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Reshaping Intratumoral Mononuclear Phagocytes with Antibody-Opsonized Immunometabolic Nanoparticles.Advanced Science (Weinheim,... Dec 2023Mononuclear phagocytes (MPs) are vital components of host immune defenses against cancer. However, tumor-infiltrating MPs often present tolerogenic and pro-tumorigenic...
Mononuclear phagocytes (MPs) are vital components of host immune defenses against cancer. However, tumor-infiltrating MPs often present tolerogenic and pro-tumorigenic phenotypes via metabolic switching triggered by excessive lipid accumulation in solid tumors. Inspired by viral infection-mediated MP modulation, here enveloped immunometabolic nanoparticles (immeNPs) are designed to co-deliver a viral RNA analog and a fatty acid oxidation regulator for synergistic reshaping of intratumoral MPs. These immeNPs are camouflaged with cancer cell membranes for tumor homing and opsonized with anti-CD163 antibodies for specific MP recognition and uptake. It is found that internalized immeNPs coordinate lipid metabolic reprogramming with innate immune stimulation, inducing M2-to-M1 macrophage repolarization and tolerogenic-to-immunogenic dendritic cell differentiation for cytotoxic T cell infiltration. The authors further demonstrate that the use of immeNPs confers susceptibility to anti-PD-1 therapy in immune checkpoint blockade-resistant breast and ovarian tumors, and thereby provide a promising strategy to expand the potential of conventional immunotherapy.
Topics: Humans; T-Lymphocytes, Cytotoxic; Neoplasms; Antibodies; Macrophages; Nanoparticles; Lipids
PubMed: 37867225
DOI: 10.1002/advs.202303298 -
ELife Sep 2023Billions of apoptotic cells are removed daily in a human adult by professional phagocytes (e.g. macrophages) and neighboring nonprofessional phagocytes (e.g. stromal...
Billions of apoptotic cells are removed daily in a human adult by professional phagocytes (e.g. macrophages) and neighboring nonprofessional phagocytes (e.g. stromal cells). Despite being a type of professional phagocyte, neutrophils are thought to be excluded from apoptotic sites to avoid tissue inflammation. Here, we report a fundamental and unexpected role of neutrophils as the predominant phagocyte responsible for the clearance of apoptotic hepatic cells in the steady state. In contrast to the engulfment of dead cells by macrophages, neutrophils burrowed directly into apoptotic hepatocytes, a process we term , and ingested the effete cells from the inside. The depletion of neutrophils caused defective removal of apoptotic bodies, induced tissue injury in the mouse liver, and led to the generation of autoantibodies. Human autoimmune liver disease showed similar defects in the neutrophil-mediated clearance of apoptotic hepatic cells. Hence, neutrophils possess a specialized immunologically silent mechanism for the clearance of apoptotic hepatocytes through perforocytosis, and defects in this key housekeeping function of neutrophils contribute to the genesis of autoimmune liver disease.
Topics: Adult; Humans; Animals; Mice; Neutrophils; Hepatocytes; Phagocytes; Macrophages; Autoantibodies; Autoimmune Diseases
PubMed: 37728612
DOI: 10.7554/eLife.86591 -
Frontiers in Immunology 2023Macrophages are immune cells that originate from embryogenesis or from the differentiation of monocytes. They can adopt numerous phenotypes depending on their origin,... (Review)
Review
Macrophages are immune cells that originate from embryogenesis or from the differentiation of monocytes. They can adopt numerous phenotypes depending on their origin, tissue distribution and in response to different stimuli and tissue environment. Thus, , macrophages are endowed with a continuum of phenotypes that are rarely strictly pro-inflammatory or anti-inflammatory and exhibit a broad expression profile that sweeps over the whole polarization spectrum. Schematically, three main macrophage subpopulations coexist in human tissues: naïve macrophages also called M0, pro-inflammatory macrophages referred as M1 macrophages, and anti-inflammatory macrophages also known as M2 macrophages. Naïve macrophages display phagocytic functions, recognize pathogenic agents, and rapidly undergo polarization towards pro or anti-inflammatory macrophages to acquire their full panel of functions. Pro-inflammatory macrophages are widely involved in inflammatory response, during which they exert anti-microbial and anti-tumoral functions. By contrast, anti-inflammatory macrophages are implicated in the resolution of inflammation, the phagocytosis of cell debris and tissue reparation following injuries. Macrophages also play important deleterious or beneficial roles in the initiation and progression of different pathophysiological settings including solid and hematopoietic cancers. A better understanding of the molecular mechanisms involved in the generation, activation and polarization of macrophages is a prerequisite for the development of new therapeutic strategies to modulate macrophages functions in pathological situations.
Topics: Humans; Macrophages; Monocytes; Phagocytosis; Neoplasms; Anti-Inflammatory Agents
PubMed: 37143666
DOI: 10.3389/fimmu.2023.1178337 -
Cell Reports Feb 2023The diversity of mononuclear phagocyte (MNP) subpopulations across tissues is one of the key physiological characteristics of the immune system. Here, we focus on...
The diversity of mononuclear phagocyte (MNP) subpopulations across tissues is one of the key physiological characteristics of the immune system. Here, we focus on understanding the metabolic variability of MNPs through metabolic network analysis applied to three large-scale transcriptional datasets: we introduce (1) an ImmGen MNP open-source dataset of 337 samples across 26 tissues; (2) a myeloid subset of ImmGen Phase I dataset (202 MNP samples); and (3) a myeloid mouse single-cell RNA sequencing (scRNA-seq) dataset (51,364 cells) assembled based on Tabula Muris Senis. To analyze such large-scale datasets, we develop a network-based computational approach, genes and metabolites (GAM) clustering, for unbiased identification of the key metabolic subnetworks based on transcriptional profiles. We define 9 metabolic subnetworks that encapsulate the metabolic differences within MNP from 38 different tissues. Obtained modules reveal that cholesterol synthesis appears particularly active within the migratory dendritic cells, while glutathione synthesis is essential for cysteinyl leukotriene production by peritoneal and lung macrophages.
Topics: Animals; Mice; Phagocytes; Single-Cell Analysis
PubMed: 36708514
DOI: 10.1016/j.celrep.2023.112046 -
Pharmacological Research May 2023Nicotinic acetylcholine receptors are not only expressed by the nervous system and at the neuro-muscular junction but also by mononuclear phagocytes, which belong to the... (Review)
Review
Nicotinic acetylcholine receptors are not only expressed by the nervous system and at the neuro-muscular junction but also by mononuclear phagocytes, which belong to the innate immune system. Mononuclear phagocyte is an umbrella term for monocytes, macrophages, and dendritic cells. These cells play pivotal roles in host defense against infection but also in numerous often debilitating diseases that are characterized by exuberant inflammation. Nicotinic acetylcholine receptors of the neuronal type dominate in these cells, and their stimulation is mainly associated with anti-inflammatory effects. Although the cholinergic modulation of mononuclear phagocytes is of eminent clinical relevance for the prevention and treatment of inflammatory diseases and neuropathic pain, we are only beginning to understand the underlying mechanisms on the molecular level. The purpose of this review is to report and critically discuss the current knowledge on signal transduction mechanisms elicited by nicotinic acetylcholine receptors in mononuclear phagocytes.
Topics: Humans; Receptors, Nicotinic; Macrophages; Monocytes; Signal Transduction; Inflammation
PubMed: 36966897
DOI: 10.1016/j.phrs.2023.106727 -
Infection and Immunity Nov 2023The pathogenic yeast represents a global threat of the utmost clinical relevance. This emerging fungal species is remarkable in its resistance to commonly used...
The pathogenic yeast represents a global threat of the utmost clinical relevance. This emerging fungal species is remarkable in its resistance to commonly used antifungal agents and its persistence in the nosocomial settings. The innate immune system is one the first lines of defense preventing the dissemination of pathogens in the host. is susceptible to circulating phagocytes, and understanding the molecular details of these interactions may suggest routes to improved therapies. In this work, we examined the interactions of this yeast with macrophages. We found that macrophages avidly phagocytose ; however, intracellular replication is not inhibited, indicating that resists the killing mechanisms imposed by the phagocyte. Unlike , phagocytosis of does not induce macrophage lysis. The transcriptional response of to macrophage phagocytosis is very similar to other members of the CUG clade (), i.e., downregulation of transcription/translation and upregulation of alternative carbon metabolism pathways, transporters, and induction of oxidative stress response and proteolysis. Gene family expansions are common in this yeast, and we found that many of these genes are induced in response to macrophage co-incubation. Among these, amino acid and oligopeptide transporters, as well as lipases and proteases, are upregulated. Thus, shares key transcriptional signatures shared with other fungal pathogens and capitalizes on the expansion of gene families coding for potential virulence attributes that allow its survival, persistence, and evasion of the innate immune system.
Topics: Candida; Candida auris; Candida albicans; Antifungal Agents; Macrophages; Candida parapsilosis
PubMed: 37815367
DOI: 10.1128/iai.00274-23 -
Mucosal Immunology Jun 2022Monocyte-derived macrophages (Mφs) are crucial regulators during muscularis inflammation. However, it is unclear which micro-environmental factors are responsible for...
Monocyte-derived macrophages (Mφs) are crucial regulators during muscularis inflammation. However, it is unclear which micro-environmental factors are responsible for monocyte recruitment and anti-inflammatory Mφ differentiation in this paradigm. Here, we investigate Mφ heterogeneity at different stages of muscularis inflammation and determine how environmental cues can attract and activate tissue-protective Mφs. Results showed that muscularis inflammation induced marked alterations in mononuclear phagocyte populations associated with a rapid infiltration of Ly6c monocytes that locally acquired unique transcriptional states. Trajectory inference analysis revealed two main pro-resolving Mφ subpopulations during the resolution of muscularis inflammation, i.e. Cd206 MhcII and Timp2 MhcII Mφs. Interestingly, we found that damage to the micro-environment upon muscularis inflammation resulted in EGC activation, which in turn stimulated monocyte infiltration and the consequent differentiation in anti-inflammatory CD206 Mφs via CCL2 and CSF1, respectively. In addition, CSF1-CSF1R signaling was shown to be essential for the differentiation of monocytes into CD206 Mφs and EGC proliferation during muscularis inflammation. Our study provides a comprehensive insight into pro-resolving Mφ differentiation and their regulators during muscularis inflammation. We deepened our understanding in the interaction between EGCs and Mφs, thereby highlighting pro-resolving Mφ differentiation as a potential novel therapeutic strategy for the treatment of intestinal inflammation.
Topics: Humans; Macrophages; Monocytes; Inflammation; Neuroglia; Anti-Inflammatory Agents
PubMed: 36071145
DOI: 10.1038/s41385-022-00563-2 -
Frontiers in Immunology 2021Phagocytes, which include neutrophils, monocytes, macrophages, and dendritic cells, protect the body by removing foreign particles, bacteria, and dead or dying cells.... (Review)
Review
Phagocytes, which include neutrophils, monocytes, macrophages, and dendritic cells, protect the body by removing foreign particles, bacteria, and dead or dying cells. Phagocytic integrins are greatly involved in the recognition of and adhesion to specific antigens on cells and pathogens during phagocytosis as well as the recruitment of immune cells. β2 integrins, including αLβ2, αMβ2, αXβ2, and αDβ2, are the major integrins presented on the phagocyte surface. The activation of β2 integrins is essential to the recruitment and phagocytic function of these phagocytes and is critical for the regulation of inflammation and immune defense. However, aberrant activation of β2 integrins aggravates auto-immune diseases, such as psoriasis, arthritis, and multiple sclerosis, and facilitates tumor metastasis, making them double-edged swords as candidates for therapeutic intervention. Therefore, precise regulation of phagocyte activities by targeting β2 integrins should promote their host defense functions with minimal side effects on other cells. Here, we reviewed advances in the regulatory mechanisms underlying β2 integrin inside-out signaling, as well as the roles of β2 integrin activation in phagocyte functions.
Topics: Animals; CD18 Antigens; Humans; Phagocytes; Phagocytosis; Signal Transduction
PubMed: 33868253
DOI: 10.3389/fimmu.2021.633639 -
ELife Nov 2022Phagocyte oxidase plays an essential role in the first line of host defense against pathogens. It oxidizes intracellular NADPH to reduce extracellular oxygen to produce...
Phagocyte oxidase plays an essential role in the first line of host defense against pathogens. It oxidizes intracellular NADPH to reduce extracellular oxygen to produce superoxide anions that participate in pathogen killing. The resting phagocyte oxidase is a heterodimeric complex formed by two transmembrane proteins NOX2 and p22. Despite the physiological importance of this complex, its structure remains elusive. Here, we reported the cryo-EM structure of the functional human NOX2-p22 complex in nanodisc in the resting state. NOX2 shows a canonical 6-TM architecture of NOX and p22 has four transmembrane helices. M3, M4, and M5 of NOX2, and M1 and M4 helices of p22 are involved in the heterodimer formation. Dehydrogenase (DH) domain of NOX2 in the resting state is not optimally docked onto the transmembrane domain, leading to inefficient electron transfer and NADPH binding. Structural analysis suggests that the cytosolic factors might activate the NOX2-p22 complex by stabilizing the DH in a productive docked conformation.
Topics: Humans; NADPH Oxidases; NADP; Phagocytes; Superoxides; Membrane Proteins
PubMed: 36413210
DOI: 10.7554/eLife.83743 -
Pflugers Archiv : European Journal of... Jun 2022Ischemic retinopathies (IR) are vision-threatening diseases that affect a substantial amount of people across all age groups worldwide. The current treatment options of... (Review)
Review
Ischemic retinopathies (IR) are vision-threatening diseases that affect a substantial amount of people across all age groups worldwide. The current treatment options of photocoagulation and anti-VEGF therapy have side effects and are occasionally unable to prevent disease progression. It is therefore worthwhile to consider other molecular targets for the development of novel treatment strategies that could be safer and more efficient. During the manifestation of IR, the retina, normally an immune privileged tissue, encounters enhanced levels of cellular stress and inflammation that attract mononuclear phagocytes (MPs) from the blood stream and activate resident MPs (microglia). Activated MPs have a multitude of effects within the retinal tissue and have the potential to both counter and exacerbate the harmful tissue microenvironment. The present review discusses the current knowledge about the role of inflammation and activated retinal MPs in the major IRs: retinopathy of prematurity and diabetic retinopathy. We focus particularly on MPs and their secreted factors and cell-cell-based interactions between MPs and endothelial cells. We conclude that activated MPs play a major role in the manifestation and progression of IRs and could therefore become a promising new target for novel pharmacological intervention strategies in these diseases.
Topics: Endothelial Cells; Humans; Infant, Newborn; Inflammation; Ischemia; Neovascularization, Pathologic; Phagocytes; Retina; Retinal Diseases
PubMed: 35524802
DOI: 10.1007/s00424-022-02695-7