The Role of Macrophages in Physiological and Pathophysiological Inflammation

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 32074

Special Issue Editor


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Guest Editor
Immunotherapy Unit, Department of Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria
Interests: innate immunity; immunotherapy; P2Y11 receptor

Special Issue Information

Dear Colleagues,

Macrophages fulfil numerous tasks during innate immune responses, that range from early sentinel to late scavenging and repair functions. Macrophages sense and respond to invading pathogens by producing inflammatory cytokines and lipid mediators. The dysregulation of macrophage responses resulting in hyperinflammation can be detrimental to the host and cause inflammatory disease, as exemplified by the excessive macrophage activation and coagulation that is seen in patients with severe forms of COVID-19 disease.

In this Special Issue, we will address how different macrophage subsets contribute to the onset or resolution of inflammation. We will discuss the receptor signalling pathways, as well as the underlying metabolic reprogramming that leads to the production of inflammatory or anti-inflammatory molecules. The metabolic and epigenetic rewiring of macrophages also promotes the generation of an innate form of immune memory called “trained immunity”. Training macrophages may either lead to an augmented immune response to a secondary stimulus, as initially described for Bacillus Calmette Guérin (BCG), or to a state of hypo-responsiveness, such as that observed in endotoxin tolerance. The major goal of this article collection is to improve our understanding of host immune responses to microbial aggression, fostering the development of novel therapeutic approaches.

Prof. Dr. Martin Thurnher
Guest Editor

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Keywords

  • macrophages
  • receptor signaling
  • cytokines
  • lipid mediators
  • metabolism
  • trained immunity
  • inflammatory disease

Published Papers (7 papers)

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Research

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21 pages, 5262 KiB  
Article
Cytokine-Mediated Regulation of ARG1 in Macrophages and Its Impact on the Control of Salmonella enterica Serovar Typhimurium Infection
by Natascha Brigo, Christa Pfeifhofer-Obermair, Piotr Tymoszuk, Egon Demetz, Sabine Engl, Marina Barros-Pinkelnig, Stefanie Dichtl, Christine Fischer, Lara Valente De Souza, Verena Petzer, Laura von Raffay, Richard Hilbe, Sylvia Berger, Markus Seifert, Ulrike Schleicher, Christian Bogdan and Günter Weiss
Cells 2021, 10(7), 1823; https://doi.org/10.3390/cells10071823 - 19 Jul 2021
Cited by 12 | Viewed by 3726
Abstract
Arginase 1 (ARG1) is a cytosolic enzyme that cleaves L-arginine, the substrate of inducible nitric oxide synthase (iNOS), and thereby impairs the control of various intracellular pathogens. Herein, we investigated the role of ARG1 during infection with Salmonella enterica serovar Typhimurium (S [...] Read more.
Arginase 1 (ARG1) is a cytosolic enzyme that cleaves L-arginine, the substrate of inducible nitric oxide synthase (iNOS), and thereby impairs the control of various intracellular pathogens. Herein, we investigated the role of ARG1 during infection with Salmonella enterica serovar Typhimurium (S.tm). To study the impact of ARG1 on Salmonella infections in vitro, bone marrow-derived macrophages (BMDM) from C57BL/6N wild-type, ARG1-deficient Tie2Cre+/−ARG1fl/fl and NRAMPG169 C57BL/6N mice were infected with S.tm. In wild-type BMDM, ARG1 was induced by S.tm and further upregulated by the addition of interleukin (IL)-4, whereas interferon-γ had an inhibitory effect. Deletion of ARG1 did not result in a reduction in bacterial numbers. In vivo, Arg1 mRNA was upregulated in the spleen, but not in the liver of C57BL/6N mice following intraperitoneal S.tm infection. The genetic deletion of ARG1 (Tie2Cre+/−ARG1fl/fl) or its pharmacological inhibition with CB-1158 neither affected the numbers of S.tm in spleen, liver and blood nor the expression of host response genes such as iNOS, IL-6 or tumour necrosis factor (TNF). Furthermore, ARG1 was dispensable for pathogen control irrespective of the presence or absence of the phagolysosomal natural resistance-associated macrophage protein 1 (NRAMP1). Thus, unlike the detrimental function of ARG1 seen during infections with other intraphagosomal microorganisms, ARG1 did not support bacterial survival in systemic salmonellosis, indicating differential roles of arginine metabolism for host immune response and microbe persistence depending on the type of pathogen. Full article
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16 pages, 2984 KiB  
Article
Decitabine Promotes Modulation in Phenotype and Function of Monocytes and Macrophages That Drive Immune Response Regulation
by Fabiana Albani Zambuzi, Priscilla Mariane Cardoso-Silva, Ricardo Cardoso Castro, Caroline Fontanari, Flavio da Silva Emery and Fabiani Gai Frantz
Cells 2021, 10(4), 868; https://doi.org/10.3390/cells10040868 - 12 Apr 2021
Cited by 7 | Viewed by 2488
Abstract
Decitabine is an approved hypomethylating agent used for treating hematological malignancies. Although decitabine targets altered cells, epidrugs can trigger immunomodulatory effects, reinforcing the hypothesis of immunoregulation in treated patients. We therefore aimed to evaluate the impact of decitabine treatment on the phenotype and [...] Read more.
Decitabine is an approved hypomethylating agent used for treating hematological malignancies. Although decitabine targets altered cells, epidrugs can trigger immunomodulatory effects, reinforcing the hypothesis of immunoregulation in treated patients. We therefore aimed to evaluate the impact of decitabine treatment on the phenotype and functions of monocytes and macrophages, which are pivotal cells of the innate immunity system. In vitro decitabine administration increased bacterial phagocytosis and IL-8 release, but impaired microbicidal activity of monocytes. In addition, during monocyte-to-macrophage differentiation, treatment promoted the M2-like profile, with increased expression of CD206 and ALOX15. Macrophages also demonstrated reduced infection control when exposed to Mycobacterium tuberculosis in vitro. However, cytokine production remained unchanged, indicating an atypical M2 macrophage. Furthermore, when macrophages were cocultured with lymphocytes, decitabine induced a reduction in the release of inflammatory cytokines such as IL-1β, TNF-α, and IFN-γ, maintaining IL-10 production, suggesting that decitabine could potentialize M2 polarization and might be considered as a therapeutic against the exacerbated immune response. Full article
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14 pages, 3192 KiB  
Article
STAT6 Signaling Mediates PPARγ Activation and Resolution of Acute Sterile Inflammation in Mice
by Ye-JI Lee, Bo-Min Kim, Young-Ho Ahn, Ji Ha Choi, Youn-Hee Choi and Jihee Lee Kang
Cells 2021, 10(3), 501; https://doi.org/10.3390/cells10030501 - 26 Feb 2021
Cited by 17 | Viewed by 2982
Abstract
The signal transducer and activator of transcription 6 (STAT6) transcription factor promotes activation of the peroxisome proliferator-activated receptor gamma (PPARγ) pathway in macrophages. Little is known about the effect of proximal signal transduction leading to PPARγ activation for the resolution of acute inflammation. [...] Read more.
The signal transducer and activator of transcription 6 (STAT6) transcription factor promotes activation of the peroxisome proliferator-activated receptor gamma (PPARγ) pathway in macrophages. Little is known about the effect of proximal signal transduction leading to PPARγ activation for the resolution of acute inflammation. Here, we studied the role of STAT6 signaling in PPARγ activation and the resolution of acute sterile inflammation in a murine model of zymosan-induced peritonitis. First, we showed that STAT6 is aberrantly activated in peritoneal macrophages after zymosan injection. Utilizing STAT6−/− and wild-type (WT) mice, we found that STAT6 deficiency further enhanced zymosan-induced proinflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-6, and macrophage inflammatory protein-2 in peritoneal lavage fluid (PLF) and serum, neutrophil numbers and total protein amount in PLF, but reduced proresolving molecules, such as IL-10 and hepatocyte growth factor, in PLF. The peritoneal macrophages and spleens of STAT6−/− mice exhibited lower mRNA and protein levels of PPARγ and its target molecules over the course of inflammation than those of WT mice. The deficiency of STAT6 was shown to impair efferocytosis by peritoneal macrophages. Taken together, these results suggest that enhanced STAT6 signaling results in PPARγ-mediated macrophage programming, contributing to increased efferocytosis and inflammation resolution. Full article
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14 pages, 1293 KiB  
Article
Choline Glycerophospholipid-Derived Prostaglandins Attenuate TNFα Gene Expression in Macrophages via a cPLA2α/COX-1 Pathway
by Alma M. Astudillo, Juan P. Rodríguez, Carlos Guijas, Julio M. Rubio, María A. Balboa and Jesús Balsinde
Cells 2021, 10(2), 447; https://doi.org/10.3390/cells10020447 - 19 Feb 2021
Cited by 6 | Viewed by 2215
Abstract
Macrophages are professional antigen presenting cells with intense phagocytic activity, strategically distributed in tissues and cavities. These cells are capable of responding to a wide variety of innate inflammatory stimuli, many of which are signaled by lipid mediators. The distribution of arachidonic acid [...] Read more.
Macrophages are professional antigen presenting cells with intense phagocytic activity, strategically distributed in tissues and cavities. These cells are capable of responding to a wide variety of innate inflammatory stimuli, many of which are signaled by lipid mediators. The distribution of arachidonic acid (AA) among glycerophospholipids and its subsequent release and conversion into eicosanoids in response to inflammatory stimuli such as zymosan, constitutes one of the most studied models. In this work, we used liquid and/or gas chromatography coupled to mass spectrometry to study the changes in the levels of membrane glycerophospholipids of mouse peritoneal macrophages and the implication of group IVA cytosolic phospholipase A2 (cPLA2α) in the process. In the experimental model used, we observed that the acute response of macrophages to zymosan stimulation involves solely the cyclooxygenase-1 (COX-1), which mediates the rapid synthesis of prostaglandins E2 and I2. Using pharmacological inhibition and antisense inhibition approaches, we established that cPLA2α is the enzyme responsible for AA mobilization. Zymosan stimulation strongly induced the hydrolysis of AA-containing choline glycerophospholipids (PC) and a unique phosphatidylinositol (PI) species, while the ethanolamine-containing glycerophospholipids remained constant or slightly increased. Double-labeling experiments with 3H- and 14C-labeled arachidonate unambiguously demonstrated that PC is the major, if not the exclusive source, of AA for prostaglandin E2 production, while both PC and PI appeared to contribute to prostaglandin I2 synthesis. Importantly, in this work we also show that the COX-1-derived prostaglandins produced during the early steps of macrophage activation restrict tumor necrosis factor-α production. Collectively, these findings suggest new approaches and targets to the selective inhibition of lipid mediator production in response to fungal infection. Full article
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Review

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22 pages, 16208 KiB  
Review
Physiological and Pathological Inflammation Induced by Antibodies and Pentraxins
by Chiara Elisabeth Geyer, Lynn Mes, Melissa Newling, Jeroen den Dunnen and Willianne Hoepel
Cells 2021, 10(5), 1175; https://doi.org/10.3390/cells10051175 - 12 May 2021
Cited by 9 | Viewed by 4602
Abstract
Macrophages play a key role in induction of inflammatory responses. These inflammatory responses are mostly considered to be instigated by activation of pattern recognition receptors (PRRs) or cytokine receptors. However, recently it has become clear that also antibodies and pentraxins, which can both [...] Read more.
Macrophages play a key role in induction of inflammatory responses. These inflammatory responses are mostly considered to be instigated by activation of pattern recognition receptors (PRRs) or cytokine receptors. However, recently it has become clear that also antibodies and pentraxins, which can both activate Fc receptors (FcRs), induce very powerful inflammatory responses by macrophages that can even be an order of magnitude greater than PRRs. While the physiological function of this antibody-dependent inflammation (ADI) is to counteract infections, undesired activation or over-activation of this mechanism will lead to pathology, as observed in a variety of disorders, including viral infections such as COVID-19, chronic inflammatory disorders such as Crohn’s disease, and autoimmune diseases such as rheumatoid arthritis. In this review we discuss how physiological ADI provides host defense by inducing pathogen-specific immunity, and how erroneous activation of this mechanism leads to pathology. Moreover, we will provide an overview of the currently known signaling and metabolic pathways that underlie ADI, and how these can be targeted to counteract pathological inflammation. Full article
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21 pages, 1263 KiB  
Review
Control of Macrophage Inflammation by P2Y Purinergic Receptors
by Dominik Klaver and Martin Thurnher
Cells 2021, 10(5), 1098; https://doi.org/10.3390/cells10051098 - 04 May 2021
Cited by 28 | Viewed by 4983
Abstract
Macrophages comprise a phenotypically and functionally diverse group of hematopoietic cells. Versatile macrophage subsets engage to ensure maintenance of tissue integrity. To perform tissue stress surveillance, macrophages express many different stress-sensing receptors, including purinergic P2X and P2Y receptors that respond to extracellular nucleotides [...] Read more.
Macrophages comprise a phenotypically and functionally diverse group of hematopoietic cells. Versatile macrophage subsets engage to ensure maintenance of tissue integrity. To perform tissue stress surveillance, macrophages express many different stress-sensing receptors, including purinergic P2X and P2Y receptors that respond to extracellular nucleotides and their sugar derivatives. Activation of G protein-coupled P2Y receptors can be both pro- and anti-inflammatory. Current examples include the observation that P2Y14 receptor promotes STAT1-mediated inflammation in pro-inflammatory M1 macrophages as well as the demonstration that P2Y11 receptor suppresses the secretion of tumor necrosis factor (TNF)-α and concomitantly promotes the release of soluble TNF receptors from anti-inflammatory M2 macrophages. Here, we review macrophage regulation by P2Y purinergic receptors, both in physiological and disease-associated inflammation. Therapeutic targeting of anti-inflammatory P2Y receptor signaling is desirable to attenuate excessive inflammation in infectious diseases such as COVID-19. Conversely, anti-inflammatory P2Y receptor signaling must be suppressed during cancer therapy to preserve its efficacy. Full article
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19 pages, 2032 KiB  
Review
The Role of Macrophages in the Development of Acute and Chronic Inflammatory Lung Diseases
by Jae-Won Lee, Wanjoo Chun, Hee Jae Lee, Jae-Hong Min, Seong-Man Kim, Ji-Yun Seo, Kyung-Seop Ahn and Sei-Ryang Oh
Cells 2021, 10(4), 897; https://doi.org/10.3390/cells10040897 - 14 Apr 2021
Cited by 100 | Viewed by 9575
Abstract
Macrophages play an important role in the innate and adaptive immune responses of organ systems, including the lungs, to particles and pathogens. Cumulative results show that macrophages contribute to the development and progression of acute or chronic inflammatory responses through the secretion of [...] Read more.
Macrophages play an important role in the innate and adaptive immune responses of organ systems, including the lungs, to particles and pathogens. Cumulative results show that macrophages contribute to the development and progression of acute or chronic inflammatory responses through the secretion of inflammatory cytokines/chemokines and the activation of transcription factors in the pathogenesis of inflammatory lung diseases, such as acute lung injury (ALI), acute respiratory distress syndrome (ARDS), ARDS related to COVID-19 (coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), allergic asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). This review summarizes the functions of macrophages and their associated underlying mechanisms in the development of ALI, ARDS, COVID-19-related ARDS, allergic asthma, COPD, and IPF and briefly introduces the acute and chronic experimental animal models. Thus, this review suggests an effective therapeutic approach that focuses on the regulation of macrophage function in the context of inflammatory lung diseases. Full article
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