressed transcript in the monocytes was lysozyme, and high levels of both properdin and ficolin were observed. However, with regard to connective tissue components, such as fibronectin, lubricin, syndecan 3, and extracellular matrix protein 1, which were highly expressed by the peritoneal MΦs, the monocytes almost totally lacked transcripts. In contrast, monocytes expressed high levels of MHC Class II, whereas the peritoneal MΦs showed very low levels of these antigen-presenting molecules. Altogether, the present study provides a novel view of the phenotype of the major MΦ subpopulation in the mouse peritoneum and the large peritoneal MΦs and places the transcriptome profile of the peritoneal MΦs in a broader context, including a comparison of the peritoneal MΦ transcriptome with that of human peripheral blood monocytes and the liver. Full article
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Review

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24 pages, 1433 KiB  
Review
Monocyte Differentiation and Heterogeneity: Inter-Subset and Interindividual Differences
by Helen Williams, Corinne Mack, Rana Baraz, Rekha Marimuthu, Sravanthi Naralashetty, Stephen Li and Heather Medbury
Int. J. Mol. Sci. 2023, 24(10), 8757; https://doi.org/10.3390/ijms24108757 - 15 May 2023
Cited by 6 | Viewed by 3382
Abstract
The three subsets of human monocytes, classical, intermediate, and nonclassical, show phenotypic heterogeneity, particularly in their expression of CD14 and CD16. This has enabled researchers to delve into the functions of each subset in the steady state as well as in disease. Studies [...] Read more.
The three subsets of human monocytes, classical, intermediate, and nonclassical, show phenotypic heterogeneity, particularly in their expression of CD14 and CD16. This has enabled researchers to delve into the functions of each subset in the steady state as well as in disease. Studies have revealed that monocyte heterogeneity is multi-dimensional. In addition, that their phenotype and function differ between subsets is well established. However, it is becoming evident that heterogeneity also exists within each subset, between health and disease (current or past) states, and even between individuals. This realisation casts long shadows, impacting how we identify and classify the subsets, the functions we assign to them, and how they are examined for alterations in disease. Perhaps the most fascinating is evidence that, even in relative health, interindividual differences in monocyte subsets exist. It is proposed that the individual’s microenvironment could cause long-lasting or irreversible changes to monocyte precursors that echo to monocytes and through to their derived macrophages. Here, we will discuss the types of heterogeneity recognised in monocytes, the implications of these for monocyte research, and most importantly, the relevance of this heterogeneity for health and disease. Full article
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24 pages, 8139 KiB  
Review
An Eye on Kupffer Cells: Development, Phenotype and the Macrophage Niche
by Andrey Elchaninov, Polina Vishnyakova, Egor Menyailo, Gennady Sukhikh and Timur Fatkhudinov
Int. J. Mol. Sci. 2022, 23(17), 9868; https://doi.org/10.3390/ijms23179868 - 30 Aug 2022
Cited by 9 | Viewed by 4976
Abstract
Macrophages are key participants in the maintenance of tissue homeostasis under normal and pathological conditions, and implement a rich diversity of functions. The largest population of resident tissue macrophages is found in the liver. Hepatic macrophages, termed Kupffer cells, are involved in the [...] Read more.
Macrophages are key participants in the maintenance of tissue homeostasis under normal and pathological conditions, and implement a rich diversity of functions. The largest population of resident tissue macrophages is found in the liver. Hepatic macrophages, termed Kupffer cells, are involved in the regulation of multiple liver functionalities. Specific differentiation profiles and functional activities of tissue macrophages have been attributed to the shaping role of the so-called tissue niche microenvironments. The fundamental macrophage niche concept was lately shaken by a flood of new data, leading to a revision and substantial update of the concept, which constitutes the main focus of this review. The macrophage community discusses contemporary evidence on the developmental origins of resident macrophages, notably Kupffer cells and the issues of heterogeneity of the hepatic macrophage populations, as well as the roles of proliferation, cell death and migration processes in the maintenance of macrophage populations of the liver. Special consideration is given to interactions of Kupffer cells with other local cell lineages, including Ito cells, sinusoidal endothelium and hepatocytes, which participate in the maintenance of their phenotypical and functional identity. Full article
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