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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 -
Inflammation Feb 2019Acute lung injury (ALI), developing as a component of the systemic inflammatory response syndrome (SIRS), leads to significant morbidity and mortality. Reactive oxygen...
Acute lung injury (ALI), developing as a component of the systemic inflammatory response syndrome (SIRS), leads to significant morbidity and mortality. Reactive oxygen species (ROS), produced in part by the neutrophil NADPH oxidase 2 (Nox2), have been implicated in the pathogenesis of ALI. Previous studies in our laboratory demonstrated the development of pulmonary inflammation in Nox2-deficient (gp91) mice that was absent in WT mice in a murine model of SIRS. Given this finding, we hypothesized that Nox2 in a resident cell in the lung, specifically the alveolar macrophage, has an essential anti-inflammatory role. Using a murine model of SIRS, we examined whole-lung digests and bronchoalveolar lavage fluid (BALf) from WT and gp91 mice. Both genotypes demonstrated neutrophil sequestration in the lung during SIRS, but neutrophil migration into the alveolar space was only present in the gp91 mice. Macrophage inflammatory protein (MIP)-1α gene expression and protein secretion were higher in whole-lung digest from uninjected gp91 mice compared to the WT mice. Gene expression of MIP-1α, MCP-1, and MIP-2 was upregulated in alveolar macrophages obtained from gp91 mice at baseline compared with WT mice. Further, ex vivo analysis of alveolar macrophages, but not bone marrow-derived macrophages or peritoneal macrophages, demonstrated higher gene expression of MIP-1α and MIP-2. Moreover, isolated lung polymorphonuclear neutrophils migrate to BALf obtained from gp91 mice, further providing evidence of a cell-specific anti-inflammatory role for Nox2 in alveolar macrophages. We speculate that Nox2 represses the development of inflammatory lung injury by modulating chemokine expression by the alveolar macrophage.
Topics: Acute Lung Injury; Animals; Cell Movement; Chemokines; Inflammation; Lung; Macrophages, Alveolar; Mice; NADPH Oxidase 2; Neutrophils; Reactive Oxygen Species; Systemic Inflammatory Response Syndrome
PubMed: 30288635
DOI: 10.1007/s10753-018-0883-7 -
Trends in Immunology Oct 2020Alveolar macrophages (AMs) are highly abundant lung cells with important roles in homeostasis and immunity. Their function influences the outcome of lung infections,... (Review)
Review
Alveolar macrophages (AMs) are highly abundant lung cells with important roles in homeostasis and immunity. Their function influences the outcome of lung infections, lung cancer, and chronic inflammatory disease. Recent findings reveal functional heterogeneity of AMs. Following lung insult, resident AMs can either remain unchanged, acquire new functionality, or be replaced by monocyte-derived AMs. Evidence from mouse models correlates AM function with their embryonic or monocyte origin. We hypothesize that resident AMs are terminally differentiated cells with low responsiveness and limited plasticity, while recruited, monocyte-derived AMs are initially highly immunoreactive but more plastic, able to change their function in response to environmental cues. Understanding cell-intrinsic and -extrinsic mechanisms determining AM function may provide opportunities for intervention in lung disease.
Topics: Animals; Cell Plasticity; Humans; Lung; Macrophages, Alveolar; Monocytes
PubMed: 32896485
DOI: 10.1016/j.it.2020.08.008 -
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 -
Frontiers in Immunology 2021The human innate host defense molecules, SP-A1 and SP-A2 variants, differentially affect survival after infection in mice and in lung transplant patients. SP-A interacts... (Review)
Review
Human Surfactant Protein SP-A1 and SP-A2 Variants Differentially Affect the Alveolar Microenvironment, Surfactant Structure, Regulation and Function of the Alveolar Macrophage, and Animal and Human Survival Under Various Conditions.
The human innate host defense molecules, SP-A1 and SP-A2 variants, differentially affect survival after infection in mice and in lung transplant patients. SP-A interacts with the sentinel innate immune cell in the alveolus, the alveolar macrophage (AM), and modulates its function and regulation. SP-A also plays a role in pulmonary surfactant-related aspects, including surfactant structure and reorganization. For most (if not all) pulmonary diseases there is a dysregulation of host defense and inflammatory processes and/or surfactant dysfunction or deficiency. Because SP-A plays a role in both of these general processes where one or both may become aberrant in pulmonary disease, SP-A stands to be an important molecule in health and disease. In humans (unlike in rodents) SP-A is encoded by two genes ( and ) and each has been identified with extensive genetic and epigenetic complexity. In this review, we focus on functional, structural, and regulatory differences between the two SP-A gene-specific products, SP-A1 and SP-A2, and among their corresponding variants. We discuss the differential impact of these variants on the surfactant structure, the alveolar microenvironment, the regulation of epithelial type II miRNome, the regulation and function of the AM, the overall survival of the organism after infection, and others. Although there have been a number of reviews on SP-A, this is the first review that provides such a comprehensive account of the differences between human SP-A1 and SP-A2.
Topics: Amino Acid Sequence; Amino Acid Substitution; Animals; Biomarkers; Cellular Microenvironment; Disease Susceptibility; Genetic Variation; Humans; Macrophages, Alveolar; Mice; Models, Biological; Proteome; Proteomics; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactants; Structure-Activity Relationship
PubMed: 34484180
DOI: 10.3389/fimmu.2021.681639 -
The Journal of Heart and Lung... Jul 2024
Topics: Lung Transplantation; Humans; CD8-Positive T-Lymphocytes; Macrophages, Alveolar; Sequence Analysis, RNA; Allografts; Male; Single-Cell Analysis; Graft Rejection; Acute Disease; Middle Aged; Female
PubMed: 38490571
DOI: 10.1016/j.healun.2024.03.003 -
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... Jul 2004
Review
Topics: Animals; Asthma; Chemotaxis, Leukocyte; Cytokines; Genetic Predisposition to Disease; Humans; Immune Tolerance; Inflammation; Macrophages, Alveolar; Rats; Species Specificity
PubMed: 15208096
DOI: 10.1165/rcmb.f279 -
Immunity Jun 2021Alveolar macrophages (AMs) are central to defense against respiratory pathogens. Impediments in restoring AMs after infection increase the risk for superinfection, which...
Alveolar macrophages (AMs) are central to defense against respiratory pathogens. Impediments in restoring AMs after infection increase the risk for superinfection, which is associated with significant morbidity and mortality worldwide. In this issue of Immunity, Zhu et al. report a Wnt-β-catenin-HIF-1α axis in AMs that promotes an inflammatory phenotype while restricting proliferation and self-renewal.
Topics: Macrophages, Alveolar; Phenotype
PubMed: 34107266
DOI: 10.1016/j.immuni.2021.05.013 -
Cancer Research Jun 2023Cellular components of the tumor microenvironment, including myeloid cells, play important roles in the progression of lung adenocarcinoma (LUAD) and its response to...
UNLABELLED
Cellular components of the tumor microenvironment, including myeloid cells, play important roles in the progression of lung adenocarcinoma (LUAD) and its response to therapy. Here, we characterize the function of the ubiquitin ligases Siah1a/2 in regulating the differentiation and activity of alveolar macrophages (AM) and assess the implication of Siah1a/2 control of AMs for carcinogen-induced LUAD. Macrophage-specific genetic ablation of Siah1a/2 promoted accumulation of AMs with an immature phenotype and increased expression of protumorigenic and pro-inflammatory Stat3 and β-catenin gene signatures. Administration of urethane to wild-type mice promoted enrichment of immature-like AMs and lung tumor development, which was enhanced by macrophage-specific Siah1a/2 ablation. The profibrotic gene signature seen in Siah1a/2-ablated immature-like macrophages was associated with increased tumor infiltration of CD14+ myeloid cells and poorer survival of patients with LUAD. Single-cell RNA-seq confirmed the presence of a cluster of immature-like AMs expressing a profibrotic signature in lungs of patients with LUAD, a signature enhanced in smokers. These findings identify Siah1a/2 in AMs as gatekeepers of lung cancer development.
SIGNIFICANCE
The ubiquitin ligases Siah1a/2 control proinflammatory signaling, differentiation, and profibrotic phenotypes of alveolar macrophages to suppress lung carcinogenesis.
Topics: Animals; Mice; Macrophages, Alveolar; Adenocarcinoma of Lung; Lung Neoplasms; Tumor Microenvironment; Ubiquitin-Protein Ligases; Male; Mice, Inbred C57BL; Mice, Knockout
PubMed: 37078793
DOI: 10.1158/0008-5472.CAN-23-0258