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Macrophage Polarization: Learning to Manage It 3.0
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Macrophage Polarization: Learning to Manage It 3.0

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 April 2024) | Viewed by 11047

Special Issue Editor

Dr. Nadia Lampiasi

E-Mail Website
Guest Editor
National Research Council, Institute for Research and BioMedical Innovation “IRIB”, Via U. La Malfa, 153, 90146 Palermo, Italy
Interests: inflammation and innate immunity; macrophages polarization; osteoimmunology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Macrophages are crucial components of innate immunity. They possess high plasticity and the ability to differentiate in response to numerous stimuli. The physiological and/or pathological conditions characterize the environment in which the macrophages reside, and determine their heterogeneity. There is a plethora of different specialized functional phenotypes, among which inflammatory (M1) and reparative (M2) subtypes are proposed, which are almost exactly opposite to each other. Two key cytokines, IFN-γ and TNF-α, are responsible for M1, or classical activation, while alternate activation in M2 is mediated mainly by IL-4 and IL-13. Interestingly, microRNAs and some immunomodulators are critical regulators of macrophage polarization. The link with many human diseases and infections, including cancer, autoimmunity, and periodontitis, is to be found in the dysregulation of macrophage plasticity. Furthermore, recent studies on naturally occurring compounds emphasize their regulatory effects on macrophage polarization, suggesting that some of them could be promising for the treatment of sensitive diseases.

This Special Issue aims to cover all areas of molecular research, but is not limited to this, as it may include clinical studies with biomolecular experiments.

Dr. Nadia Lampiasi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • macrophages
  • macrophage plasticity
  • macrophage polarization
  • innate immunity
  • IFN-γ
  • TNF-α
  • immunomodulators
  • diseases
  • homeostasis
  • inflammation
  • cancer

Related Special Issues

Published Papers (7 papers)

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Research

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22 pages, 6695 KiB  
Article
PARP14 Contributes to the Development of the Tumor-Associated Macrophage Phenotype
by Isotta Sturniolo, Csongor Váróczy, Zsolt Regdon, Anett Mázló, Szabolcs Muzsai, Attila Bácsi, Giorgia Intili, Csaba Hegedűs, Mark R. Boothby, Jacob Holechek, Dana Ferraris, Herwig Schüler and László Virág
Int. J. Mol. Sci. 2024, 25(7), 3601; https://doi.org/10.3390/ijms25073601 - 22 Mar 2024
Viewed by 733
Abstract
Cancers reprogram macrophages (MΦs) to a tumor-growth-promoting TAM (tumor-associated MΦ) phenotype that is similar to the anti-inflammatory M2 phenotype. Poly(ADP-ribose) polymerase (PARP) enzymes regulate various aspects of MΦ biology, but their role in the development of TAM phenotype has not yet been investigated. [...] Read more.
Cancers reprogram macrophages (MΦs) to a tumor-growth-promoting TAM (tumor-associated MΦ) phenotype that is similar to the anti-inflammatory M2 phenotype. Poly(ADP-ribose) polymerase (PARP) enzymes regulate various aspects of MΦ biology, but their role in the development of TAM phenotype has not yet been investigated. Here, we show that the multispectral PARP inhibitor (PARPi) PJ34 and the PARP14 specific inhibitor MCD113 suppress the expression of M2 marker genes in IL-4-polarized primary murine MΦs, in THP-1 monocytic human MΦs, and in primary human monocyte-derived MΦs. MΦs isolated from PARP14 knockout mice showed a limited ability to differentiate to M2 cells. In a murine model of TAM polarization (4T1 breast carcinoma cell supernatant transfer to primary MΦs) and in a human TAM model (spheroids formed from JIMT-1 breast carcinoma cells and THP-1-MΦs), both PARPis and the PARP14 KO phenotype caused weaker TAM polarization. Increased JIMT-1 cell apoptosis in co-culture spheroids treated with PARPis suggested reduced functional TAM reprogramming. Protein profiling arrays identified lipocalin-2, macrophage migration inhibitory factor, and plasminogen activator inhibitor-1 as potential (ADP-ribosyl)ation-dependent mediators of TAM differentiation. Our data suggest that PARP14 inhibition might be a viable anticancer strategy with a potential to boost anticancer immune responses by reprogramming TAMs. Full article
(This article belongs to the Special Issue Macrophage Polarization: Learning to Manage It 3.0)
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24 pages, 10966 KiB  
Article
Three-Dimensionally Cultured Jaw Periosteal Cells Attenuate Macrophage Activation of CD4+ T Cells and Inhibit Osteoclastogenesis
by Fang He, Liuran Wang, Felix Umrath, Andreas Naros, Siegmar Reinert and Dorothea Alexander
Int. J. Mol. Sci. 2024, 25(4), 2355; https://doi.org/10.3390/ijms25042355 - 16 Feb 2024
Viewed by 758
Abstract
The implementation of a successful therapeutic approach that includes tissue-engineered grafts requires detailed analyses of graft-immune cell interactions in order to predict possible immune reactions after implantation. The phenotypic plasticity of macrophages plays a central role in immune cell chemotaxis, inflammatory regulation and [...] Read more.
The implementation of a successful therapeutic approach that includes tissue-engineered grafts requires detailed analyses of graft-immune cell interactions in order to predict possible immune reactions after implantation. The phenotypic plasticity of macrophages plays a central role in immune cell chemotaxis, inflammatory regulation and bone regeneration. The present study addresses effects emanating from JPC-seeded β-TCP constructs (3DJPCs) co-cultivated with THP-1 derived M1/M2 macrophages within a horizontal co-culture system. After five days of co-culture, macrophage phenotype and chemokine secretion were analyzed by flow cytometry, quantitative PCR and proteome arrays. The results showed that pro-inflammatory factors in M1 macrophages were inhibited by 3DJPCs, while anti-inflammatory factors were activated, possibly affected by the multiple chemokines secreted by 3D-cultured JPCs. In addition, osteoclast markers of polarized macrophages were inhibited by osteogenically induced 3DJPCs. Functional assays revealed a significantly lower percentage of proliferating CD4+ T cells in the groups treated with secretomes from M1/M2 macrophages previously co-cultured with 3DJPCs compared to controls without secretomes. Quantifications of pit area resorption assays showed evidence that supernatants from 3DJPCs co-cultured with M1/M2 macrophages were able to completely suppress osteoclast maturation, compared to the control group without secretomes. These findings demonstrate the ability of 3D cultured JPCs to modulate macrophage plasticity. Full article
(This article belongs to the Special Issue Macrophage Polarization: Learning to Manage It 3.0)
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20 pages, 6686 KiB  
Article
Effects of Mycobacterium vaccae NCTC 11659 and Lipopolysaccharide Challenge on Polarization of Murine BV-2 Microglial Cells
by Luke W. Desmond, Evan M. Holbrook, Caelan T. O. Wright, Cristian A. Zambrano, Christopher E. Stamper, Adam D. Bohr, Matthew G. Frank, Brendan K. Podell, Julie A. Moreno, Andrew S. MacDonald, Stefan O. Reber, Rogelio Hernández-Pando and Christopher A. Lowry
Int. J. Mol. Sci. 2024, 25(1), 474; https://doi.org/10.3390/ijms25010474 - 29 Dec 2023
Viewed by 1221
Abstract
Previous studies have shown that the in vivo administration of soil-derived bacteria with anti-inflammatory and immunoregulatory properties, such as Mycobacterium vaccae NCTC 11659, can prevent a stress-induced shift toward an inflammatory M1 microglial immunophenotype and microglial priming in the central nervous system (CNS). [...] Read more.
Previous studies have shown that the in vivo administration of soil-derived bacteria with anti-inflammatory and immunoregulatory properties, such as Mycobacterium vaccae NCTC 11659, can prevent a stress-induced shift toward an inflammatory M1 microglial immunophenotype and microglial priming in the central nervous system (CNS). It remains unclear whether M. vaccae NCTC 11659 can act directly on microglia to mediate these effects. This study was designed to determine the effects of M. vaccae NCTC 11659 on the polarization of naïve BV-2 cells, a murine microglial cell line, and BV-2 cells subsequently challenged with lipopolysaccharide (LPS). Briefly, murine BV-2 cells were exposed to 100 µg/mL whole-cell, heat-killed M. vaccae NCTC 11659 or sterile borate-buffered saline (BBS) vehicle, followed, 24 h later, by exposure to 0.250 µg/mL LPS (Escherichia coli 0111: B4; n = 3) in cell culture media vehicle (CMV) or a CMV control condition. Twenty-four hours after the LPS or CMV challenge, cells were harvested to isolate total RNA. An analysis using the NanoString platform revealed that, by itself, M. vaccae NCTC 11659 had an “adjuvant-like” effect, while exposure to LPS increased the expression of mRNAs encoding proinflammatory cytokines, chemokine ligands, the C3 component of complement, and components of inflammasome signaling such as Nlrp3. Among LPS-challenged cells, M. vaccae NCTC 11659 had limited effects on differential gene expression using a threshold of 1.5-fold change. A subset of genes was assessed using real-time reverse transcription polymerase chain reaction (real-time RT-PCR), including Arg1, Ccl2, Il1b, Il6, Nlrp3, and Tnf. Based on the analysis using real-time RT-PCR, M. vaccae NCTC 11659 by itself again induced “adjuvant-like” effects, increasing the expression of Il1b, Il6, and Tnf while decreasing the expression of Arg1. LPS by itself increased the expression of Ccl2, Il1b, Il6, Nlrp3, and Tnf while decreasing the expression of Arg1. Among LPS-challenged cells, M. vaccae NCTC 11659 enhanced LPS-induced increases in the expression of Nlrp3 and Tnf, consistent with microglial priming. In contrast, among LPS-challenged cells, although M. vaccae NCTC 11659 did not fully prevent the effects of LPS relative to vehicle-treated control conditions, it increased Arg1 mRNA expression, suggesting that M. vaccae NCTC 11659 induces an atypical microglial phenotype. Thus, M. vaccae NCTC 11659 acutely (within 48 h) induced immune-activating and microglial-priming effects when applied directly to murine BV-2 microglial cells, in contrast to its long-term anti-inflammatory and immunoregulatory effects observed on the CNS when whole-cell, heat-killed preparations of M. vaccae NCTC 11659 were given peripherally in vivo. Full article
(This article belongs to the Special Issue Macrophage Polarization: Learning to Manage It 3.0)
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32 pages, 29868 KiB  
Article
Establishment and Characterization of Free-Floating 3D Macrophage Programming Model in the Presence of Cancer Cell Spheroids
by Ksenija Korotkaja, Juris Jansons, Karina Spunde, Zhanna Rudevica and Anna Zajakina
Int. J. Mol. Sci. 2023, 24(13), 10763; https://doi.org/10.3390/ijms241310763 - 28 Jun 2023
Cited by 2 | Viewed by 1842
Abstract
Reprogramming of tumor-associated macrophages (TAMs) is a promising strategy for cancer immunotherapy. Several studies have shown that cancer cells induce/support the formation of immunosuppressive TAMs phenotypes. However, the specific factors that orchestrate this immunosuppressive process are unknown or poorly studied. In vivo studies [...] Read more.
Reprogramming of tumor-associated macrophages (TAMs) is a promising strategy for cancer immunotherapy. Several studies have shown that cancer cells induce/support the formation of immunosuppressive TAMs phenotypes. However, the specific factors that orchestrate this immunosuppressive process are unknown or poorly studied. In vivo studies are expensive, complex, and ethically constrained. Therefore, 3D cell interaction models could become a unique framework for the identification of important TAMs programming factors. In this study, we have established and characterized a new in vitro 3D model for macrophage programming in the presence of cancer cell spheroids. First, it was demonstrated that the profile of cytokines, chemokines, and surface markers of 3D-cultured macrophages did not differ conceptually from monolayer-cultured M1 and M2-programmed macrophages. Second, the possibility of reprogramming macrophages in 3D conditions was investigated. In total, the dynamic changes in 6 surface markers, 11 cytokines, and 22 chemokines were analyzed upon macrophage programming (M1 and M2) and reprogramming (M1→M2 and M2→M1). According to the findings, the reprogramming resulted in a mixed macrophage phenotype that expressed both immunosuppressive and anti-cancer immunostimulatory features. Third, cancer cell spheroids were shown to stimulate the production of immunosuppressive M2 markers as well as pro-tumor cytokines and chemokines. In summary, the newly developed 3D model of cancer cell spheroid/macrophage co-culture under free-floating conditions can be used for studies on macrophage plasticity and for the development of targeted cancer immunotherapy. Full article
(This article belongs to the Special Issue Macrophage Polarization: Learning to Manage It 3.0)
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Review

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17 pages, 1090 KiB  
Review
New Strategies for Macrophage Re-Education in Cancer: An Update
by Nadia Lampiasi
Int. J. Mol. Sci. 2024, 25(6), 3414; https://doi.org/10.3390/ijms25063414 - 18 Mar 2024
Viewed by 778
Abstract
The association between cancer and inflammation is well established. Chronic inflammation represents a fundamental step in the development and progression of some types of cancer. Tumors are composed of a heterogeneous population of infiltrating cells including macrophages, fibroblasts, lymphocytes, granulocytes, and mast cells, [...] Read more.
The association between cancer and inflammation is well established. Chronic inflammation represents a fundamental step in the development and progression of some types of cancer. Tumors are composed of a heterogeneous population of infiltrating cells including macrophages, fibroblasts, lymphocytes, granulocytes, and mast cells, which respond to signals from the microenvironment and, in turn, produce cytokines, chemokines, transcription factors, receptors, and miRNAs. Recent data demonstrate that, in addition to classical (M1) and alternative (M2) macrophage subtypes, there are many intermediate subtypes that potentially play different roles in response to environmental stimuli. Tumors are infiltrated by macrophages called TAMs that mainly display an M2-like phenotype and tumor growth-permissive activities. There is a bidirectional interaction between tumor cells and tumor-infiltrating cells that determines macrophage polarization and ultimately tumor progression or regression. These complex interactions are still unclear but understanding them is fundamental for the development of new therapeutic strategies. Re-educating tumor-permissive macrophages into anti-tumor macrophages is a new focus of research. This review aims to analyze the most recent articles investigating the interplay between tumors, tumor-infiltrating cells, and TAMs, and the strategies for re-educating tumor-permissive macrophages. Full article
(This article belongs to the Special Issue Macrophage Polarization: Learning to Manage It 3.0)
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16 pages, 1853 KiB  
Review
Cholinergic Polarization of Human Macrophages
by Natalia Roa-Vidal, Adriana S. Rodríguez-Aponte, José A. Lasalde-Dominicci, Coral M. Capó-Vélez and Manuel Delgado-Vélez
Int. J. Mol. Sci. 2023, 24(21), 15732; https://doi.org/10.3390/ijms242115732 - 29 Oct 2023
Cited by 1 | Viewed by 1816
Abstract
Macrophages serve as vital defenders, protecting the body by exhibiting remarkable cellular adaptability in response to invading pathogens and various stimuli. These cells express nicotinic acetylcholine receptors, with the α7-nAChR being extensively studied due to its involvement in activating the cholinergic anti-inflammatory pathway. [...] Read more.
Macrophages serve as vital defenders, protecting the body by exhibiting remarkable cellular adaptability in response to invading pathogens and various stimuli. These cells express nicotinic acetylcholine receptors, with the α7-nAChR being extensively studied due to its involvement in activating the cholinergic anti-inflammatory pathway. Activation of this pathway plays a crucial role in suppressing macrophages’ production of proinflammatory cytokines, thus mitigating excessive inflammation and maintaining host homeostasis. Macrophage polarization, which occurs in response to specific pathogens or insults, is a process that has received limited attention concerning the activation of the cholinergic anti-inflammatory pathway and the contributions of the α7-nAChR in this context. This review aims to present evidence highlighting how the cholinergic constituents in macrophages, led by the α7-nAChR, facilitate the polarization of macrophages towards anti-inflammatory phenotypes. Additionally, we explore the influence of viral infections on macrophage inflammatory phenotypes, taking into account cholinergic mechanisms. We also review the current understanding of macrophage polarization in response to these infections. Finally, we provide insights into the relatively unexplored partial duplication of the α7-nAChR, known as dup α7, which is emerging as a significant factor in macrophage polarization and inflammation scenarios. Full article
(This article belongs to the Special Issue Macrophage Polarization: Learning to Manage It 3.0)
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19 pages, 1150 KiB  
Review
Emerging Roles of Lysophosphatidic Acid in Macrophages and Inflammatory Diseases
by Shufan Jiang, Huili Yang and Mingqing Li
Int. J. Mol. Sci. 2023, 24(15), 12524; https://doi.org/10.3390/ijms241512524 - 07 Aug 2023
Cited by 2 | Viewed by 1480
Abstract
Lysophosphatidic acid (LPA) is a bioactive phospholipid that regulates physiological and pathological processes in numerous cell biological functions, including cell migration, apoptosis, and proliferation. Macrophages are found in most human tissues and have multiple physiological and pathological functions. There is growing evidence that [...] Read more.
Lysophosphatidic acid (LPA) is a bioactive phospholipid that regulates physiological and pathological processes in numerous cell biological functions, including cell migration, apoptosis, and proliferation. Macrophages are found in most human tissues and have multiple physiological and pathological functions. There is growing evidence that LPA signaling plays a significant role in the physiological function of macrophages and accelerates the development of diseases caused by macrophage dysfunction and inflammation, such as inflammation-related diseases, cancer, atherosclerosis, and fibrosis. In this review, we summarize the roles of LPA in macrophages, analyze numerous macrophage- and inflammation-associated diseases triggered by LPA, and discuss LPA-targeting therapeutic strategies. Full article
(This article belongs to the Special Issue Macrophage Polarization: Learning to Manage It 3.0)
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