Alveolar Macrophages: Adaptation to Their Anatomic Niche during and after Inflammation

At the early stages of life development, alveoli are colonized by embryonic macrophages, which become resident alveolar macrophages (ResAM) and self-sustain by local division. Genetic and epigenetic signatures and, to some extent, the functions of ResAM are dictated by the lung microenvironment, which uses cytokines, ligand-receptor interactions, and stroma cells to orchestrate lung homeostasis. In resting conditions, the lung microenvironment induces in ResAM a tolerogenic programming that prevents unnecessary and potentially harmful inflammation responses to the foreign bodies, which continuously challenge the airways. Throughout life, any episode of acute inflammation, pneumonia being likely the most frequent cause, depletes the pool of ResAM, leaving space for the recruitment of inflammatory monocytes that locally develop in monocyte-derived alveolar macrophages (InfAM). During lung infection, the local microenvironment induces a temporary inflammatory signature to the recruited InfAM to handle the tissue injury and eliminate the pathogens. After a few days, the recruited InfAM, which locally self-sustain and develop as new ResAM, gain profibrotic functions required for tissue healing. After the complete resolution of the infectious episode, the functional programming of both embryonic and monocyte-derived ResAM remains altered for months and possibly for the entire life. Adult lungs thus contain a wide diversity of ResAM since every infection brings new waves of InfAM which fill the room left open by the inflammatory process. The memory of these innate cells called trained immunity constitutes an immunologic scar left by inflammation, notably pneumonia. This memory of ResAM has advantages and drawbacks. In some cases, lung-trained immunity offers better defense capacities against autoimmune disorders and the long-term risk of infection. At the opposite, it can perpetuate a harmful process and lead to a pathological state, as is the case among critically ill patients who have immune paralysis and are highly susceptible to hospital-acquired pneumonia and acute respiratory distress syndrome. The progress in understanding the kinetics of response of alveolar macrophages (AM) to lung inflammation is paving the way to new treatments of pneumonia and lung inflammatory process.

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Oxidative Stress and Inflammation in Renal and Cardiovascular Complications of Diabetes

Biology ◽

10.3390/biology10010018 ◽

2020 ◽

Vol 10 (1) ◽

pp. 18

Author(s):

Amelia Charlton ◽

Jessica Garzarella ◽

Karin A. M. Jandeleit-Dahm ◽

Jay C. Jha

Keyword(s):

Oxidative Stress ◽

Cardiovascular Disease ◽

Tissue Injury ◽

Cardiovascular Complications ◽

Therapeutic Strategies ◽

Cellular Damage ◽

Antioxidant Defenses ◽

Pathological State ◽

Oxygen Species ◽

Emerging Therapies

Oxidative stress and inflammation are considered major drivers in the pathogenesis of diabetic complications, including renal and cardiovascular disease. A symbiotic relationship also appears to exist between oxidative stress and inflammation. Several emerging therapies target these crucial pathways, to alleviate the burden of the aforementioned diseases. Oxidative stress refers to an imbalance between reactive oxygen species (ROS) and antioxidant defenses, a pathological state which not only leads to direct cellular damage but also an inflammatory cascade that further perpetuates tissue injury. Emerging therapeutic strategies tackle these pathways in a variety of ways, from increasing antioxidant defenses (antioxidants and Nrf2 activators) to reducing ROS production (NADPH oxidase inhibitors and XO inhibitors) or inhibiting the associated inflammatory pathways (NLRP3 inflammasome inhibitors, lipoxins, GLP-1 receptor agonists, and AT-1 receptor antagonists). This review summarizes the mechanisms by which oxidative stress and inflammation contribute to and perpetuate diabetes associated renal and cardiovascular disease along with the therapeutic strategies which target these pathways to provide reno and cardiovascular protection in the setting of diabetes.

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Serum factor requirement for reactive oxygen intermediate release by rabbit alveolar macrophages.

Journal of Experimental Medicine ◽

10.1084/jem.161.2.392 ◽

1985 ◽

Vol 161 (2) ◽

pp. 392-408 ◽

Cited By ~ 22

Author(s):

G F Gerberick ◽

J B Willoughby ◽

W F Willoughby

Keyword(s):

Alveolar Macrophages ◽

Tissue Injury ◽

Reactive Oxygen ◽

Rabbit Serum ◽

Reactive Oxygen Intermediate ◽

Serum Free Medium ◽

Free Medium ◽

Oxygen Intermediates ◽

Serum Free ◽

Mediator Systems

Alveolar macrophages (AM) from pathogen-free rabbits were unable to release reactive oxygen intermediates (ROI) unless they were conditioned in serum for 24-48 h before triggering with membrane-active agents. The degree of serum conditioning of AM depended upon the concentration of serum used; optimal ROI release was obtained at or above 7.5% fetal bovine serum (FBS). FBS, autologous rabbit serum, pooled rabbit serum, and pooled human serum were each capable of conditioning AM for release of ROI. Serum conditioning of AM requires synthesis of new protein(s); and the enzyme required for ROI production, NADPH oxidase, was only detectable in serum-conditioned cells. Moreover, serum-conditioned cells lost their ability to release ROI after transfer to serum-free medium, while cells maintained in serum-free medium acquired the capacity to release ROI after their transfer to serum-containing medium, demonstrating the reversibility of the phenomenon. Initial purification data indicate that conditioning is mediated by a discrete serum constituent, which precipitates 40-80% saturated ammonium sulfate, does not bind to Cibacron Blue columns, and has a molecular weight of 30,000 to 50,000, as determined by molecular exclusion chromatography. Unlike gamma interferon, which also enhances ROI release by macrophages, our serum-conditioning factor is not acid labile, retaining 67% of its activity after 120 min incubation at pH 2.0. Moreover, it does not appear to be a contaminating endotoxin, since LPS neither conditioned AM for ROI production, nor triggered ROI production by serum-conditioned AM. We propose that such a conditioning requirement may normally protect the lung against ROI-mediated tissue injury. However, during a pulmonary inflammatory reaction initiated by other mediator systems, the resulting transudation of plasma proteins into the alveolar spaces may condition AM in situ for ROI production.

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Proinflammatory Responses of Heme in Alveolar Macrophages: Repercussion in Lung Hemorrhagic Episodes

Mediators of Inflammation ◽

10.1155/2013/946878 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 9

Author(s):

Rafael L. Simões ◽

Maria Augusta Arruda ◽

Cláudio Canetti ◽

Carlos H. Serezani ◽

Iolanda M. Fierro ◽

...

Keyword(s):

Inflammatory Response ◽

Alveolar Macrophages ◽

Nuclear Translocation ◽

Tissue Injury ◽

Proinflammatory Responses ◽

Proinflammatory Molecule ◽

Free Heme ◽

Inflammatory Processes ◽

Lung Hemorrhage ◽

And Function

Clinical and experimental observations have supported the notion that free heme released during hemorrhagic and hemolytic episodes may have a major role in lung inflammation. With alveolar macrophages (AM) being the main line of defense in lung environments, the influence of free heme on AM activity and function was investigated. We observed that heme in a concentration range found during hemolytic episodes (3–30 μM) elicits AM to present a proinflammatory profile, stimulating reactive oxygen species (ROS) and nitric oxide (NO) generation and inducing IL-1β, IL-6, and IL-10 secretion. ROS production is NADPH oxidase-dependent, being inhibited by DPI and apocynin, and involves p47 subunit phosphorylation. Furthermore, heme induces NF-κB nuclear translocation, iNOS, and also HO-1 expression. Moreover, AM stimulated with free heme show enhanced phagocytic and bactericidal activities. Taken together, the data support a dual role for heme in the inflammatory response associated with lung hemorrhage, acting as a proinflammatory molecule that can either act as both an adjuvant of the innate immunity and as an amplifier of the inflammatory response, leading tissue injury. The understanding of heme effects on pulmonary inflammatory processes can lead to the development of new strategies to ameliorate tissue damage associated with hemorrhagic episodes.

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The effects of deformation, ischemia, and reperfusion on the development of muscle damage during prolonged loading

Journal of Applied Physiology ◽

10.1152/japplphysiol.00389.2011 ◽

2011 ◽

Vol 111 (4) ◽

pp. 1168-1177 ◽

Cited By ~ 83

Author(s):

S. Loerakker ◽

E. Manders ◽

G. J. Strijkers ◽

K. Nicolay ◽

F. P. T. Baaijens ◽

...

Keyword(s):

Muscle Damage ◽

Tissue Injury ◽

Severe Form ◽

Anatomical Location ◽

Pathological State ◽

Ischemia And Reperfusion ◽

Damage Development ◽

Deep Tissue Injury ◽

Intrinsic Factors ◽

Prolonged Loading

Deep tissue injury (DTI) is a severe form of pressure ulcer where tissue damage starts in deep tissues underneath intact skin. In the present study, the contributions of deformation, ischemia, and reperfusion to skeletal muscle damage development were examined in a rat model during a 6-h period. Magnetic resonance imaging (MRI) was used to study perfusion (contrast-enhanced MRI) and tissue integrity (T2-weighted MRI). The levels of tissue deformation were estimated using finite element models. Complete ischemia caused a gradual homogeneous increase in T2 (∼20% during the 6-h period). The effect of reperfusion on T2 was highly variable, depending on the anatomical location. In experiments involving deformation, inevitably associated with partial ischemia, a variable T2 increase (17–66% during the 6-h period) was observed reflecting the significant variation in deformation (with two-dimensional strain energies of 0.60–1.51 J/mm) and ischemia (50.8–99.8% of the leg) between experiments. These results imply that deformation, ischemia, and reperfusion all contribute to the damage process during prolonged loading, although their importance varies with time. The critical deformation threshold and period of ischemia that cause muscle damage will certainly vary between individuals. These variations are related to intrinsic factors, such as pathological state, which partly explain the individual susceptibility to the development of DTI and highlight the need for regular assessments of individual subjects.

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Simvastatin regulates CXC chemokine formation in streptococcal M1 protein-induced neutrophil infiltration in the lung

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00422.2010 ◽

2011 ◽

Vol 300 (6) ◽

pp. L930-L939 ◽

Cited By ~ 23

Author(s):

Songen Zhang ◽

Milladur Rahman ◽

Su Zhang ◽

Zhongquan Qi ◽

Heiko Herwald ◽

...

Keyword(s):

Gene Expression ◽

Acute Lung Injury ◽

Lung Injury ◽

Alveolar Macrophages ◽

Tissue Injury ◽

Neutrophil Infiltration ◽

Streptococcal Toxic Shock Syndrome ◽

Edema Formation ◽

M1 Protein ◽

Cxcr2 Antagonist

Streptococcus pyogenes of the M1 serotype can cause streptococcal toxic shock syndrome and acute lung injury. Statins exert beneficial effects in septic patients although the mechanisms remain elusive. This study examined effects of simvastatin on M1 protein-provoked pulmonary inflammation and tissue injury. Male C57BL/6 mice were pretreated with simvastatin or a CXCR2 antagonist before M1 protein challenge. Bronchoalveolar fluid and lung tissue were harvested for determination of neutrophil infiltration, formation of edema, and CXC chemokines. Flow cytometry was used to determine Mac-1 expression on neutrophils. Gene expression of CXC chemokines was determined in alveolar macrophages by using quantitative RT-PCR. M1 protein challenge caused massive infiltration of neutrophils, edema formation, and production of CXC chemokines in the lung as well as upregulation of Mac-1 on circulating neutrophils. Simvastatin reduced M1 protein-induced infiltration of neutrophils and edema in the lung. In addition, M1 protein-induced Mac-1 expression on neutrophils was abolished by simvastatin. Furthermore, simvastatin markedly decreased pulmonary formation of CXC chemokines and gene expression of CXC chemokines in alveolar macrophages. Moreover, the CXCR2 antagonist reduced M1 protein-induced neutrophil expression of Mac-1 and accumulation of neutrophils as well as edema formation in the lung. These novel findings indicate that simvastatin is a powerful inhibitor of neutrophil infiltration in acute lung damage triggered by streptococcal M1 protein. The inhibitory effect of simvastatin on M1 protein-induced neutrophil recruitment appears related to reduced pulmonary generation of CXC chemokines. Thus, simvastatin may be a useful tool to ameliorate acute lung injury in streptococcal infections.

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Exosomes From M2 Macrophage Promote Peritendinous Fibrosis Posterior Tendon Injury via the MiR-15b-5p/FGF-1/7/9 Pathway by Delivery of circRNA-Ep400

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.595911 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yinxian Yu ◽

Binbin Sun ◽

Zhuoying Wang ◽

Mengkai Yang ◽

Zhi Cui ◽

...

Keyword(s):

High Throughput Sequencing ◽

Tissue Injury ◽

Achilles Tendon Rupture ◽

Tendon Injury ◽

Circular Rnas ◽

M2 Macrophage ◽

Tissue Microenvironment ◽

Inflammatory Monocytes ◽

Injury Treatment ◽

And Migration

Achilles tendon rupture prognosis is usually unsatisfactory. After the tendon is injured, it may not function properly because of the fibrotic healing response, which restrains tendon motion. Inflammatory monocytes and tissue-resident macrophages are indispensable regulators in tissue repair, fibrosis, and regeneration. Exosomes from macrophages are crucial factors in tissue microenvironment regulation following tissue injury. This study therefore aimed to clarify the roles of macrophage exosomes in tendon injury (TI) repair. The results show that macrophages play a role after TI. M1 macrophages were increased relative to peritendinous fibrosis after TI. High-throughput sequencing showed abnormal expression of circular RNAs (circRNAs) between exosomes from M2 and M0 macrophages. Among the abnormal expressions of circRNA, circRNA-Ep400 was significantly increased in M2 macrophage exosomes. The results also show that M2 macrophage-derived circRNA-Ep400-containing exosomes are important for promoting peritendinous fibrosis after TI. Bioinformatics and dual-luciferase reporting experiments confirmed that miR-15b-5p and fibroblast growth factor (FGF)-1/7/9 were downstream targets of circRNA-Ep400. High circRNA-Ep400-containing exosome treatment inhibited miR-15b-5p, but promoted FGF1/7/9 expression in both fibroblasts and tenocytes. Furthermore, high circRNA-Ep400-containing exosome treatment promoted fibrosis, proliferation, and migration in both fibroblasts and tenocytes. Taken together, the results show that M2 macrophage-derived circRNA-Ep400-containing exosomes promote peritendinous fibrosis after TI via the miR-15b-5p/FGF-1/7/9 pathway, which suggests novel therapeutics for tendon injury treatment.

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Hyperoxia upregulates the NO pathway in alveolar macrophages in vitro: role of AP-1 and NF-κB

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2001.280.5.l905 ◽

2001 ◽

Vol 280 (5) ◽

pp. L905-L913 ◽

Cited By ~ 32

Author(s):

Sonja Pepperl ◽

Martina Dörger ◽

Florian Ringel ◽

Christian Kupatt ◽

Fritz Krombach

Keyword(s):

Transcription Factors ◽

Alveolar Macrophages ◽

Tissue Injury ◽

Binding Activity ◽

Pyrrolidine Dithiocarbamate ◽

Intracellular Ros ◽

Ifn Γ ◽

Stress Response Gene

The inducible nitric oxide (NO) synthase gene in alveolar macrophages (AMs) is a stress response gene that may contribute to tissue injury in the lung after respiration with high O2concentrations through extensive production of NO. In this study, we investigated the influence of hyperoxia on the NO pathway in rat AMs in vitro, its regulation by the transcription factors nuclear factor (NF)-κB and activator protein (AP)-1, and the role of reactive oxygen species (ROS). AMs were treated with lipopolysaccharide (LPS) and/or interferon (IFN)-γ and incubated under 21 or 85% O2. Stimulation with LPS and IFN-γ led to induction of the NO pathway that was further upregulated by hyperoxia. The binding activity of NF-κB, in contrast to that of AP-1, was activated on stimulation with LPS and IFN-γ, and both were further increased under hyperoxia. The antioxidants pyrrolidine dithiocarbamate and N-acetyl-l-cysteine inhibited intracellular ROS production and the NO pathway under both normoxic and hyperoxic conditions but had diverse effects on the transcription factors. The results presented here indicate that hyperoxia can upregulate the NO pathway in stimulated AMs through increased production of intracellular ROS and activation of NF-κB and AP-1.

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Dipyridamole stimulates urokinase production and suppresses procoagulant activity of rabbit alveolar macrophages: a possible mechanism of antithrombotic action

Blood ◽

10.1182/blood.v69.2.660.660 ◽

1987 ◽

Vol 69 (2) ◽

pp. 660-667 ◽

Cited By ~ 19

Author(s):

JD Hasday ◽

RG Sitrin

Keyword(s):

Plasminogen Activator ◽

Alveolar Macrophages ◽

Tissue Injury ◽

Polyclonal Antibodies ◽

Mononuclear Phagocytes ◽

Procoagulant Activity ◽

Fibrin Deposition ◽

Beneficial Effects ◽

Injury And Repair

Abstract Dipyridamole, an inhibitor of platelet aggregation, has been shown to have beneficial effects in disorders characterized by extravascular fibrin deposition. Mononuclear phagocytes are present in extravascular sites and are capable of expressing both plasminogen activator and procoagulant activities, which suggests these cells play a central role in extravascular fibrin turnover. We therefore sought to determine whether dipyridamole affects the expression of plasminogen activator and procoagulant activities by rabbit alveolar macrophages cultured in vitro. We found that dipyridamole (10 to 100 mumol/L) caused increases in both cell-associated and released plasminogen activator activity, which reached levels of 240% (P less than .05) and 543% (P less than .01) of controls, respectively. In contrast, dipyridamole decreased the cell-associated procoagulant activity of alveolar macrophages to as little as 21.3% of controls (P less than .01). Similar effects were seen in cells cotreated with lymphokines. The procoagulant activity expressed by these cells functioned as a tissue thromboplastin. The plasminogen activator of control and treated cells was a urokinase as determined by molecular weight characteristics (50 kilodaltons) and by antibody neutralization profiles using polyclonal antibodies against human urokinase and tissue plasminogen activator. These effects of dipyridamole could not be duplicated by structurally dissimilar agents sharing some of the pharmacological actions of dipyridamole; however, two pyrimidopyrimidine compounds structurally similar to dipyridamole effectively mimicked the effects on both procoagulant and plasminogen activator activities. We conclude that dipyridamole may have antithrombotic effects by directly modulating the role of mononuclear phagocytes in fibrin turnover. Thus, dipyridamole may be useful in situations where extravascular fibrin deposition is important to the pathogenesis of tissue injury and repair.

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Emergence of immunoregulatory Ym1+Ly6Chi monocytes during recovery phase of tissue injury

Science Immunology ◽

10.1126/sciimmunol.aat0207 ◽

2018 ◽

Vol 3 (28) ◽

pp. eaat0207 ◽

Cited By ~ 25

Author(s):

Naoki Ikeda ◽

Kenichi Asano ◽

Kenta Kikuchi ◽

Yoshimi Uchida ◽

Hiroki Ikegami ◽

...

Keyword(s):

Bone Marrow ◽

Tissue Repair ◽

De Novo ◽

Tissue Injury ◽

Recovery Phase ◽

Regulatory Cells ◽

Resolution Of Inflammation ◽

Inflammatory Monocytes ◽

Delayed Recovery

Ly6Chi monocytes migrate to injured sites and induce inflammation in the acute phase of tissue injury. However, once the causes of tissue injury are eliminated, monocyte-derived macrophages contribute to the resolution of inflammation and tissue repair. It remains unclear whether the emergence of these immunoregulatory macrophages is attributed to the phenotypic conversion of inflammatory monocytes in situ or to the recruitment of bone marrow–derived regulatory cells de novo. Here, we identified a subpopulation of Ly6Chi monocytes that contribute to the resolution of inflammation and tissue repair. Ym1+Ly6Chi monocytes greatly expanded in bone marrow during the recovery phase of systemic inflammation or tissue injury. Ym1+Ly6Chi monocytes infiltrating into an injured site exhibited immunoregulatory and tissue-reparative phenotypes. Deletion of Ym1+Ly6Chi monocytes resulted in delayed recovery from colitis. These results demonstrate that a distinct monocyte subpopulation destined to act in immunoregulation is generated in bone marrow and participates in resolution of inflammation and tissue repair.

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TLR4 is required for macrophage efferocytosis during resolution of ventilator-induced lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00226.2021 ◽

2021 ◽

Vol 321 (4) ◽

pp. L787-L801

Author(s):

Kai Su ◽

Lulong Bo ◽

Chunling Jiang ◽

Xiaoming Deng ◽

You-Yang Zhao ◽

...

Keyword(s):

Mechanical Ventilation ◽

Lung Injury ◽

Alveolar Macrophage ◽

Alveolar Macrophages ◽

Molecular Mechanisms ◽

Tissue Injury ◽

Lung Damage ◽

Lung Edema ◽

Apoptotic Cells ◽

Ventilator Induced Lung Injury

Mechanical ventilation is a life-sustaining therapy for patients with respiratory failure but can cause further lung damage known as ventilator-induced lung injury (VILI). However, the intrinsic molecular mechanisms underlying recovery of VILI remain unknown. Phagocytosis of apoptotic cells (also known as efferocytosis) is a key mechanism orchestrating successful resolution of inflammation. Here we show the positive regulation of macrophage Toll-like receptor (TLR) 4 in efferocytosis and resolution of VILI. Mice were depleted of alveolar macrophages and then subjected to injurious ventilation (tidal volume, 20 mL/kg) for 4 h. On day 1 after mechanical ventilation, Tlr4+/+ or Tlr4−/− bone marrow-derived macrophages (BMDMs) were intratracheally administered to alveolar macrophage-depleted mice. We observed that mice depleted of alveolar macrophages exhibited defective resolution of neutrophilic inflammation, exuded protein, lung edema, and lung tissue injury after ventilation, whereas these delayed responses were reversed by administration of Tlr4+/+ BMDMs. Importantly, these proresolving effects by Tlr4+/+ BMDMs were abolished in mice receiving Tlr4−/− BMDMs. The number of macrophages containing apoptotic cells or bodies in bronchoalveolar lavage fluid was much less in mice receiving Tlr4−/− BMDMs than that in those receiving Tlr4+/+ BMDMs. Macrophage TLR4 deletion facilitated a disintegrin and metalloprotease 17 maturation and enhanced Mer cleavage in response to mechanical ventilation. Heat shock protein 70 dramatically increased Mer tyrosine kinase surface expression, phagocytosis of apoptotic neutrophils, and rescued the inflammatory phenotype in alveolar macrophage-depleted mice receiving Tlr4+/+ BMDMs, but not Tlr4−/− BMDMs. Our results suggest that macrophage TLR4 promotes resolution of VILI via modulation of Mer-mediated efferocytosis.

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