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The Journal of Clinical Investigation Feb 2021Alveolar macrophages orchestrate the response to viral infections. Age-related changes in these cells may underlie the differential severity of pneumonia in older...
Alveolar macrophages orchestrate the response to viral infections. Age-related changes in these cells may underlie the differential severity of pneumonia in older patients. We performed an integrated analysis of single-cell RNA-Seq data that revealed homogenous age-related changes in the alveolar macrophage transcriptome in humans and mice. Using genetic lineage tracing with sequential injury, heterochronic adoptive transfer, and parabiosis, we found that the lung microenvironment drove an age-related resistance of alveolar macrophages to proliferation that persisted during influenza A viral infection. Ligand-receptor pair analysis localized these changes to the extracellular matrix, where hyaluronan was increased in aged animals and altered the proliferative response of bone marrow-derived macrophages to granulocyte macrophage colony-stimulating factor (GM-CSF). Our findings suggest that strategies targeting the aging lung microenvironment will be necessary to restore alveolar macrophage function in aging.
Topics: Aging; Animals; Cellular Microenvironment; Humans; Lung; Macrophages, Alveolar; Mice; Mice, Transgenic; RNA-Seq
PubMed: 33586677
DOI: 10.1172/JCI140299 -
Frontiers in Immunology 2023Respiratory disorders caused by allergy have been associated to bronchiolar inflammation leading to life-threatening airway narrowing. However, whether airway allergy...
Respiratory disorders caused by allergy have been associated to bronchiolar inflammation leading to life-threatening airway narrowing. However, whether airway allergy causes alveolar dysfunction contributing to the pathology of allergic asthma remains unaddressed. To explore whether airway allergy causes alveolar dysfunction that might contribute to the pathology of allergic asthma, alveolar structural and functional alterations were analyzed during house dust mite (HDM)-induced airway allergy in mice, by flow cytometry, light and electron microscopy, monocyte transfer experiments, assessment of intra-alveolarly-located cells, analysis of alveolar macrophage regeneration in : chimeras, analysis of surfactant-associated proteins, and study of lung surfactant biophysical properties by captive bubble surfactometry. Our results demonstrate that HDM-induced airway allergic reactions caused severe alveolar dysfunction, leading to alveolar macrophage death, pneumocyte hypertrophy and surfactant dysfunction. SP-B/C proteins were reduced in allergic lung surfactant, that displayed a reduced efficiency to form surface-active films, increasing the risk of atelectasis. Original alveolar macrophages were replaced by monocyte-derived alveolar macrophages, that persisted at least two months after the resolution of allergy. Monocyte to alveolar macrophage transition occurred through an intermediate stage of pre-alveolar macrophage and was paralleled with translocation into the alveolar space, Siglec-F upregulation, and downregulation of CX3CR1. These data support that the severe respiratory disorders caused by asthmatic reactions not only result from bronchiolar inflammation, but additionally from alveolar dysfunction compromising an efficient gas exchange.
Topics: Mice; Animals; Macrophages, Alveolar; Hypersensitivity; Asthma; Inflammation; Pulmonary Surfactants; Surface-Active Agents
PubMed: 37234176
DOI: 10.3389/fimmu.2023.1125984 -
Oxidative Medicine and Cellular... 2021Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common critical diseases. Bone marrow mesenchymal stem cell (BMSC) transplantation is...
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common critical diseases. Bone marrow mesenchymal stem cell (BMSC) transplantation is previously shown to effectively rescue injured lung tissues. The therapeutic mechanism of BMSC-derived exosomes is not fully understood. Here, we investigated the BMSC-derived exosomal microRNAs (miRNAs) on effecting lipopolysaccharide- (LPS-) induced ALI and its mechanism. , rat alveolar macrophages were treated with or without exosomes in the presence of 10 g/ml LPS for 24 h. Cell viability was determined with Cell Counting Kit-8 assay. Apoptotic ratio was determined with TUNEL and Annexin V-FITC/PI double staining. The levels of miR-384-5p and autophagy-associated genes were measured by RT-qPCR and western blot. Autophagy was observed by TEM and assessed by means of the mRFP-GFP-LC3 adenovirus transfection assay. , we constructed LPS-induced ALI rat models. Exosomes were injected into rats via the caudal vein or trachea 4 h later after LPS treatment. The lung histological pathology was determined by H&E staining. Pulmonary vascular permeability was assessed by wet-to-dry weight ratio and Evans blue dye leakage assay, and inflammatory cytokines in serum and BALF were measured by ELISA. Furthermore, the therapeutic mechanism involved in miR-384-5p and Beclin-1 was determined. The results showed that BMSC-derived exosomes were taken up by the alveolar macrophages and attenuated LPS-induced alveolar macrophage viability loss and apoptosis. Exosomes effectively improved the survival rate of ALI rats within 7 days, which was associated with alleviating lung pathological changes and pulmonary vascular permeability and attenuating inflammatory response. Furthermore, this study for the first time found that miR-384-5p was enriched in BMSC-derived exosomes, and exosomal miR-384-5p resulted in relieving LPS-injured autophagy disorder in alveolar macrophages by targeting Beclin-1. Therefore, exosomal miR-384-5p could be demonstrated as a promising therapeutic strategy for ALI/ARDS.
Topics: Acute Lung Injury; Animals; Autophagy; Exosomes; Humans; Lipopolysaccharides; Macrophages, Alveolar; Male; Mesenchymal Stem Cells; MicroRNAs; Rats
PubMed: 34234888
DOI: 10.1155/2021/9973457 -
Cell Nov 2018Lung development and function arises from the interactions between diverse cell types and lineages. Using single-cell RNA sequencing (RNA-seq), we characterize the...
Lung development and function arises from the interactions between diverse cell types and lineages. Using single-cell RNA sequencing (RNA-seq), we characterize the cellular composition of the lung during development and identify vast dynamics in cell composition and their molecular characteristics. Analyzing 818 ligand-receptor interaction pairs within and between cell lineages, we identify broadly interacting cells, including AT2, innate lymphocytes (ILCs), and basophils. Using interleukin (IL)-33 receptor knockout mice and in vitro experiments, we show that basophils establish a lung-specific function imprinted by IL-33 and granulocyte-macrophage colony-stimulating factor (GM-CSF), characterized by unique signaling of cytokines and growth factors important for stromal, epithelial, and myeloid cell fates. Antibody-depletion strategies, diphtheria toxin-mediated selective depletion of basophils, and co-culture studies show that lung resident basophils are important regulators of alveolar macrophage development and function. Together, our study demonstrates how whole-tissue signaling interaction map on the single-cell level can broaden our understanding of cellular networks in health and disease.
Topics: Animals; Basophils; Cell Communication; Cell Differentiation; Cell Line, Tumor; Cells, Cultured; Female; Genomic Imprinting; Granulocyte-Macrophage Colony-Stimulating Factor; Interleukin-33; Macrophages, Alveolar; Male; Mice; Mice, Inbred C57BL; Signal Transduction; Single-Cell Analysis; Transcriptome
PubMed: 30318149
DOI: 10.1016/j.cell.2018.09.009 -
The Journal of Experimental Medicine Apr 2018To understand how infection by (Mtb) is modulated by host cell phenotype, we characterized those host phagocytes that controlled or supported bacterial growth during...
To understand how infection by (Mtb) is modulated by host cell phenotype, we characterized those host phagocytes that controlled or supported bacterial growth during early infection, focusing on the ontologically distinct alveolar macrophage (AM) and interstitial macrophage (IM) lineages. Using fluorescent Mtb reporter strains, we found that bacilli in AM exhibited lower stress and higher bacterial replication than those in IM. Interestingly, depletion of AM reduced bacterial burden, whereas depletion of IM increased bacterial burden. Transcriptomic analysis revealed that IMs were glycolytically active, whereas AMs were committed to fatty acid oxidation. Intoxication of infected mice with the glycolytic inhibitor, 2-deoxyglucose, decreased the number of IMs yet increased the bacterial burden in the lung. Furthermore, in in vitro macrophage infections, 2-deoxyglucose treatment increased bacterial growth, whereas the fatty acid oxidation inhibitor etomoxir constrained bacterial growth. We hypothesize that different macrophage lineages respond divergently to Mtb infection, with IMs exhibiting nutritional restriction and controlling bacterial growth and AMs representing a more nutritionally permissive environment.
Topics: Animals; Bystander Effect; Cell Cycle; Cell Proliferation; Cellular Reprogramming; Fatty Acids; Genes, Reporter; Glycolysis; Host-Pathogen Interactions; Macrophages, Alveolar; Metabolic Networks and Pathways; Mice, Inbred C57BL; Models, Biological; Monocytes; Mycobacterium tuberculosis; Oxidation-Reduction; Phagocytes; Transcription, Genetic; Tuberculosis
PubMed: 29500179
DOI: 10.1084/jem.20172020 -
Frontiers in Immunology 2019
Topics: Animals; Cytokines; Gene Expression; Humans; Lung; Macrophage Activation; Macrophages, Alveolar; Pneumonia
PubMed: 31616438
DOI: 10.3389/fimmu.2019.02275 -
American Journal of Respiratory Cell... Aug 2022
Topics: Macrophages; Macrophages, Alveolar; Phagocytosis; Respiratory System; Smoking
PubMed: 35580150
DOI: 10.1165/rcmb.2022-0160ED -
Frontiers in Immunology 2023Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disorder that is characterized by the abnormal accumulation of surfactant within the alveoli. Alveolar... (Review)
Review
Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disorder that is characterized by the abnormal accumulation of surfactant within the alveoli. Alveolar macrophages (AMs) have been identified as playing a pivotal role in the pathogenesis of PAP. In most of PAP cases, the disease is triggered by impaired cholesterol clearance in AMs that depend on granulocyte-macrophage colony-stimulating factor (GM-CSF), resulting in defective alveolar surfactant clearance and disruption of pulmonary homeostasis. Currently, novel pathogenesis-based therapies are being developed that target the GM-CSF signaling, cholesterol homeostasis, and immune modulation of AMs. In this review, we summarize the origin and functional role of AMs in PAP, as well as the latest therapeutic strategies aimed at addressing this disease. Our goal is to provide new perspectives and insights into the pathogenesis of PAP, and thereby identify promising new treatments for this disease.
Topics: Humans; Pulmonary Alveolar Proteinosis; Macrophages, Alveolar; Granulocyte-Macrophage Colony-Stimulating Factor; Pulmonary Alveoli; Pulmonary Surfactants; Rare Diseases; Surface-Active Agents
PubMed: 37388737
DOI: 10.3389/fimmu.2023.1195988 -
Biomaterials May 2019Nanocellulose is a promising bio-nanomaterial with attractive properties suitable for multiple industrial applications. The increased use of nanocellulose may lead to...
Nanocellulose is a promising bio-nanomaterial with attractive properties suitable for multiple industrial applications. The increased use of nanocellulose may lead to occupational exposure and negative health outcomes. However, knowledge on its health effects is limited, and while nanocellulose exposure may induce acute inflammatory responses in the lung, the underlying mechanisms are unknown. Alveolar macrophages are key cells in alveolar particle clearance. Their activation and function may be affected by various particles. Here, we investigated the uptake of pristine cellulose nanocrystals (CNC), and their effects on alveolar macrophage polarization and biological function. CNC uptake enhanced the secretion of several cytokines but did not on its own induce a complete macrophage polarization. In presence of macrophage activators, such as LPS/IFNG and IL4/IL13, CNC exposure enhanced the expression of M1 phenotype markers and the secretion of pro-inflammatory cytokines and chemokines, while decreasing M2 markers. CNC exposure also affected the function of activated alveolar macrophages resulting in a prominent cytokine burst and altered phagocytic activity. In conclusion, CNC exposure may result in dysregulation of macrophage activation and function that are critical in inflammatory responses in the lung.
Topics: Animals; Cell Line; Cell Proliferation; Cell Survival; Cellulose; Macrophages, Alveolar; Mice; Microscopy, Electron, Scanning; Nanoparticles; Phagocytes; Phagocytosis; Phenotype
PubMed: 30851491
DOI: 10.1016/j.biomaterials.2019.02.025 -
Journal of Visualized Experiments : JoVE Mar 2019Alveolar macrophages (AMs) guard the alveolar space of the lung. Phagocytosis by AMs plays a critical role in the defense against invading pathogens, the removal of dead...
Alveolar macrophages (AMs) guard the alveolar space of the lung. Phagocytosis by AMs plays a critical role in the defense against invading pathogens, the removal of dead cells or foreign particles, and in the resolution of inflammatory responses and tissue remodeling, processes that are mediated by various surface receptors of the AMs. Here, we report methods for the analysis of the phagocytic function of AMs using in vitro and in vivo assays and experimental strategies to differentiate between the pattern recognition receptor-, complement receptor-, and Fc gamma receptor-mediated phagocytosis. Finally, we discuss a method to establish and characterize a P. aeruginosa pneumonia model in mice to assess bacterial clearance in vivo. These assays represent the most common methods to evaluate AM functions and can also be used to study macrophage function and bacterial clearance in other organs.
Topics: Animals; Cells, Cultured; Female; Green Fluorescent Proteins; Macrophages, Alveolar; Mice, Inbred C57BL; Phagocytosis; Pseudomonas aeruginosa; Receptors, Complement; Receptors, IgG
PubMed: 30882784
DOI: 10.3791/59088