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The Journal of Experimental Medicine Jul 2023Macrophages play a central role in tissue homeostasis and host defense. However, the properties of human macrophages in non-diseased tissues remain poorly understood....
Macrophages play a central role in tissue homeostasis and host defense. However, the properties of human macrophages in non-diseased tissues remain poorly understood. Here, we characterized human tonsil macrophages and identified three subsets with distinct phenotype, transcriptome, life cycle, and function. CD36hi macrophages were related to monocytes, while CD36lo macrophages showed features of embryonic origin and CD36int macrophages had a mixed profile. scRNA-seq on non-human primate tonsils showed that monocyte recruitment did not pre-exist an immune challenge. Functionally, CD36hi macrophages were specialized for stimulating T follicular helper cells, by producing Activin A. Combining reconstruction of ligand-receptor interactions and functional assays, we identified stromal cell-derived TNF-α as an inducer of Activin A secretion. However, only CD36hi macrophages were primed for Activin A expression, via the activity of IRF1. Our results provide insight into the heterogeneity of human lymphoid organ macrophages and show that tonsil CD36hi macrophage specialization is the result of both intrinsic features and interaction with stromal cells.
Topics: Animals; Humans; Palatine Tonsil; Macrophages; Monocytes; Phenotype; Transcriptome
PubMed: 37036425
DOI: 10.1084/jem.20230002 -
International Journal of Molecular... Nov 2023Monocytes and macrophages are the innate immune cells that are the first-line responders to invading pathogens or foreign objects[...].
Monocytes and macrophages are the innate immune cells that are the first-line responders to invading pathogens or foreign objects[...].
Topics: Animals; Humans; Monocytes; Macrophages; Homeostasis; Immunity, Innate
PubMed: 38003587
DOI: 10.3390/ijms242216397 -
Journal of Extracellular Vesicles Dec 2023Macrophages play major roles in the pathophysiology of various neurological disorders, being involved in seemingly opposing processes such as lesion progression and...
Macrophages play major roles in the pathophysiology of various neurological disorders, being involved in seemingly opposing processes such as lesion progression and resolution. Yet, the molecular mechanisms that drive their harmful and benign effector functions remain poorly understood. Here, we demonstrate that extracellular vesicles (EVs) secreted by repair-associated macrophages (RAMs) enhance remyelination ex vivo and in vivo by promoting the differentiation of oligodendrocyte precursor cells (OPCs). Guided by lipidomic analysis and applying cholesterol depletion and enrichment strategies, we find that EVs released by RAMs show markedly elevated cholesterol levels and that cholesterol abundance controls their reparative impact on OPC maturation and remyelination. Mechanistically, EV-associated cholesterol was found to promote OPC differentiation predominantly through direct membrane fusion. Collectively, our findings highlight that EVs are essential for cholesterol trafficking in the brain and that changes in cholesterol abundance support the reparative impact of EVs released by macrophages in the brain, potentially having broad implications for therapeutic strategies aimed at promoting repair in neurodegenerative disorders.
Topics: Extracellular Vesicles; Brain; Macrophages; Cell Differentiation; Cholesterol
PubMed: 38124258
DOI: 10.1002/jev2.12394 -
Cells May 2024Pulmonary surfactants play a crucial role in managing lung lipid metabolism, and dysregulation of this process is evident in various lung diseases. Alternations in lipid... (Review)
Review
Pulmonary surfactants play a crucial role in managing lung lipid metabolism, and dysregulation of this process is evident in various lung diseases. Alternations in lipid metabolism lead to pulmonary surfactant damage, resulting in hyperlipidemia in response to lung injury. Lung macrophages are responsible for recycling damaged lipid droplets to maintain lipid homeostasis. The inflammatory response triggered by external stimuli such as cigarette smoke, bleomycin, and bacteria can interfere with this process, resulting in the formation of lipid-laden macrophages (LLMs), also known as foamy macrophages. Recent studies have highlighted the potential significance of LLM formation in a range of pulmonary diseases. Furthermore, growing evidence suggests that LLMs are present in patients suffering from various pulmonary conditions. In this review, we summarize the essential metabolic and signaling pathways driving the LLM formation in chronic obstructive pulmonary disease, pulmonary fibrosis, tuberculosis, and acute lung injury.
Topics: Humans; Lung Diseases; Lipid Metabolism; Animals; Macrophages; Macrophages, Alveolar; Signal Transduction
PubMed: 38891022
DOI: 10.3390/cells13110889 -
Mucosal Immunology Aug 2023Short-chain fatty acids (SCFAs) are metabolites that are produced after microbial fermentation of dietary fiber and impact cell metabolism and anti-inflammatory pathways...
Short-chain fatty acids (SCFAs) are metabolites that are produced after microbial fermentation of dietary fiber and impact cell metabolism and anti-inflammatory pathways both locally in the gut and systemically. In preclinical models, administration of SCFAs, such as butyrate, ameliorates a range of inflammatory disease models including allergic airway inflammation, atopic dermatitis, and influenza infection. Here we report the effect of butyrate on a bacteria-induced acute neutrophil-driven immune response in the airways. Butyrate impacted discrete aspects of hematopoiesis in the bone marrow resulting in the accumulation of immature neutrophils. During Pseudomonas aeruginosa infection, butyrate treatment led to the enhanced mobilization of neutrophils to the lungs as a result of increased CXCL2 expression by lung macrophages. Despite this increase in granulocyte numbers and their enhanced phagocytic capacity, neutrophils failed to control early bacterial growth. Butyrate reduced the expression of nicotinamide adenine dinucleotide phosphate, oxidase complex components required for reactive oxygen species production, and reduced secondary granule enzymes, culminating in impaired bactericidal activity. These data reveal that SCFAs tune neutrophil maturation and effector function in the bone marrow under homeostatic conditions, potentially to mitigate against excessive granulocyte-driven immunopathology, but their consequently restricted bactericidal capacity impairs early control of Pseudomonas infection.
Topics: Humans; Butyrates; Neutrophils; Fatty Acids, Volatile; Lung; Inflammation; Homeostasis; Anti-Infective Agents
PubMed: 37178819
DOI: 10.1016/j.mucimm.2023.05.005 -
Circulation Nov 2023Interferon-γ (IFNγ) signaling plays a complex role in atherogenesis. IFNγ stimulation of macrophages permits in vitro exploration of proinflammatory mechanisms and...
BACKGROUND
Interferon-γ (IFNγ) signaling plays a complex role in atherogenesis. IFNγ stimulation of macrophages permits in vitro exploration of proinflammatory mechanisms and the development of novel immune therapies. We hypothesized that the study of macrophage subpopulations could lead to anti-inflammatory interventions.
METHODS
Primary human macrophages activated by IFNγ (M(IFNγ)) underwent analyses by single-cell RNA sequencing, time-course cell-cluster proteomics, metabolite consumption, immunoassays, and functional tests (phagocytic, efferocytotic, and chemotactic). RNA-sequencing data were analyzed in LINCS (Library of Integrated Network-Based Cellular Signatures) to identify compounds targeting M(IFNγ) subpopulations. The effect of compound BI-2536 was tested in human macrophages in vitro and in a murine model of atherosclerosis.
RESULTS
Single-cell RNA sequencing identified 2 major clusters in M(IFNγ): inflammatory (M(IFNγ)) and phagocytic (M(IFNγ)). M(IFNγ) had elevated expression of inflammatory chemokines and higher amino acid consumption compared with M(IFNγ). M(IFNγ) were more phagocytotic and chemotactic with higher Krebs cycle activity and less glycolysis than M(IFNγ). Human carotid atherosclerotic plaques contained 2 such macrophage clusters. Bioinformatic LINCS analysis using our RNA-sequencing data identified BI-2536 as a potential compound to decrease the M(IFNγ) subpopulation. BI-2536 in vitro decreased inflammatory chemokine expression and secretion in M(IFNγ) by shrinking the M(IFNγ) subpopulation while expanding the M(IFNγ) subpopulation. BI-2536 in vivo shifted the phenotype of macrophages, modulated inflammation, and decreased atherosclerosis and calcification.
CONCLUSIONS
We characterized 2 clusters of macrophages in atherosclerosis and combined our cellular data with a cell-signature drug library to identify a novel compound that targets a subset of macrophages in atherosclerosis. Our approach is a precision medicine strategy to identify new drugs that target atherosclerosis and other inflammatory diseases.
Topics: Humans; Animals; Mice; Gene Regulatory Networks; Macrophages; Atherosclerosis; Plaque, Atherosclerotic; RNA; Biology
PubMed: 37850387
DOI: 10.1161/CIRCULATIONAHA.123.064794 -
Clinical and Experimental Hypertension... Dec 2023To investigate the level and significance of neutrophils to high-density lipoprotein cholesterol ratio (NHR) and monocytes to high-density lipoprotein cholesterol ratio...
OBJECTIVE
To investigate the level and significance of neutrophils to high-density lipoprotein cholesterol ratio (NHR) and monocytes to high-density lipoprotein cholesterol ratio (MHR) in patients with non-dipping hypertension.
METHODS
A total of 228 patients were retrospectively enrolled in the study. They were divided into the dipping hypertension group ( = 76), the non-dipping hypertension group ( = 77) and the control group ( = 75) according to 24-h ambulatory blood pressure monitoring system (ABPM) recordings. NHR and MHR were calculated and compared statistically. Receiver operating characteristic (ROC) curve analyses were performed for NHR and MHR. Binary logistic regression analyses were introduced to investigate the independent associations of NHR and MHR with non-dipping hypertension.
RESULTS
The NHR and MHR were significantly higher in the non-dipping hypertension group compared with the control group ( = .001, < .001, respectively) and the dipping hypertension group ( = .039, = .003, respectively). According to ROC curve analyses, NHR>73.35 and MHR>7.54 were regarded as high-risk groups. The area under the curve (AUC) was 0.642 ( < .001) for NHR and 0.718 ( < .001) for MHR. In multivariate analysis, compared with NHR, only MHR was still recognized as a marker for detection of non-dipping hypertension (odds ratio [OR]: 1.208, 95% confidence interval [CI]: 1.076 to 1.356, = .001).
CONCLUSIONS
Our data indicated that not NHR but MHR as new composite marker of inflammation and lipid metabolism may predict non-dipping hypertension to some extent.
Topics: Humans; Cholesterol, HDL; Monocytes; Neutrophils; Retrospective Studies; Blood Pressure Monitoring, Ambulatory; Biomarkers; Hypertension
PubMed: 37165667
DOI: 10.1080/10641963.2023.2210785 -
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 -
Cell Reports Aug 2023Cell identity is orchestrated through an interplay between transcription factor (TF) action and genome architecture. The mechanisms used by TFs to shape...
Cell identity is orchestrated through an interplay between transcription factor (TF) action and genome architecture. The mechanisms used by TFs to shape three-dimensional (3D) genome organization remain incompletely understood. Here we present evidence that the lineage-instructive TF CEBPA drives extensive chromatin compartment switching and promotes the formation of long-range chromatin hubs during induced B cell-to-macrophage transdifferentiation. Mechanistically, we find that the intrinsically disordered region (IDR) of CEBPA undergoes in vitro phase separation (PS) dependent on aromatic residues. Both overexpressing B cells and native CEBPA-expressing cell types such as primary granulocyte-macrophage progenitors, liver cells, and trophectoderm cells reveal nuclear CEBPA foci and long-range 3D chromatin hubs at CEBPA-bound regions. In short, we show that CEBPA can undergo PS through its IDR, which may underlie in vivo foci formation and suggest a potential role of PS in regulating CEBPA function.
Topics: Chromatin; Gene Expression Regulation; Cell Nucleus; Macrophages
PubMed: 37516962
DOI: 10.1016/j.celrep.2023.112897 -
Journal of Neuroinflammation Oct 2023Myelin that surrounds axons breaks in trauma and disease; e.g., peripheral nerve and spinal cord injuries (PNI and SCI) and multiple sclerosis (MS). Resulting myelin...
Deletion of CD47 from Schwann cells and macrophages hastens myelin disruption/dismantling and scavenging in Schwann cells and augments myelin debris phagocytosis in macrophages.
BACKGROUND
Myelin that surrounds axons breaks in trauma and disease; e.g., peripheral nerve and spinal cord injuries (PNI and SCI) and multiple sclerosis (MS). Resulting myelin debris hinders repair if not effectively scavenged by Schwann cells and macrophages in PNI and by microglia in SCI and MS. We showed previously that myelin debris evades phagocytosis as CD47 on myelin ligates SIRPα (signal regulatory protein-α) on macrophages and microglia, triggering SIRPα to inhibit phagocytosis in phagocytes. Using PNI as a model, we tested the in vivo significance of SIRPα-dependent phagocytosis inhibition in SIRPα null mice, showing that SIRPα deletion leads to accelerated myelin debris clearance, axon regeneration and recovery of function from PNI. Herein, we tested how deletion of CD47, a SIRPα ligand and a cell surface receptor on Schwann cells and phagocytes, affects recovery from PNI.
METHODS
Using CD47 null (CD47-/-) and wild type mice, we studied myelin disruption/dismantling and debris clearance, axon regeneration and recovery of function from PNI.
RESULTS
As expected from CD47 on myelin acting as a SIRPα ligand that normally triggers SIRPα-dependent phagocytosis inhibition in phagocytes, myelin debris clearance, axon regeneration and function recovery were all faster in CD47-/- mice than in wild type mice. Unexpectedly compared with wild type mice, myelin debris clearance started sooner and CD47-deleted Schwann cells displayed enhanced disruption/dismantling and scavenging of myelin in CD47-/- mice. Furthermore, CD47-deleted macrophages from CD47-/- mice phagocytosed more myelin debris than CD47-expressing phagocytes from wild type mice.
CONCLUSIONS
This study reveals two novel normally occurring CD47-dependent mechanisms that impede myelin debris clearance. First, CD47 expressed on Schwann cells inhibits myelin disruption/dismantling and debris scavenging in Schwann cells. Second, CD47 expressed on macrophages inhibits myelin debris phagocytosis in phagocytes. The two add to a third mechanism that we previously documented whereby CD47 on myelin ligates SIRPα on macrophages and microglia, triggering SIRPα-dependent phagocytosis inhibition in phagocytes. Thus, CD47 plays multiple inhibitory roles that combined impede myelin debris clearance, leading to delayed recovery from PNI. Similar inhibitory roles in microglia may hinder recovery from other pathologies in which repair depends on efficient phagocytosis (e.g., SCI and MS).
Topics: Animals; Mice; Axons; CD47 Antigen; Ligands; Macrophages; Myelin Sheath; Nerve Regeneration; Peripheral Nerve Injuries; Phagocytosis; Schwann Cells
PubMed: 37872624
DOI: 10.1186/s12974-023-02929-0