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Biomedicine & Pharmacotherapy =... Oct 2023Tumor-associated macrophages (TAMs) are the most critical effector cells of innate immunity and the most abundant tumor-infiltrating immune cells. They play a key role... (Review)
Review
Tumor-associated macrophages (TAMs) are the most critical effector cells of innate immunity and the most abundant tumor-infiltrating immune cells. They play a key role in the clearance of apoptotic bodies, regulation of inflammation, and tissue repair to maintain homeostasis in vivo. With the progression of triple-negative breast cancer(TNBC), TAMs are "subverted" from tumor-promoting immune cells to tumor-promoting immune suppressor cells, which play a significant role in tumor development and are considered potential targets for cancer therapy. Here, we explored how macrophages, as the most important part of the TNBC ecosystem, are "subverted" to drive cancer evolution and the uniqueness of TAMs in TNBC progression and metastasis. Similarly, we discuss the rationale and available evidence for TAMs as potential targets for TNBC therapy.
Topics: Humans; Triple Negative Breast Neoplasms; Ecosystem; Macrophages; Tumor-Associated Macrophages; Immunity, Innate
PubMed: 37660651
DOI: 10.1016/j.biopha.2023.115414 -
Cancer Immunology, Immunotherapy : CII Dec 2023Macrophages are important precursor cell types of the innate immune system and bridge adaptive immune responses through the antigen presentation system. Meanwhile,... (Review)
Review
Macrophages are important precursor cell types of the innate immune system and bridge adaptive immune responses through the antigen presentation system. Meanwhile, macrophages constitute substantial portion of the stromal cells in the tumor microenvironment (TME) (referred to as tumor-associated macrophages, or TAMs) and exhibit conflicting roles in the development, invasion, and metastasis of thyroid cancer (TC). Moreover, TAMs play a crucial role to the behavior of TC due to their high degree of infiltration and prognostic relevance. Generally, TAMs can be divided into two subgroups; M1-like TAMs are capable of directly kill tumor cells, and recruiting and activating other immune cells in the early stages of cancer. However, due to changes in the TME, M2-like TAMs gradually increase and promote tumor progression. This review aims to discuss the impact of TAMs on TC, including their role in tumor promotion, gene mutation, and other factors related to the polarization of TAMs. Finally, we will explore the M2-like TAM-centered therapeutic strategies, including chemotherapy, clinical trials, and combinatorial immunotherapy.
Topics: Humans; Tumor-Associated Macrophages; Thyroid Neoplasms; Prognosis; Macrophages; Immunotherapy; Tumor Microenvironment
PubMed: 37796300
DOI: 10.1007/s00262-023-03549-6 -
Immunological Reviews Oct 2023The failure to resolve inflammation underpins to several prevalent diseases, like atherosclerosis, and so identifying ways to boost resolution is unmet clinical needs.... (Review)
Review
The failure to resolve inflammation underpins to several prevalent diseases, like atherosclerosis, and so identifying ways to boost resolution is unmet clinical needs. The resolution of inflammation is governed by several factors such as specialized pro-resolving mediators (SPMs) that counter-regulate pro-inflammatory pathways and promote tissue repair without compromising host defense. A major function of nearly all SPMs is to enhance the clearance of dead cells or efferocytosis. As such, phagocytes, such as macrophages, are essential cellular players in the resolution of inflammation because of their ability to rapidly and efficiently clear dead cells. This review highlights the role of SPMs in the clearance of apoptotic and necroptotic cells and offers insights into how targeting efferocytosis may provide new treatments for non-resolving diseases, like atherosclerosis.
Topics: Humans; Inflammation; Phagocytosis; Atherosclerosis; Macrophages; Inflammation Mediators
PubMed: 37787174
DOI: 10.1111/imr.13278 -
Metabolic heterogeneity of tissue-resident macrophages in homeostasis and during helminth infection.Nature Communications Sep 2023Tissue-resident macrophage populations constitute a mosaic of phenotypes, yet how their metabolic states link to the range of phenotypes and functions in vivo is still...
Tissue-resident macrophage populations constitute a mosaic of phenotypes, yet how their metabolic states link to the range of phenotypes and functions in vivo is still poorly defined. Here, using high-dimensional spectral flow cytometry, we observe distinct metabolic profiles between different organs and functionally link acetyl CoA carboxylase activity to efferocytotic capacity. Additionally, differences in metabolism are evident within populations from a specific site, corresponding to relative stages of macrophage maturity. Immune perturbation with intestinal helminth infection increases alternative activation and metabolic rewiring of monocyte-derived macrophage populations, while resident TIM4 intestinal macrophages remain immunologically and metabolically hyporesponsive. Similar metabolic signatures in alternatively-activated macrophages are seen from different tissues using additional helminth models, but to different magnitudes, indicating further tissue-specific contributions to metabolic states. Thus, our high-dimensional, flow-based metabolic analyses indicates complex metabolic heterogeneity and dynamics of tissue-resident macrophage populations at homeostasis and during helminth infection.
Topics: Humans; Homeostasis; Histiocytes; Helminthiasis; Macrophages; Flow Cytometry
PubMed: 37699869
DOI: 10.1038/s41467-023-41353-z -
Journal of Molecular Medicine (Berlin,... May 2024Diabetic retinopathy (DR) is recognized as a neurovascular complication of diabetes, and emerging evidence underscores the pivotal role of inflammation in its... (Review)
Review
Diabetic retinopathy (DR) is recognized as a neurovascular complication of diabetes, and emerging evidence underscores the pivotal role of inflammation in its pathophysiology. Macrophage activation is increasingly acknowledged as a key contributor to the onset and progression of DR. Different populations of macrophages originating from distinct sources contribute to DR-associated inflammation. Retinal macrophages can be broadly categorized into two main groups based on their origin: intrinsic macrophages situated within the retina and vitreoretinal interface and macrophages derived from infiltrating monocytes. The former comprises microglia (MG), perivascular macrophages, and macrophage-like hyalocytes. Retinal MG, as the principal population of tissue-resident population of mononuclear phagocytes, exhibits high heterogeneity and plasticity while serving as a crucial connector between retinal capillaries and synapses. This makes MG actively involved in the pathological processes across various stages of DR. Activated hyalocytes also contribute to the pathological progression of advanced DR. Additionally, recruited monocytes, displaying rapid turnover in circulation, augment the population of retinal macrophages during DR pathogenesis, exerting pathogenic or protective effect based on different subtypes. In this review, we examine novel perspectives on macrophage biology based on recent studies elucidating the diversity of macrophage identity and function, as well as the mechanisms influencing macrophage behavior. These insights may pave the way for innovative therapeutic strategies in the management of DR.
Topics: Diabetic Retinopathy; Humans; Animals; Macrophages; Macrophage Activation; Retina; Microglia; Monocytes
PubMed: 38429382
DOI: 10.1007/s00109-024-02437-5 -
Frontiers in Immunology 2023Cancer progression is primarily caused by interactions between transformed cells and the components of the tumor microenvironment (TME). TAMs (tumor-associated... (Review)
Review
Cancer progression is primarily caused by interactions between transformed cells and the components of the tumor microenvironment (TME). TAMs (tumor-associated macrophages) make up the majority of the invading immune components, which are further categorized as anti-tumor M1 and pro-tumor M2 subtypes. While M1 is known to have anti-cancer properties, M2 is recognized to extend a protective role to the tumor. As a result, the tumor manipulates the TME in such a way that it induces macrophage infiltration and M1 to M2 switching bias to secure its survival. This M2-TAM bias in the TME promotes cancer cell proliferation, neoangiogenesis, lymphangiogenesis, epithelial-to-mesenchymal transition, matrix remodeling for metastatic support, and TME manipulation to an immunosuppressive state. TAMs additionally promote the emergence of cancer stem cells (CSCs), which are known for their ability to originate, metastasize, and relapse into tumors. CSCs also help M2-TAM by revealing immune escape and survival strategies during the initiation and relapse phases. This review describes the reasons for immunotherapy failure and, thereby, devises better strategies to impair the tumor-TAM crosstalk. This study will shed light on the understudied TAM-mediated tumor progression and address the much-needed holistic approach to anti-cancer therapy, which encompasses targeting cancer cells, CSCs, and TAMs all at the same time.
Topics: Humans; Tumor-Associated Macrophages; Tumor Microenvironment; Macrophages; Neovascularization, Pathologic; Recurrence
PubMed: 38035101
DOI: 10.3389/fimmu.2023.1295257 -
ACS Nano Sep 2023Cytokine storm is a common complication of COVID-19 pneumonia and has been proven to contribute to high mortality rates. However, current treatment approaches exhibit...
Cytokine storm is a common complication of COVID-19 pneumonia and has been proven to contribute to high mortality rates. However, current treatment approaches exhibit limited potential to balance immune response and overproduction of inflammatory cytokines, leading to poor therapeutic outcomes. Herein, a smart bioengineered neutrophil, Extinguisher, composed of live neutrophils encapsulating the liposome formulation of NF-κB suppressor MLN4924 and STING inhibitor H-151 (Lip@MH), is developed for alleviating the hyperinflammatory cytokine storm. Extinguisher inherits motility and chemotaxis characteristics of neutrophils, allowing for the specific delivery and sustained release of Lip@MH within inflamed tissues. Subsequently, Lip@MH effectively transports anti-inflammatory agents into macrophages and synergistically inhibits inflammatory pathways of NF-κB and STING, leading to decreased production of cytokines. studies demonstrate that Extinguisher not only selectively accumulates at the site of pneumonia caused by -induced acute lung injury but inhibits the production of inflammatory factors through regulating NF-κB/STING signaling pathways, thereby effectively calming cytokine storm. Importantly, Extinguisher significantly improves therapeutic benefits and survival in mice with acute pneumonia. Therefore, Extinguisher represents an appropriate combination of cell therapy and immunoregulation for cytokine storm intervention and may bring insights into the treatment of COVID-19 pneumonia.
Topics: Animals; Mice; COVID-19; Neutrophils; NF-kappa B; Cytokine Release Syndrome; Pneumonia; Macrophages; Cytokines
PubMed: 37596997
DOI: 10.1021/acsnano.3c00227 -
Journal of Experimental & Clinical... Sep 2023Macrophages are highly plastic in different tissues and can differentiate into functional subpopulations under different stimuli. Tumor-associated macrophages (TAMs) are... (Review)
Review
Macrophages are highly plastic in different tissues and can differentiate into functional subpopulations under different stimuli. Tumor-associated macrophages (TAMs) are one of the most important innate immune cells implicated in the establishment of an immunosuppressive tumor microenvironment (TME). Recent evidence pinpoints the critical role of metabolic reprogramming in dictating pro-tumorigenic functions of TAMs. Both tumor cells and macrophages undergo metabolic reprogramming to meet energy demands in the TME. Understanding the metabolic rewiring in TAMs can shed light on immune escape mechanisms and provide insights into repolarizing TAMs towards anti-tumorigenic function. Here, we discuss how metabolism impinges on the functional divergence of macrophages and its relevance to macrophage polarization in the TME.
Topics: Humans; Tumor-Associated Macrophages; Macrophages; Carcinogenesis; Immunosuppressive Agents; Macrophage Activation; Tumor Microenvironment
PubMed: 37740232
DOI: 10.1186/s13046-023-02832-9 -
Proceedings of the National Academy of... Sep 2023A hallmark of multiple sclerosis (MS) is the formation of multiple focal demyelinating lesions within the central nervous system (CNS). These lesions mainly consist of...
A hallmark of multiple sclerosis (MS) is the formation of multiple focal demyelinating lesions within the central nervous system (CNS). These lesions mainly consist of phagocytes that play a key role in lesion progression and remyelination, and therefore represent a promising therapeutic target in MS. We recently showed that unsaturated fatty acids produced by stearoyl-CoA desaturase-1 induce inflammatory foam cell formation during demyelination. These fatty acids are elongated by the "elongation of very long chain fatty acids" proteins (ELOVLs), generating a series of functionally distinct lipids. Here, we show that the expression and activity of ELOVLs are altered in myelin-induced foam cells. Especially ELOVL6, an enzyme responsible for converting saturated and monounsaturated C16 fatty acids into C18 species, was found to be up-regulated in myelin phagocytosing phagocytes in vitro and in MS lesions. Depletion of induced a repair-promoting phagocyte phenotype through activation of the S1P/PPARγ pathway. -deficient foamy macrophages showed enhanced ABCA1-mediated lipid efflux, increased production of neurotrophic factors, and reduced expression of inflammatory mediators. Moreover, our data show that ELOVL6 hampers CNS repair, as deficiency prevented demyelination and boosted remyelination in organotypic brain slice cultures and the mouse cuprizone model. These findings indicate that targeting ELOVL6 activity may be an effective strategy to stimulate CNS repair in MS and other neurodegenerative diseases.
Topics: Animals; Mice; Adipogenesis; Disease Models, Animal; Fatty Acids; Fatty Acids, Monounsaturated; Foam Cells; Multiple Sclerosis; Remyelination
PubMed: 37669365
DOI: 10.1073/pnas.2301030120 -
Journal of Extracellular Vesicles Aug 2023While apolipoprotein E (apoE) expression by myeloid cells is recognized to control inflammation, whether such benefits can be communicated via extracellular vesicles is...
While apolipoprotein E (apoE) expression by myeloid cells is recognized to control inflammation, whether such benefits can be communicated via extracellular vesicles is not known. Through the study of extracellular vesicles produced by macrophages derived from the bone marrow of Wildtype (WT-BMDM-EV) and ApoE deficient (EKO-BMDM-EV) mice, we uncovered a critical role for apoE expression in regulating their cell signaling properties. WT-BMDM-EV communicated anti-inflammatory properties to recipient myeloid cells by increasing cellular levels of apoE and miR-146a-5p, that reduced NF-κB signalling. They also downregulated cellular levels of miR-142a-3p, resulting in increased levels of its target carnitine palmitoyl transferase 1A (CPT1A) which improved fatty acid oxidation (FAO) and oxidative phosphorylation (OxPHOS) in recipient cells. Such favorable metabolic polarization enhanced cell-surface MerTK levels and the phagocytic uptake of apoptotic cells. In contrast, EKO-BMDM-EV exerted opposite effects by reducing cellular levels of apoE and miR-146a-5p, which increased NF-κB-driven GLUT1-mediated glucose uptake, aerobic glycolysis, and oxidative stress. Furthermore, EKO-BMDM-EV increased cellular miR-142a-3p levels, which reduced CPT1A levels and impaired FAO and OxPHOS in recipient myeloid cells. When cultured with naïve CD4 T lymphocytes, EKO-BMDM-EV drove their activation and proliferation, and fostered their transition to a Th1 phenotype. While infusions of WT-BMDM-EV into hyperlipidemic mice resolved inflammation, infusions of EKO-BMDM-EV increased hematopoiesis and drove inflammatory responses in myeloid cells and T lymphocytes. ApoE-dependent immunometabolic signaling by macrophage extracellular vesicles was dependent on transcriptional axes controlled by miR-146a-5p and miR-142a-3p that could be reproduced by infusing miR-146a mimics & miR-142a antagonists into hyperlipidemic apoE-deficient mice. Together, our findings unveil a novel property for apoE expression in macrophages that modulates the immunometabolic regulatory properties of their secreted extracellular vesicles.
Topics: Animals; Mice; Extracellular Vesicles; NF-kappa B; Hyperlipidemias; Signal Transduction; Macrophages; Inflammation; Apolipoproteins E; MicroRNAs
PubMed: 37593979
DOI: 10.1002/jev2.12345