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Thorax Jan 2022Cigarette smoking is the leading cause of preventable death worldwide. It causes chronic lung disease and predisposes individuals to acute lung injury and pulmonary... (Review)
Review
Cigarette smoking is the leading cause of preventable death worldwide. It causes chronic lung disease and predisposes individuals to acute lung injury and pulmonary infection. Alveolar macrophages are sentinel cells strategically positioned in the interface between the airway lumen and the alveolar spaces. These are the most abundant immune cells and are the first line of defence against inhaled particulates and pathogens. Recently, there has been a better understanding about the ontogeny, phenotype and function of alveolar macrophages and their role, not only in phagocytosis, but also in initiating and resolving immune response. Many of the functions of the alveolar macrophage have been shown to be dysregulated following exposure to cigarette smoke. While the mechanisms for these changes remain poorly understood, they are important in the understanding of cigarette smoking-induced lung disease. We review the mechanisms by which smoking influences alveolar macrophage: (1) recruitment, (2) phenotype, (3) immune function (bacterial killing, phagocytosis, proteinase/anti-proteinase release and reactive oxygen species production) and (4) homeostasis (surfactant/lipid processing, iron homeostasis and efferocytosis). Further understanding of the mechanisms of cigarette smoking on alveolar macrophages and other lung monocyte/macrophage populations may allow novel ways of restoring cellular function in those patients who have stopped smoking in order to reduce the risk of subsequent infection or further lung injury.
Topics: Humans; Lung; Macrophages, Alveolar; Phagocytosis; Pneumonia; Smoke; Smoking
PubMed: 33986144
DOI: 10.1136/thoraxjnl-2020-216296 -
Cell Jul 2021Cytomegaloviruses (CMVs) have co-evolved with their mammalian hosts for millions of years, leading to remarkable host specificity and high infection prevalence....
Cytomegaloviruses (CMVs) have co-evolved with their mammalian hosts for millions of years, leading to remarkable host specificity and high infection prevalence. Macrophages, which already populate barrier tissues in the embryo, are the predominant immune cells at potential CMV entry sites. Here we show that, upon CMV infection, macrophages undergo a morphological, immunophenotypic, and metabolic transformation process with features of stemness, altered migration, enhanced invasiveness, and provision of the cell cycle machinery for viral proliferation. This complex process depends on Wnt signaling and the transcription factor ZEB1. In pulmonary infection, mouse CMV primarily targets and reprograms alveolar macrophages, which alters lung physiology and facilitates primary CMV and secondary bacterial infection by attenuating the inflammatory response. Thus, CMV profoundly perturbs macrophage identity beyond established limits of plasticity and rewires specific differentiation processes, allowing viral spread and impairing innate tissue immunity.
Topics: Animals; Antigen Presentation; Bystander Effect; Cell Cycle; Cell Line, Transformed; Cellular Reprogramming; Cytomegalovirus; Cytomegalovirus Infections; Green Fluorescent Proteins; Lung; Macrophages, Alveolar; Mice, Inbred BALB C; Mice, Inbred C57BL; Phenotype; Stem Cells; Virus Replication; Wnt Signaling Pathway; Mice
PubMed: 34115982
DOI: 10.1016/j.cell.2021.05.009 -
Molecules and Cells May 2021Macrophages residing in various tissue types are unique in terms of their anatomical locations, ontogenies, developmental pathways, gene expression patterns, and... (Review)
Review
Macrophages residing in various tissue types are unique in terms of their anatomical locations, ontogenies, developmental pathways, gene expression patterns, and immunological functions. Alveolar macrophages (AMs) reside in the alveolar lumen of the lungs and serve as the first line of defense for the respiratory tract. The immunological functions of AMs are implicated in the pathogenesis of various pulmonary diseases such as allergic asthma, chronic obstructive pulmonary disorder (COPD), pulmonary alveolar proteinosis (PAP), viral infection, and bacterial infection. Thus, the molecular mechanisms driving the development and function of AMs have been extensively investigated. In this review article, we discuss the roles of granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor (TGF)-β in AM development, and provide an overview of the anti-inflammatory and proinflammatory functions of AMs in various contexts. Notably, we examine the relationships between the metabolic status of AMs and their development processes and functions. We hope that this review will provide new information and insight into AM development and function.
Topics: Humans; Macrophages, Alveolar
PubMed: 33972474
DOI: 10.14348/molcells.2021.0058 -
Respiratory Research Mar 2018Acute lung injury (ALI) and its severe form, known as acute respiratory distress syndrome (ARDS), are caused by direct pulmonary insults and indirect systemic... (Review)
Review
Acute lung injury (ALI) and its severe form, known as acute respiratory distress syndrome (ARDS), are caused by direct pulmonary insults and indirect systemic inflammatory responses that result from conditions such as sepsis, trauma, and major surgery. The reciprocal influences between pulmonary and systemic inflammation augments the inflammatory process in the lung and promotes the development of ALI. Emerging evidence has revealed that alveolar macrophage (AM) death plays important roles in the progression of lung inflammation through its influence on other immune cell populations in the lung. Cell death and tissue inflammation form a positive feedback cycle, ultimately leading to exaggerated inflammation and development of disease. Pharmacological manipulation of AM death signals may serve as a logical therapeutic strategy for ALI/ARDS. This review will focus on recent advances in the regulation and underlying mechanisms of AM death as well as the influence of AM death on the development of ALI.
Topics: Acute Lung Injury; Animals; Cell Death; Humans; Macrophages, Alveolar; Pneumonia; Respiratory Distress Syndrome; Signal Transduction
PubMed: 29587748
DOI: 10.1186/s12931-018-0756-5 -
The Journal of Experimental Medicine Aug 2017Little is known about the relative importance of monocyte and tissue-resident macrophages in the development of lung fibrosis. We show that specific genetic deletion of...
Little is known about the relative importance of monocyte and tissue-resident macrophages in the development of lung fibrosis. We show that specific genetic deletion of monocyte-derived alveolar macrophages after their recruitment to the lung ameliorated lung fibrosis, whereas tissue-resident alveolar macrophages did not contribute to fibrosis. Using transcriptomic profiling of flow-sorted cells, we found that monocyte to alveolar macrophage differentiation unfolds continuously over the course of fibrosis and its resolution. During the fibrotic phase, monocyte-derived alveolar macrophages differ significantly from tissue-resident alveolar macrophages in their expression of profibrotic genes. A population of monocyte-derived alveolar macrophages persisted in the lung for one year after the resolution of fibrosis, where they became increasingly similar to tissue-resident alveolar macrophages. Human homologues of profibrotic genes expressed by mouse monocyte-derived alveolar macrophages during fibrosis were up-regulated in human alveolar macrophages from fibrotic compared with normal lungs. Our findings suggest that selectively targeting alveolar macrophage differentiation within the lung may ameliorate fibrosis without the adverse consequences associated with global monocyte or tissue-resident alveolar macrophage depletion.
Topics: Animals; Cell Differentiation; Fibrosis; Humans; Lung; Macrophages, Alveolar; Mice; Monocytes
PubMed: 28694385
DOI: 10.1084/jem.20162152 -
Frontiers in Immunology 2021Inhaled allergens promote inflammatory response, tissue damage, and airway hyperresponsiveness in the lungs, leading to allergic asthma. NLRP3, as an immune sensor of...
Inhaled allergens promote inflammatory response, tissue damage, and airway hyperresponsiveness in the lungs, leading to allergic asthma. NLRP3, as an immune sensor of infections and cellular stress, is associated with the development and exacerbation of asthma. However, the mechanism by which NLRP3 affects asthma requires further investigation. Here, we showed that inhaled house dust mite (HDM) promotes NLRP3 inflammasome activation in the lungs and specifically induces the maturation of caspase-1 and IL-1β in alveolar macrophages (AMs). Using -mutant mice, we found that NLRP3 promotes the inflammatory response and pathogenesis in HDM-induced allergic asthma in an inflammasome-dependent manner. Treatment with RRx-001, an NLRP3 inhibitor, significantly reduced inflammatory cell infiltration and mucus secretion in the airway. Our results showed that NLRP3 in myeloid cells promoted the development and progression of allergic asthma in an inflammasome-dependent manner. Small molecules targeting the NLRP3 inflammasome may provide new treatment options for this disease.
Topics: Allergens; Animals; Asthma; Biomarkers; Disease Models, Animal; Disease Susceptibility; Immunohistochemistry; Inflammasomes; Macrophage Activation; Macrophages, Alveolar; Mice; Mice, Knockout; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroglyphidae
PubMed: 34413860
DOI: 10.3389/fimmu.2021.718779 -
Nature Immunology May 2019Fine control of macrophage activation is needed to prevent inflammatory disease, particularly at barrier sites such as the lungs. However, the dominant mechanisms that...
Fine control of macrophage activation is needed to prevent inflammatory disease, particularly at barrier sites such as the lungs. However, the dominant mechanisms that regulate the activation of pulmonary macrophages during inflammation are poorly understood. We found that alveolar macrophages (AlvMs) were much less able to respond to the canonical type 2 cytokine IL-4, which underpins allergic disease and parasitic worm infections, than macrophages from lung tissue or the peritoneal cavity. We found that the hyporesponsiveness of AlvMs to IL-4 depended upon the lung environment but was independent of the host microbiota or the lung extracellular matrix components surfactant protein D (SP-D) and mucin 5b (Muc5b). AlvMs showed severely dysregulated metabolism relative to that of cavity macrophages. After removal from the lungs, AlvMs regained responsiveness to IL-4 in a glycolysis-dependent manner. Thus, impaired glycolysis in the pulmonary niche regulates AlvM responsiveness during type 2 inflammation.
Topics: Animals; Inflammation; Interleukin-4; Larva; Lung; Macrophage Activation; Macrophages, Alveolar; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mucin-5B; Nippostrongylus; Pulmonary Surfactant-Associated Protein D; Strongylida Infections
PubMed: 30936493
DOI: 10.1038/s41590-019-0352-y -
Frontiers in Cellular and Infection... 2021Acute lung injury (ALI) induced by sepsis is characterized by disruption of the epithelial barrier and activation of alveolar macrophages (AMs), which leads to...
Acute lung injury (ALI) induced by sepsis is characterized by disruption of the epithelial barrier and activation of alveolar macrophages (AMs), which leads to uncontrolled pulmonary inflammation. However, effective treatments for ALI are unavailable. The exact mechanism by which the initial mediator of alveolar epithelial cells (AECs) induces inflammation remains elusive. Here we investigated the roles of AEC-derived exosomes in AM activation and sepsis-induced ALI and . Cecal ligation and puncture (CLP) was utilized to establish septic lung injury model in rats. The effect of exosomal inhibition by intratracheal GW4869 administration on lung injury was investigated. To assess the effects of AEC-derived exosomes on ALI, we treated the rat alveolar epithelial cell line RLE-6TN with LPS to induce cell damage. Exosomes from conditioned medium of LPS-treated AECs (LPS-Exos) were isolated by ultracentrifugation. The miRNAs in LPS-Exos were screened by miRNA expression profile analysis. The effects of miR-92a-3p on the function of AMs were studied. We found that intratracheal GW4869 administration ameliorated lung injury following CLP-induced ALI. LPS-Exos were taken up by AMs and activated these cells. Consistently, administration of LPS-Exos in rats significantly aggravated pulmonary inflammation and alveolar permeability. Moreover, miR-92a-3p was enriched in LPS-Exos and could be delivered to AMs. Inhibition of miR-92a-3p in AECs diminished the proinflammatory effects of LPS-Exos and . Mechanistically, miR-92a-3p activates AMs along with pulmonary inflammation. This process results in activation of the NF-κB pathway and downregulation of PTEN expression, which was confirmed by a luciferase reporter assay. In conclusion, AEC-derived exosomes activate AMs and induce pulmonary inflammation mediated by miR-92a-3p in ALI. The present findings revealed a previously unidentified role of exosomal miR-92a-3p in mediating the crosstalk between injured AEC and AMs. miR-92a-3p in AEC exosomes might represent a novel diagnostic biomarker for ALI, which may lead to a new therapeutic approach.
Topics: Acute Lung Injury; Alveolar Epithelial Cells; Animals; Exosomes; Macrophage Activation; Macrophages, Alveolar; MicroRNAs; Rats; Sepsis
PubMed: 34041043
DOI: 10.3389/fcimb.2021.646546 -
Frontiers in Immunology 2023Lung macrophages constitute the first line of defense against airborne particles and microbes and are key to maintaining pulmonary immune homeostasis. There is... (Review)
Review
Lung macrophages constitute the first line of defense against airborne particles and microbes and are key to maintaining pulmonary immune homeostasis. There is increasing evidence suggesting that macrophages also participate in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), including the modulation of inflammatory responses and the repair of damaged lung tissues. The diversity of their functions may be attributed to their polarized states. Classically activated or inflammatory (M1) macrophages and alternatively activated or anti-inflammatory (M2) macrophages are the two main polarized macrophage phenotypes. The precise regulatory mechanism of macrophage polarization is a complex process that is not completely understood. A growing body of literature on immunometabolism has demonstrated the essential role of immunometabolism and its metabolic intermediates in macrophage polarization. In this review, we summarize macrophage polarization phenotypes, the role of immunometabolism, and its metabolic intermediates in macrophage polarization and ALI/ARDS, which may represent a new target and therapeutic direction.
Topics: Humans; Macrophages, Alveolar; Lung; Macrophages; Respiratory Distress Syndrome; Acute Lung Injury
PubMed: 37020557
DOI: 10.3389/fimmu.2023.1117548 -
Frontiers in Immunology 2020The main function of the lung is to perform gas exchange while maintaining lung homeostasis despite environmental pathogenic and non-pathogenic elements contained in... (Review)
Review
The main function of the lung is to perform gas exchange while maintaining lung homeostasis despite environmental pathogenic and non-pathogenic elements contained in inhaled air. Resident cells must keep lung homeostasis and eliminate pathogens by inducing protective immune response and silently remove innocuous particles. Which lung cell type is crucial for this function is still subject to debate, with reports favoring either alveolar macrophages (AMs) or lung epithelial cells (ECs) including airway and alveolar ECs. AMs are the main immune cells in the lung in steady-state and their function is mainly to dampen inflammatory responses. In addition, they phagocytose inhaled particles and apoptotic cells and can initiate and resolve inflammatory responses to pathogens. Although AMs release a plethora of mediators that modulate immune responses, ECs also play an essential role as they are more than just a physical barrier. They produce anti-microbial peptides and can secrete a variety of mediators that can modulate immune responses and AM functions. Furthermore, ECs can maintain AMs in a quiescent state by expressing anti-inflammatory membrane proteins such as CD200. Thus, AMs and ECs are both very important to maintain lung homeostasis and have to coordinate their action to protect the organism against infection. Thus, AMs and lung ECs communicate with each other using different mechanisms including mediators, membrane glycoproteins and their receptors, gap junction channels, and extracellular vesicles. This review will revisit characteristics and functions of AMs and lung ECs as well as different communication mechanisms these cells utilize to maintain lung immune balance and response to pathogens. A better understanding of the cross-talk between AMs and lung ECs may help develop new therapeutic strategies for lung pathogenesis.
Topics: Alveolar Epithelial Cells; Animals; Cell Communication; Homeostasis; Humans; Lung; Macrophages, Alveolar
PubMed: 33178214
DOI: 10.3389/fimmu.2020.583042