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Cells
Special Issues
Macrophage Activation and Regulation
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Macrophage Activation and Regulation

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

Deadline for manuscript submissions: closed (31 October 2024) | Viewed by 6682

Special Issue Editor

Dr. Subhankar Mukhopadhyay

E-Mail Website
Guest Editor
Faculty of Life Sciences & Medicine, King's College London, London, UK
Interests: macrophage; immunology; innate immunity; human induced pluripotent stem cells

Special Issue Information

Dear Colleagues,

Activated macrophages are a critical component of host defence that provides frontline protection against pathogens and malignant cells; they are also a potent inducer and a key regulator of inflammation. Dysregulated macrophage activation contributes to a spectrum of diseases ranging from immunodeficiency inflammatory/immune-mediated to degenerative diseases. George Mackaness first coined the term “macrophage activation” to describe a state of enhanced microbicidal capacity in response to antigen-non-specific stimuli. Since then, the concept has continually evolved through multiple revisions and refinements. Nathan et al. showed that interferon-gamma is the key inducer of “classical activation”, soon followed by Gordon et al.’s discovery that IL-4/13 induces an alternative activation. Mantovani proposed the M1/M2 paradigm; a more flexible spectrum model is now preferred by many investigators, avoiding binary definitions. More recently, Netea et al. championed the concept of “trained immunity” as an antigen-non-specific innate immune memory.

Over the years, much has been learned about the pathways that induce or regulate macrophage activation and their role in homeostasis and diseases. This Special Issue of Cells aims to highlight the latest developments and cutting-edge research in this exciting and ever-evolving field of research. We invite submissions of original research articles and comprehensive reviews from investigators across the globe.

Dr. Subhankar Mukhopadhyay
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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • macrophage activation
  • classical and alternative activation
  • M1 and M2 activation, inflammatory and regulatory cytokines
  • inflammatory and pro-resolution lipid mediators
  • immune activatory and inhibitory receptors
  • ITAM and ITIMs

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Published Papers (5 papers)

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Research

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22 pages, 7463 KiB  
Article
Ly6Chi Monocytes Are Metabolically Reprogrammed in the Blood during Inflammatory Stimulation and Require Intact OxPhos for Chemotaxis and Monocyte to Macrophage Differentiation
by Gareth S. D. Purvis, Eileen McNeill, Benjamin Wright, Keith M. Channon and David R. Greaves
Cells 2024, 13(11), 916; https://doi.org/10.3390/cells13110916 - 26 May 2024
Cited by 1 | Viewed by 1729
Abstract
Acute inflammation is a rapid and dynamic process involving the recruitment and activation of multiple cell types in a coordinated and precise manner. Here, we investigate the origin and transcriptional reprogramming of monocytes using a model of acute inflammation, zymosan-induced peritonitis. Monocyte trafficking [...] Read more.
Acute inflammation is a rapid and dynamic process involving the recruitment and activation of multiple cell types in a coordinated and precise manner. Here, we investigate the origin and transcriptional reprogramming of monocytes using a model of acute inflammation, zymosan-induced peritonitis. Monocyte trafficking and adoptive transfer experiments confirmed that monocytes undergo rapid phenotypic change as they exit the blood and give rise to monocyte-derived macrophages that persist during the resolution of inflammation. Single-cell transcriptomics revealed significant heterogeneity within the surface marker-defined CD11b+Ly6G−Ly6Chi monocyte populations within the blood and at the site of inflammation. We show that two major transcriptional reprogramming events occur during the initial six hours of Ly6Chi monocyte mobilisation, one in the blood priming monocytes for migration and a second at the site of inflammation. Pathway analysis revealed an important role for oxidative phosphorylation (OxPhos) during both these reprogramming events. Experimentally, we demonstrate that OxPhos via the intact mitochondrial electron transport chain is essential for murine and human monocyte chemotaxis. Moreover, OxPhos is needed for monocyte-to-macrophage differentiation and macrophage M(IL-4) polarisation. These new findings from transcriptional profiling open up the possibility that shifting monocyte metabolic capacity towards OxPhos could facilitate enhanced macrophage M2-like polarisation to aid inflammation resolution and tissue repair. Full article
(This article belongs to the Special Issue Macrophage Activation and Regulation)
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21 pages, 5518 KiB  
Article
Effects of Akt Activator SC79 on Human M0 Macrophage Phagocytosis and Cytokine Production
by Robert J. Lee, Nithin D. Adappa and James N. Palmer
Cells 2024, 13(11), 902; https://doi.org/10.3390/cells13110902 - 24 May 2024
Viewed by 1319
Abstract
Akt is an important kinase in metabolism. Akt also phosphorylates and activates endothelial and neuronal nitric oxide (NO) synthases (eNOS and nNOS, respectively) expressed in M0 (unpolarized) macrophages. We showed that e/nNOS NO production downstream of bitter taste receptors enhances macrophage phagocytosis. In [...] Read more.
Akt is an important kinase in metabolism. Akt also phosphorylates and activates endothelial and neuronal nitric oxide (NO) synthases (eNOS and nNOS, respectively) expressed in M0 (unpolarized) macrophages. We showed that e/nNOS NO production downstream of bitter taste receptors enhances macrophage phagocytosis. In airway epithelial cells, we also showed that the activation of Akt by a small molecule (SC79) enhances NO production and increases levels of nuclear Nrf2, which reduces IL-8 transcription during concomitant stimulation with Toll-like receptor (TLR) 5 agonist flagellin. We hypothesized that SC79’s production of NO in macrophages might likewise enhance phagocytosis and reduce the transcription of some pro-inflammatory cytokines. Using live cell imaging of fluorescent biosensors and indicator dyes, we found that SC79 induces Akt activation, NO production, and downstream cGMP production in primary human M0 macrophages. This was accompanied by a reduction in IL-6, IL-8, and IL-12 production during concomitant stimulation with bacterial lipopolysaccharide, an agonist of pattern recognition receptors including TLR4. Pharmacological inhibitors suggested that this effect was dependent on Akt and Nrf2. Together, these data suggest that several macrophage immune pathways are regulated by SC79 via Akt. A small-molecule Akt activator may be useful in some infection settings, warranting future in vivo studies. Full article
(This article belongs to the Special Issue Macrophage Activation and Regulation)
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17 pages, 2691 KiB  
Article
The BK Channel Limits the Pro-Inflammatory Activity of Macrophages
by Yihe Chen, Nikita Markov, Lea Gigon, Aref Hosseini, Shida Yousefi, Darko Stojkov and Hans-Uwe Simon
Cells 2024, 13(4), 322; https://doi.org/10.3390/cells13040322 - 9 Feb 2024
Viewed by 1538
Abstract
Macrophages play a crucial role in the innate immune response, serving as key effector cells in the defense against pathogens. Although the role of the large-conductance voltage and calcium-activated potassium channel, also known as the KCa1.1 or BK channel, in regulating [...] Read more.
Macrophages play a crucial role in the innate immune response, serving as key effector cells in the defense against pathogens. Although the role of the large-conductance voltage and calcium-activated potassium channel, also known as the KCa1.1 or BK channel, in regulating neurotransmitter release and smooth muscle contraction is well known, its potential involvement in immune regulation remains unclear. We employed BK-knockout macrophages and noted that the absence of a BK channel promotes the polarization of macrophages towards a pro-inflammatory phenotype known as M1 macrophages. Specifically, the absence of the BK channel resulted in a significant increase in the secretion of the pro-inflammatory cytokine IL-6 and enhanced the activity of extracellular signal-regulated kinases 1 and 2 (Erk1/2 kinases), Ca2+/calmodulin-dependent protein kinase II (CaMKII), and the transcription factor ATF-1 within M1 macrophages. Additionally, the lack of the BK channel promoted the activation of the AIM2 inflammasome without affecting the activation of the NLRC4 and NLRP3 inflammasomes. To further investigate the role of the BK channel in regulating AIM2 inflammasome activation, we utilized BK channel inhibitors, such as paxilline and iberiotoxin, along with the BK channel activator NS-11021. Pharmacological inactivation of the BK channel increased, and its stimulation inhibited IL-1β production following AIM2 inflammasome activation in wild-type macrophages. Moreover, wild-type macrophages displayed increased calcium influx when activated with the AIM2 inflammasome, whereas BK-knockout macrophages did not due to the impaired extracellular calcium influx upon activation. Furthermore, under conditions of a calcium-free medium, IL-1β production following AIM2 inflammasome activation was increased in both wild-type and BK-knockout macrophages. This suggests that the BK channel is required for the influx of extracellular calcium in macrophages, thus limiting AIM2 inflammasome activation. In summary, our study reveals a regulatory role of the BK channel in macrophages under inflammatory conditions. Full article
(This article belongs to the Special Issue Macrophage Activation and Regulation)
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Review

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19 pages, 2156 KiB  
Review
How to Use Macrophages Against Cancer
by Jacek Kuźnicki, Natalia Janicka, Barbara Białynicka-Birula, Wojciech Kuźnicki, Hanna Chorążyczewska, Iwona Deszcz and Julita Kulbacka
Cells 2024, 13(23), 1948; https://doi.org/10.3390/cells13231948 (registering DOI) - 23 Nov 2024
Abstract
Numerous studies have demonstrated the significant influence of immune cells on cancer development and treatment. This study specifically examines tumor-associated macrophages (TAMs), detailing their characteristics and roles in tumorigenesis and analyzing the impact of the ratio of TAM subtypes on patient survival and [...] Read more.
Numerous studies have demonstrated the significant influence of immune cells on cancer development and treatment. This study specifically examines tumor-associated macrophages (TAMs), detailing their characteristics and roles in tumorigenesis and analyzing the impact of the ratio of TAM subtypes on patient survival and prognosis. It is established that TAMs interact with immunotherapy, radiotherapy, and chemotherapy, thereby influencing the efficacy of these treatments. Emerging therapies are explored, such as the use of nanoparticles (NPs) for drug delivery to target TAMs and modify the tumor microenvironment (TME). Additionally, novel anticancer strategies like the use of chimeric antigen receptor macrophages (CAR-Ms) show promising results. Investigations into the training of macrophages using magnetic fields, plasma stimulation, and electroporation are also discussed. Finally, this study presents prospects for the combination of TAM-based therapies for enhanced cancer treatment outcomes. Full article
(This article belongs to the Special Issue Macrophage Activation and Regulation)
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16 pages, 2113 KiB  
Review
Focal Adhesion Kinase and Colony Stimulating Factors: Intestinal Homeostasis and Innate Immunity Crosstalk
by Nicholas D. Brown and Emilie E. Vomhof-DeKrey
Cells 2024, 13(14), 1178; https://doi.org/10.3390/cells13141178 - 11 Jul 2024
Viewed by 1340
Abstract
Thousands struggle with acute and chronic intestinal injury due to various causes. Epithelial intestinal healing is dependent on phenotypic transitions to a mobile phenotype. Focal adhesion kinase (FAK) is a ubiquitous protein that is essential for cell mobility. This phenotype change is mediated [...] Read more.
Thousands struggle with acute and chronic intestinal injury due to various causes. Epithelial intestinal healing is dependent on phenotypic transitions to a mobile phenotype. Focal adhesion kinase (FAK) is a ubiquitous protein that is essential for cell mobility. This phenotype change is mediated by FAK activation and proves to be a promising target for pharmaceutical intervention. While FAK is crucial for intestinal healing, new evidence connects FAK with innate immunity and the importance it plays in macrophage/monocyte chemotaxis, as well as other intracellular signaling cascades. These cascades play a part in macrophage/monocyte polarization, maturation, and inflammation that is associated with intestinal injury. Colony stimulating factors (CSFs) such as macrophage colony stimulating factor (M-CSF/CSF-1) and granulocyte macrophage colony stimulating factor (GM-CSF/CSF-2) play a critical role in maintaining homeostasis within intestinal mucosa by crosstalk capabilities between macrophages and epithelial cells. The communication between these cells is imperative in orchestrating healing upon injury. Diving deeper into these connections may allow us a greater insight into the role that our immune system plays in healing, as well as a better comprehension of inflammatory diseases of the gut. Full article
(This article belongs to the Special Issue Macrophage Activation and Regulation)
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