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Cellular and Molecular Life Sciences :... Sep 2021Different types of multinucleated giant cells (MGCs) of myeloid origin have been described; osteoclasts are the most extensively studied because of their importance in... (Review)
Review
Different types of multinucleated giant cells (MGCs) of myeloid origin have been described; osteoclasts are the most extensively studied because of their importance in bone homeostasis. MGCs are formed by cell-to-cell fusion, and most types have been observed in pathological conditions, especially in infectious and non-infectious chronic inflammatory contexts. The precise role of the different MGCs and the mechanisms that govern their formation remain poorly understood, likely due to their heterogeneity. First, we will introduce the main populations of MGCs derived from the monocyte/macrophage lineage. We will then discuss the known molecular actors mediating the early stages of fusion, focusing on cell-surface receptors involved in the cell-to-cell adhesion steps that ultimately lead to multinucleation. Given that cell-to-cell fusion is a complex and well-coordinated process, we will also describe what is currently known about the evolution of F-actin-based structures involved in macrophage fusion, i.e., podosomes, zipper-like structures, and tunneling nanotubes (TNT). Finally, the localization and potential role of the key fusion mediators related to the formation of these F-actin structures will be discussed. This review intends to present the current status of knowledge of the molecular and cellular mechanisms supporting multinucleation of myeloid cells, highlighting the gaps still existing, and contributing to the proposition of potential disease-specific MGC markers and/or therapeutic targets.
Topics: Cell Adhesion; Giant Cells; Humans; Integrins; Macrophages; Myeloid Cells; Osteoclasts; Osteogenesis; Podosomes; Receptors, Immunologic
PubMed: 34296319
DOI: 10.1007/s00018-021-03875-x -
International Journal of Molecular... Aug 2018Recent evidence suggests that myeloid cells are critical in cancer development and therapy resistance processes. Pharmacological targeting of tumor-associated myeloid... (Review)
Review
Recent evidence suggests that myeloid cells are critical in cancer development and therapy resistance processes. Pharmacological targeting of tumor-associated myeloid cells is an emerging approach among upcoming immune therapies. Surprisingly, myeloid cells are heterogeneous, including a subset of the myeloid cell displaying angiogenic properties in solid tumors. There is an urgent need to delineate angiogenic myeloid cell populations in order to facilitate specific targeting of protumor myeloid cells among heterogeneous pool. This review article is intended to compile all the relevant information in the literature for improved understanding of angiogenic myeloid cells and their role in tumor refractoriness to cancer therapy.
Topics: Animals; Antigens, CD; Cadherins; Humans; Immunotherapy; Myeloid Cells; Neoplasms; Platelet Endothelial Cell Adhesion Molecule-1; Receptor, TIE-2; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2
PubMed: 30158456
DOI: 10.3390/ijms19092565 -
Seminars in Immunology Aug 2014Diabetes can promote a state of chronic inflammation associated with serious complications that are difficult to treat, including ulceration of the lower extremities and... (Review)
Review
Diabetes can promote a state of chronic inflammation associated with serious complications that are difficult to treat, including ulceration of the lower extremities and chronic wounds. Chronic wounds are often incurable and contribute to both a reduced quality of life for patients and an enormous burden for healthcare services. In diabetes, the inflammatory response early in wound healing is inappropriately amplified and prolonged, leading to the persistent presence in the wound of vastly elevated numbers of dysfunctional, hyperpolarised macrophages that fail to transition to a pro-healing phenotype. Recent evidence suggests that systemic chronic inflammation induces intrinsic defects in monocytes via chromatin modifications that may pre-programme monocytes to a pro-inflammatory phenotype, while the local wound environment inhibits differentiation to a pro-healing phenotype. Current understanding remains incomplete, and careful dissection of how local and systemic inflammation combine to negatively influence myeloid cell development will be key to developing effective therapies aimed at healing the diabetic wound.
Topics: Animals; Diabetes Complications; Humans; Inflammation; Mice; Myeloid Cells; Wound Healing
PubMed: 24954378
DOI: 10.1016/j.smim.2014.04.006 -
Cells Oct 2021Myeloid cells are a key determinant of tumor progression and patient outcomes in a range of cancers and are therefore being actively pursued as targets of new... (Review)
Review
Myeloid cells are a key determinant of tumor progression and patient outcomes in a range of cancers and are therefore being actively pursued as targets of new immunotherapies. The recent use of high-dimensional single-cell approaches, e.g., mass cytometry and single-cell RNA-sequencing (scRNA-seq) has reinforced the predominance of myeloid cells in the tumor microenvironment and uncovered their phenotypic diversity in different cancers. The cancerous metabolic environment has emerged as a critical modulator of myeloid cell functions in anti-tumor immunity versus immune suppression and immune evasion. Here, we discuss mechanisms of immune-metabolic crosstalk in tumorigenesis, with a particular focus on the tumor-associated myeloid cell's metabolic programs. We highlight the impact of several metabolic pathways on the pro-tumoral functions of tumor-associated macrophages and myeloid-derived suppressor cells and discuss the potential myeloid cell metabolic checkpoints for cancer immunotherapy, either as monotherapies or in combination with other immunotherapies.
Topics: Clinical Trials as Topic; Glycolysis; Humans; Lipid Metabolism; Myeloid Cells; Tumor Microenvironment; Wnt Proteins
PubMed: 34831183
DOI: 10.3390/cells10112960 -
Advanced Drug Delivery Reviews Apr 2016The tumor microenvironment is recognized as a key factor in the multiple stages of cancer progression, mediating local resistance, immune-escape and metastasis. Cancer... (Review)
Review
The tumor microenvironment is recognized as a key factor in the multiple stages of cancer progression, mediating local resistance, immune-escape and metastasis. Cancer growth and progression require remodeling of the tumor stromal microenvironment, such as the development of tumor-associated blood vessels, recruitment of bone marrow-derived cells and cytokine processing. Extracellular matrix breakdown achieved by proteases like the fibrinolytic factor plasmin and matrix metalloproteases is necessary for cell migration crucial for cancer invasion and metastasis. Key components of the fibrinolytic system are expressed in cells of the tumor microenvironment. Plasmin can control growth factor bioavailability, or the regulation of other proteases leading to angiogenesis, and inflammation. In this review, we will focus on the role of the fibrinolytic system in the tumor microenvironment summarizing our current understanding of the role of the fibrinolytic factors for the modulation of the local chemokine/cytokine milieu, resulting in myeloid cell recruitment, which can promote neoangiogenesis.
Topics: Cell Movement; Disease Progression; Fibrinolysis; Fibrinolytic Agents; Humans; Myeloid Cells; Neoplasms; Neovascularization, Pathologic; Tumor Microenvironment
PubMed: 26588878
DOI: 10.1016/j.addr.2015.11.010 -
Circulation Research Apr 2020Unhealthy diet, lack of exercise, psychosocial stress, and insufficient sleep are increasingly prevalent modifiable risk factors for cardiovascular disease. Accumulating... (Review)
Review
Unhealthy diet, lack of exercise, psychosocial stress, and insufficient sleep are increasingly prevalent modifiable risk factors for cardiovascular disease. Accumulating evidence indicates that these risk factors may fuel chronic inflammatory processes that are active in atherosclerosis and lead to myocardial infarction and stroke. In concert with hyperlipidemia, maladaptive immune system activities can contribute to disease progression and increase the probability of adverse events. In this review, we discuss recent insight into how the above modifiable risk factors influence innate immunity. Specifically, we focus on pathways that raise systemic myeloid cell numbers and modulate immune cell phenotypes, reviewing hematopoiesis, leukocyte trafficking, and innate immune cell accumulation in cardiovascular organs. Often, relevant mechanisms that begin with lifestyle choices and lead to cardiovascular events span multiple organ systems, including the central nervous, endocrine, metabolic, hematopoietic, immune and, finally, the cardiovascular system. We argue that deciphering such pathways provides not only support for preventive interventions but also opportunities to develop biomimetic immunomodulatory therapeutics that mitigate cardiovascular inflammation.
Topics: Animals; Cardiovascular Diseases; Diet, Healthy; Exercise; Healthy Lifestyle; Heart Disease Risk Factors; Hematopoiesis; Humans; Immunity, Innate; Myeloid Cells; Protective Factors; Risk Assessment; Risk Reduction Behavior; Signal Transduction; Sleep
PubMed: 32324501
DOI: 10.1161/CIRCRESAHA.120.315936 -
Cancer Immunology Research May 2024Solid tumors are dense three-dimensional (3D) multicellular structures that enable efficient receptor-ligand trans interactions via close cell-cell contact....
Solid tumors are dense three-dimensional (3D) multicellular structures that enable efficient receptor-ligand trans interactions via close cell-cell contact. Immunoglobulin-like transcript (ILT)2 and ILT4 are related immune-suppressive receptors that play a role in the inhibition of myeloid cells within the tumor microenvironment. The relative contribution of ILT2 and ILT4 to immune inhibition in the context of solid tumor tissue has not been fully explored. We present evidence that both ILT2 and ILT4 contribute to myeloid inhibition. We found that although ILT2 inhibits myeloid cell activation in the context of trans-engagement by MHC-I, ILT4 efficiently inhibits myeloid cells in the presence of either cis- or trans-engagement. In a 3D spheroid tumor model, dual ILT2/ILT4 blockade was required for the optimal activation of myeloid cells, including the secretion of CXCL9 and CCL5, upregulation of CD86 on dendritic cells, and downregulation of CD163 on macrophages. Humanized mouse tumor models showed increased immune activation and cytolytic T-cell activity with combined ILT2 and ILT4 blockade, including evidence of the generation of immune niches, which have been shown to correlate with clinical response to immune-checkpoint blockade. In a human tumor explant histoculture system, dual ILT2/ILT4 blockade increased CXCL9 secretion, downregulated CD163 expression, and increased the expression of M1 macrophage, IFNγ, and cytolytic T-cell gene signatures. Thus, we have revealed distinct contributions of ILT2 and ILT4 to myeloid cell biology and provide proof-of-concept data supporting the combined blockade of ILT2 and ILT4 to therapeutically induce optimal myeloid cell reprogramming in the tumor microenvironment.
Topics: Receptors, Immunologic; Animals; Humans; Mice; Tumor Microenvironment; Leukocyte Immunoglobulin-like Receptor B1; Myeloid Cells; Membrane Glycoproteins; Cell Line, Tumor; Neoplasms; Myeloid-Derived Suppressor Cells; Antigens, CD
PubMed: 38393969
DOI: 10.1158/2326-6066.CIR-23-0568 -
Cellular and Molecular Gastroenterology... 2021Pancreatic ductal adenocarcinoma (PDA), the most common pancreatic cancer, is a nearly universally lethal malignancy. PDA is characterized by extensive infiltration of... (Review)
Review
Pancreatic ductal adenocarcinoma (PDA), the most common pancreatic cancer, is a nearly universally lethal malignancy. PDA is characterized by extensive infiltration of immunosuppressive myeloid cells, including tumor-associated macrophages and myeloid-derived suppressor cells. Myeloid cells in the tumor microenvironment inhibit cytotoxic T-cell responses promoting carcinogenesis. Immune checkpoint therapy has not been effective in PDA, most likely because of this robust immune suppression, making it critical to elucidate mechanisms behind this phenomenon. Here, we review myeloid cell infiltration and cellular crosstalk in PDA progression and highlight current therapeutic approaches to target myeloid cell-driven immune suppression.
Topics: Animals; Biomarkers; Cell Communication; Cell Lineage; Cell Transformation, Neoplastic; Disease Management; Disease Susceptibility; Drug Resistance, Neoplasm; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunomodulation; Myeloid Cells; Myeloid-Derived Suppressor Cells; Neoplasm Metastasis; Pancreatic Neoplasms; Signal Transduction; Single-Cell Analysis; Tumor Microenvironment; Tumor-Associated Macrophages
PubMed: 34303882
DOI: 10.1016/j.jcmgh.2021.07.006 -
Frontiers in Immunology 2020Kinase activity plays an essential role in the regulation of immune cell defenses against pathogens. The protein kinase CK2 (formerly casein kinase II) is an...
Kinase activity plays an essential role in the regulation of immune cell defenses against pathogens. The protein kinase CK2 (formerly casein kinase II) is an evolutionarily conserved kinase with hundreds of identified substrates. CK2 is ubiquitously expressed in somatic and immune cells, but the roles of CK2 in regulation of immune cell function remain largely elusive. This reflects the essential role of CK2 in organismal development and limited prior work with conditional CK2 mutant murine models. Here, we generated mice with a conditional (floxed) allele of , which encodes the catalytic CK2α subunit of CK2. When crossed to -cre mice, excision of sequence impaired CK2α expression in myeloid cells but failed to detectably alter myeloid cell development. By contrast, deficiency for CK2α increased inflammatory myeloid cell recruitment, activation, and resistance following systemic (Lm) infection. Results from mixed chimera experiments indicated that CK2α deficiency in only a subset of myeloid cells was not sufficient to reduce bacterial burdens. Nor did cell-intrinsic deficiency for CK2α suffice to alter accumulation or activation of monocytes and neutrophils in infected tissues. These data suggest that CK2α expression by -expressing cells promotes inflammatory and anti-bacterial responses through effects . Our results highlight previously undescribed suppressive effects of CK2 activity on inflammatory myeloid cell responses and illustrate that cell-extrinsic effects of CK2 can shape inflammatory and protective innate immune responses.
Topics: Animals; Casein Kinase II; Female; Inflammation; Listeria monocytogenes; Listeriosis; Male; Mice, Inbred C57BL; Mice, Knockout; Myeloid Cells
PubMed: 33363536
DOI: 10.3389/fimmu.2020.590266 -
Viruses Feb 2019Myeloid cells represent a diverse range of innate leukocytes that are crucial for mounting successful immune responses against viruses. These cells are responsible for... (Review)
Review
Myeloid cells represent a diverse range of innate leukocytes that are crucial for mounting successful immune responses against viruses. These cells are responsible for detecting pathogen-associated molecular patterns, thereby initiating a signaling cascade that results in the production of cytokines such as interferons to mitigate infections. The aim of this review is to outline recent advances in our knowledge of the roles that neutrophils and inflammatory monocytes play in initiating and coordinating host responses against viral infections. A focus is placed on myeloid cell development, trafficking and antiviral mechanisms. Although known for promoting inflammation, there is a growing body of literature which demonstrates that myeloid cells can also play critical regulatory or immunosuppressive roles, especially following the elimination of viruses. Additionally, the ability of myeloid cells to control other innate and adaptive leukocytes during viral infections situates these cells as key, yet under-appreciated mediators of pathogenic inflammation that can sometimes trigger cytokine storms. The information presented here should assist researchers in integrating myeloid cell biology into the design of novel and more effective virus-targeted therapies.
Topics: Animals; Cytokines; Host-Pathogen Interactions; Humans; Immunity, Innate; Inflammation; Interferons; Mice; Monocytes; Myeloid Cells; Neutrophils; Signal Transduction; Virus Diseases; Viruses
PubMed: 30791481
DOI: 10.3390/v11020168