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Macrophage Polarization: Learning to Manage It 2.0

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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 2023) | Viewed by 28203

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Dr. Nadia Lampiasi

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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
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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

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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.

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Keywords

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

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Published Papers (12 papers)

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Editorial

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3 pages, 234 KiB

Open AccessEditorial

Macrophage Polarization: Learning to Manage It 2.0

by Nadia Lampiasi

Int. J. Mol. Sci. 2023, 24(24), 17409; https://doi.org/10.3390/ijms242417409 - 12 Dec 2023

Cited by 1 | Viewed by 825

Abstract

The aim of this Special Issue is to investigate macrophages’ high plasticity and ability to differentiate/polarize in response to numerous stimuli in the context of diseases, infections, and biomolecules exposition (immunomodulators) [...] Full article

(This article belongs to the Special Issue Macrophage Polarization: Learning to Manage It 2.0)

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Research

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17 pages, 6548 KiB

Open AccessArticle

Methotrexate Provokes Disparate Folate Metabolism Gene Expression and Alternative Splicing in Ex Vivo Monocytes and GM-CSF- and M-CSF-Polarized Macrophages

by Ittai B. Muller, Marry Lin, Robert de Jonge, Nico Will, Baltasar López-Navarro, Conny van der Laken, Eduard A. Struys, Cees B. M. Oudejans, Yehuda G. Assaraf, Jacqueline Cloos, Amaya Puig-Kröger and Gerrit Jansen

Int. J. Mol. Sci. 2023, 24(11), 9641; https://doi.org/10.3390/ijms24119641 - 1 Jun 2023

Viewed by 1995

Abstract

Macrophages constitute important immune cell targets of the antifolate methotrexate (MTX) in autoimmune diseases, including rheumatoid arthritis. Regulation of folate/MTX metabolism remains poorly understood upon pro-inflammatory (M1-type/GM-CSF-polarized) and anti-inflammatory (M2-type/M-CSF-polarized) macrophages. MTX activity strictly relies on the folylpolyglutamate synthetase (FPGS) dependent intracellular conversion and hence retention to MTX-polyglutamate (MTX-PG) forms. Here, we determined FPGS pre-mRNA splicing, FPGS enzyme activity and MTX-polyglutamylation in human monocyte-derived M1- and M2-macrophages exposed to 50 nmol/L MTX ex vivo. Moreover, RNA-sequencing analysis was used to investigate global splicing profiles and differential gene expression in monocytic and MTX-exposed macrophages. Monocytes displayed six–eight-fold higher ratios of alternatively-spliced/wild type FPGS transcripts than M1- and M2-macrophages. These ratios were inversely associated with a six–ten-fold increase in FPGS activity in M1- and M2-macrophages versus monocytes. Total MTX-PG accumulation was four-fold higher in M1- versus M2-macrophages. Differential splicing after MTX-exposure was particularly apparent in M2-macrophages for histone methylation/modification genes. MTX predominantly induced differential gene expression in M1-macrophages, involving folate metabolic pathway genes, signaling pathways, chemokines/cytokines and energy metabolism. Collectively, macrophage polarization-related differences in folate/MTX metabolism and downstream pathways at the level of pre-mRNA splicing and gene expression may account for variable accumulation of MTX-PGs, hence possibly impacting MTX treatment efficacy. Full article

(This article belongs to the Special Issue Macrophage Polarization: Learning to Manage It 2.0)

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22 pages, 7439 KiB

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Extracellular Vesicles Released from Macrophages Infected with Mycoplasma pneumoniae Stimulate Proinflammatory Response via the TLR2-NF-κB/JNK Signaling Pathway

by Chunji Ma, Xiujing Hao, Liyang Gao, Yongyu Wang, Juan Shi, Haixia Luo and Min Li

Int. J. Mol. Sci. 2023, 24(10), 8588; https://doi.org/10.3390/ijms24108588 - 11 May 2023

Cited by 1 | Viewed by 1844

Abstract

Mycoplasma pneumoniae (M. pneumoniae, Mp) is an intracellular pathogen that causes pneumonia, tracheobronchitis, pharyngitis, and asthma in humans and can infect and survive in the host cells leading to excessive immune responses. Extracellular vesicles (EVs) from host cells carry components of pathogens to recipient cells and play a role in intercellular communication during infection. However, there is limited knowledge on whether EVs derived from M. pneumoniae-infected macrophages play as intercellular messengers and functional mechanisms. In this study, we establish a cell model of M. pneumoniae-infected macrophages that continuously secrete EVs to further asses their role as intercellular messengers and their functional mechanisms. Based on this model, we determined a method for isolating the pure EVs from M. pneumoniae-infected macrophages, which employs a sequence of operations, including differential centrifugation, filtering, and ultracentrifugation. We identified EVs and their purity using multiple methods, including electron microscopy, nanoparticle tracking analysis, Western blot, bacteria culture, and nucleic acid detection. EVs from M. pneumoniae-infected macrophages are pure, with a 30–200 nm diameter. These EVs can be taken up by uninfected macrophages and induce the production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 through the nuclear factor (NF)-κB, and mitogen-activated protein kinases (MAPK) signals pathway. Moreover, the expression of inflammatory cytokines induced by EVs relies on TLR2-NF-κB/JNK signal pathways. These findings will help us better understand a persistent inflammatory response and cell-to-cell immune modulation in the context of M. pneumoniae infection. Full article

(This article belongs to the Special Issue Macrophage Polarization: Learning to Manage It 2.0)

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16 pages, 5605 KiB

Open AccessArticle

Macrophage Migration Inhibitory Factor in Psoroptes ovis: Molecular Characterization and Potential Role in Eosinophil Accumulation of Skin in Rabbit and Its Implication in the Host–Parasite Interaction

by Xiaobin Gu, You Ge, Ya Wang, Cuirui Huang, Guangyou Yang, Yue Xie, Jing Xu, Ran He, Zhijun Zhong, Deying Yang, Zhi He and Xuerong Peng

Int. J. Mol. Sci. 2023, 24(6), 5985; https://doi.org/10.3390/ijms24065985 - 22 Mar 2023

Viewed by 1633

Abstract

Psoroptes ovis, a common surface-living mite of domestic and wild animals worldwide, results in huge economic losses and serious welfare issues in the animal industry. P. ovis infestation rapidly causes massive eosinophil infiltration in skin lesions, and increasing research revealed that eosinophils might play an important role in the pathogenesis of P. ovis infestation. Intradermal injection of P. ovis antigen invoked massive eosinophil infiltration, suggesting that this mite should contain some relative molecules involved in eosinophil accumulation in the skin. However, these active molecules have not yet been identified. Herein, we identified macrophage migration inhibitor factor (MIF) in P. ovis (PsoMIF) using bioinformatics and molecular biology methods. Sequence analyses revealed that PsoMIF appeared with high similarity to the topology of monomer and trimer formation with host MIF (RMSD = 0.28 angstroms and 2.826 angstroms, respectively) but with differences in tautomerase and thiol-protein oxidoreductase active sites. Reverse transcription PCR analysis (qRT-PCR) results showed that PsoMIF was expressed throughout all the developmental stages of P. ovis, particularly with the highest expression in female mites. Immunolocalization revealed that MIF protein located in the ovary and oviduct of female mites and also localized throughout the stratum spinosum, stratum granulosum, and even basal layers of the epidermis in skin lesions caused by P. ovis. rPsoMIF significantly upregulated eosinophil-related gene expression both in vitro (PBMC: CCL5, CCL11; HaCaT: IL-3, IL-4, IL-5, CCL5, CCL11) and in vivo (rabbit: IL-5, CCL5, CCL11, P-selectin, ICAM-1). Moreover, rPsoMIF could induce cutaneous eosinophil accumulation in a rabbit model and increased the vascular permeability in a mouse model. Our findings indicated that PsoMIF served as one of the key molecules contributing to skin eosinophil accumulation in P. ovis infection of rabbits. Full article

(This article belongs to the Special Issue Macrophage Polarization: Learning to Manage It 2.0)

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24 pages, 841 KiB

Open AccessArticle

Heterogeneity of Phenotypic and Functional Changes to Porcine Monocyte-Derived Macrophages Triggered by Diverse Polarizing Factors In Vitro

by Giulia Franzoni, Lorena Mura, Elisabetta Razzuoli, Chiara Grazia De Ciucis, Floriana Fruscione, Filippo Dell’Anno, Susanna Zinellu, Tania Carta, Antonio G. Anfossi, Silvia Dei Giudici, Simon P. Graham and Annalisa Oggiano

Int. J. Mol. Sci. 2023, 24(5), 4671; https://doi.org/10.3390/ijms24054671 - 28 Feb 2023

Cited by 5 | Viewed by 1664

Abstract

Swine are attracting increasing attention as a biomedical model, due to many immunological similarities with humans. However, porcine macrophage polarization has not been extensively analyzed. Therefore, we investigated porcine monocyte-derived macrophages (moMΦ) triggered by either IFN-γ + LPS (classical activation) or by diverse “M2-related” polarizing factors: IL-4, IL-10, TGF-β, and dexamethasone. IFN-γ and LPS polarized moMΦ toward a proinflammatory phenotype, although a significant IL-1Ra response was observed. Exposure to IL-4, IL-10, TGF-β, and dexamethasone gave rise to four distinct phenotypes, all antithetic to IFN-γ and LPS. Some peculiarities were observed: IL-4 and IL-10 both enhanced expression of IL-18, and none of the “M2-related” stimuli induced IL-10 expression. Exposures to TGF-β and dexamethasone were characterized by enhanced levels of TGF-β2, whereas stimulation with dexamethasone, but not TGF-β2, triggered CD163 upregulation and induction of CCL23. Macrophages stimulated with IL-10, TGF-β, or dexamethasone presented decreased abilities to release proinflammatory cytokines in response to TLR2 or TLR3 ligands: IL-10 showed a powerful inhibitory activity for CXCL8 and TNF release, whereas TGF-β provided a strong inhibitory signal for IL-6 production. While our results emphasized porcine macrophage plasticity broadly comparable to human and murine macrophages, they also highlighted some peculiarities in this species. Full article

(This article belongs to the Special Issue Macrophage Polarization: Learning to Manage It 2.0)

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22 pages, 4881 KiB

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The Educational Program of Macrophages toward a Hyperprogressive Disease-Related Phenotype Is Orchestrated by Tumor-Derived Extracellular Vesicles

by Serena Indino, Cristina Borzi, Claudia Moscheni, Patrizia Sartori, Loris De Cecco, Giancarla Bernardo, Valentino Le Noci, Francesca Arnaboldi, Tiziana Triulzi, Gabriella Sozzi, Elda Tagliabue, Lucia Sfondrini, Nicoletta Gagliano, Massimo Moro and Michele Sommariva

Int. J. Mol. Sci. 2022, 23(24), 15802; https://doi.org/10.3390/ijms232415802 - 13 Dec 2022

Cited by 1 | Viewed by 1726

Abstract

Hyperprogressive disease (HPD), an aggressive acceleration of tumor growth, was observed in a group of cancer patients treated with anti-PD1/PDL1 antibodies. The presence of a peculiar macrophage subset in the tumor microenvironment is reported to be a sort of “immunological prerequisite” for HPD development. These macrophages possess a unique phenotype that it is not clear how they acquire. We hypothesized that certain malignant cells may promote the induction of an “HPD-related” phenotype in macrophages. Bone-marrow-derived macrophages were exposed to the conditioned medium of five non-small cell lung cancer cell lines. Macrophage phenotype was analyzed by microarray gene expression profile and real-time PCR. We found that human NSCLC cell lines, reported as undergoing HPD-like tumor growth in immunodeficient mice, polarized macrophages towards a peculiar pro-inflammatory phenotype sharing both M1 and M2 features. Lipid-based factors contained in cancer cell-conditioned medium induced the over-expression of several pro-inflammatory cytokines and the activation of innate immune receptor signaling pathways. We also determined that tumor-derived Extracellular Vesicles represent the main components involved in the observed macrophage re-education program. The present study might represent the starting point for the future development of diagnostic tools to identify potential hyperprogressors. Full article

(This article belongs to the Special Issue Macrophage Polarization: Learning to Manage It 2.0)

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17 pages, 4391 KiB

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The Patatin–Like Phospholipase Domain Containing Protein 7 Regulates Macrophage Classical Activation through SIRT1/NF-κB and p38 MAPK Pathways

by Zheng Zhao, Christoph Heier, Huimin Pang, Yu Wang, Feifei Huang and Pingan Chang

Int. J. Mol. Sci. 2022, 23(23), 14983; https://doi.org/10.3390/ijms232314983 - 29 Nov 2022

Cited by 4 | Viewed by 1679

Abstract

Lysophosphatidylcholine (LPC) is a bioactive lipid that modulates macrophage polarization during immune responses, inflammation, and tissue remodeling. Patatin-like phospholipase domain containing protein 7 (PNPLA7) is a lysophospholipase with a preference for LPC. However, the role of PNPLA7 in macrophage polarization as an LPC hydrolase has not been explored. In the current study, we found that PNPLA7 is highly expressed in naïve macrophages and downregulated upon lipopolysaccharide (LPS)-induced polarization towards the classically activated (M1) phenotype. Consistently, overexpression of PNPLA7 suppressed the expression of proinflammatory M1 marker genes, including interleukin 1β (IL-1β), IL-6, inducible nitric oxide synthase (iNOS), and tumor necrosis factor α (TNF-α), whereas knockdown of PNPLA7 augmented the inflammatory gene expression in LPS-challenged macrophages. PNPLA7 overexpression and knockdown increased and decreased Sirtuin1 (SIRT1) mRNA and protein levels, respectively, and affected the acetylation of the nuclear factor-kappa B (NF-κB) p65 subunit, a key transcription factor in M1 polarization. In addition, the levels of phosphorylated p38 mitogen-activated protein kinase (MAPK) were suppressed and enhanced by PNPLA7 overexpression and knockdown, respectively. Taken together, these findings suggest that PNPLA7 suppresses M1 polarization of LPS-challenged macrophages by modulating SIRT1/NF-κB- and p38 MAPK-dependent pathways. Full article

(This article belongs to the Special Issue Macrophage Polarization: Learning to Manage It 2.0)

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12 pages, 1986 KiB

Open AccessArticle

Metabolism of 25-Hydroxy-Vitamin D in Human Macrophages Is Highly Dependent on Macrophage Polarization

by Rie H. Nygaard, Marlene C. Nielsen, Kristian W. Antonsen, Carsten S. Højskov, Boe S. Sørensen and Holger J. Møller

Int. J. Mol. Sci. 2022, 23(18), 10943; https://doi.org/10.3390/ijms231810943 - 19 Sep 2022

Cited by 4 | Viewed by 1610

Abstract

Macrophages synthesize active vitamin D (1,25-dihydroxy-vitamin D) and express the vitamin D receptor in the nucleus; however, vitamin D metabolism in relation to macrophage polarization and function is not well understood. We studied monocyte-derived macrophages (MDMs) from human buffy coats polarized into M0, M1 (LPS + IFNγ), M2a (IL4 + IL13) and M2c (IL10) macrophage subtypes stimulated with 25-hydroxy-vitamin D (1000 and 10,000 nanomolar). We measured vitamin D metabolites (25-hydroxy-vitamin D, 1,25-dihydroxy-vitamin D, 24,25-dihydroxy-vitamin D and 3-epi-25-hydroxy-vitamin D) in cell media with liquid chromatography-mass spectrometry-mass spectrometry. The mRNA expression (CYP27B1, CYP24A1 and CYP24A1-SV) was measured with qPCR. We found that reparative MDMs (M2a) had significantly more 1,25-dihydroxy-vitamin D compared to the other MDMs (M0, M1 and M2c). All MDMs were able to produce 3-epi-25-hydroxy-vitamin D, but this pathway was almost completely attenuated in inflammatory M1 MDMs. All MDM subtypes degraded vitamin D through the 24-hydroxylase pathway, although M1 MDMs mainly expressed an inactive splice variant of CYP24A1, coding the degrading enzyme. In conclusion, this study shows that vitamin D metabolism is highly dependent on macrophage polarization and that the C3-epimerase pathway for vitamin D is active in macrophages. Full article

(This article belongs to the Special Issue Macrophage Polarization: Learning to Manage It 2.0)

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15 pages, 3122 KiB

Open AccessArticle

Identification of Adipose Tissue as a Reservoir of Macrophages after Acute Myocardial Infarction

by Ingrid Gomez, Virginie Robert, Paul Alayrac, Adèle Arlat, Vincent Duval, Marie-Laure Renoud, José Vilar, Mathilde Lemitre, Jean-Sébastien Silvestre and Béatrice Cousin

Int. J. Mol. Sci. 2022, 23(18), 10498; https://doi.org/10.3390/ijms231810498 - 10 Sep 2022

Cited by 3 | Viewed by 1660

Abstract

Medullary and extra-medullary hematopoiesis has been shown to govern inflammatory cell infiltration and subsequently cardiac remodeling and function after acute myocardial infarction (MI). Emerging evidence positions adipose tissue (AT) as an alternative source of immune cell production. We, therefore, hypothesized that AT could act as a reservoir of inflammatory cells that participate in cardiac homeostasis after MI. To reveal the distinct role of inflammatory cells derived from AT or bone marrow (BM), chimeric mice were generated using standard repopulation assays. We showed that AMI increased the number of AT-derived macrophages in the cardiac tissue. These macrophages exhibit pro-inflammatory characteristics and their specific depletion improved cardiac function as well as decreased infarct size and interstitial fibrosis. We then reasoned that the alteration of AT-immune compartment in type 2 diabetes could, thus, contribute to defects in cardiac remodeling. However, in these conditions, myeloid cells recruited in the infarcted heart mainly originate from the BM, and AT was no longer used as a myeloid cell reservoir. Altogether, we showed here that a subpopulation of cardiac inflammatory macrophages emerges from myeloid cells of AT origin and plays a detrimental role in cardiac remodeling and function after MI. Diabetes abrogates the ability of AT-derived myeloid cells to populate the infarcted heart. Full article

(This article belongs to the Special Issue Macrophage Polarization: Learning to Manage It 2.0)

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Review

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25 pages, 809 KiB

Open AccessReview

Multiple Shades of Gray—Macrophages in Acute Allograft Rejection

by Katharina Lackner, Susanne Ebner, Katrin Watschinger and Manuel Maglione

Int. J. Mol. Sci. 2023, 24(9), 8257; https://doi.org/10.3390/ijms24098257 - 4 May 2023

Cited by 4 | Viewed by 1490

Abstract

Long-term results following solid organ transplantation do not mirror the excellent short-term results achieved in recent decades. It is therefore clear that current immunosuppressive maintenance protocols primarily addressing the adaptive immune system no longer meet the required clinical need. Identification of novel targets addressing this shortcoming is urgently needed. There is a growing interest in better understanding the role of the innate immune system in this context. In this review, we focus on macrophages, which are known to prominently infiltrate allografts and, during allograft rejection, to be involved in the surge of the adaptive immune response by expression of pro-inflammatory cytokines and direct cytotoxicity. However, this active participation is janus-faced and unspecific targeting of macrophages may not consider the different subtypes involved. Under this premise, we give an overview on macrophages, including their origins, plasticity, and important markers. We then briefly describe their role in acute allograft rejection, which ranges from sustaining injury to promoting tolerance, as well as the impact of maintenance immunosuppressants on macrophages. Finally, we discuss the observed immunosuppressive role of the vitamin-like compound tetrahydrobiopterin and the recent findings that suggest the innate immune system, particularly macrophages, as its target. Full article

(This article belongs to the Special Issue Macrophage Polarization: Learning to Manage It 2.0)

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19 pages, 1173 KiB

Open AccessReview

Macrophage Repolarization as a Therapeutic Strategy for Osteosarcoma

by Namrata Anand, Keng Hee Peh and Jill M. Kolesar

Int. J. Mol. Sci. 2023, 24(3), 2858; https://doi.org/10.3390/ijms24032858 - 2 Feb 2023

Cited by 10 | Viewed by 5165

Abstract

Macrophages are versatile immune cells and can adapt to both external stimuli and their surrounding environment. Macrophages are categorized into two major categories; M1 macrophages release pro-inflammatory cytokines and produce protective responses that lead to antimicrobial or antitumor activity. M2 or tumor-associated macrophages (TAM) release anti-inflammatory cytokines that support tumor growth, invasion capacity, and metastatic potential. Since macrophages can be re-polarized from an M2 to an M1 phenotype with a variety of strategies, this has emerged as an innovative anti-cancer approach. Osteosarcoma (OS) is a kind of bone cancer and consists of a complex niche, and immunotherapy is not very effective. Therefore, immediate attention to new strategies is required. We incorporated the recent studies that have used M2-M1 repolarization strategies in the aspect of treating OS cancer. Full article

(This article belongs to the Special Issue Macrophage Polarization: Learning to Manage It 2.0)

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18 pages, 1762 KiB

Open AccessReview

Inflammation and the Potential Implication of Macrophage-Microglia Polarization in Human ASD: An Overview

by Nadia Lampiasi, Rosa Bonaventura, Irene Deidda, Francesca Zito and Roberta Russo

Int. J. Mol. Sci. 2023, 24(3), 2703; https://doi.org/10.3390/ijms24032703 - 31 Jan 2023

Cited by 7 | Viewed by 2822

Abstract

Autism spectrum disorder (ASD) is a heterogeneous collection of neurodevelopmental disorders, difficult to diagnose and currently lacking treatment options. The possibility of finding reliable biomarkers useful for early identification would offer the opportunity to intervene with treatment strategies to improve the life quality of ASD patients. To date, there are many recognized risk factors for the development of ASD, both genetic and non-genetic. Although genetic and epigenetic factors may play a critical role, the extent of their contribution to ASD risk is still under study. On the other hand, non-genetic risk factors include pollution, nutrition, infection, psychological states, and lifestyle, all together known as the exposome, which impacts the mother’s and fetus’s life, especially during pregnancy. Pathogenic and non-pathogenic maternal immune activation (MIA) and autoimmune diseases can cause various alterations in the fetal environment, also contributing to the etiology of ASD in offspring. Activation of monocytes, macrophages, mast cells and microglia and high production of pro-inflammatory cytokines are indeed the cause of neuroinflammation, and the latter is involved in ASD’s onset and development. In this review, we focused on non-genetic risk factors, especially on the connection between inflammation, macrophage polarization and ASD syndrome, MIA, and the involvement of microglia. Full article

(This article belongs to the Special Issue Macrophage Polarization: Learning to Manage It 2.0)

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