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The lung environment controls alveolar macrophage metabolism and responsiveness in type 2 inflammation.

ABSTRACT: 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.

SUBMITTER: Svedberg FR

PROVIDER: S-EPMC8381729 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The lung environment controls alveolar macrophage metabolism and responsiveness during type-2 inflammation.

Project description:Fine control of macrophage activation is required to prevent inflammatory disease, particularly at barrier sites such as the lung. However, the dominant mechanisms that regulate pulmonary MΦs during inflammation are currently poorly understood. Here we show that airway MΦs are substantially less able to respond to the canonical type-2 cytokine IL-4, which underpins allergic disease and parasite worm infections, than lung tissue or peritoneal cavity MΦs. We reveal that MΦ hypo-responsiveness to IL-4 is dictated by the lung environment, though independent of the host microbiota or the prominent lung extracellular matrix components surfactant protein D and mucin 5b. Rather, compared to cavity MΦs, airway MΦs display severely dysregulated metabolism. Strikingly, upon removal from the lung, alveolar MΦs regain IL-4 responsiveness in a process dependent upon glycolysis. Thus, we propose that impaired glycolysis within the pulmonary niche is a central determinant for regulation of MΦ responsiveness during type-2 inflammation.

2019-03-26 | GSE126309 | GEO

The lung environment controls alveolar macrophage metabolism and responsiveness during type-2 inflammation.

Project description:The lung environment controls alveolar macrophage metabolism and responsiveness during type-2 inflammation.

| PRJNA521523 | ENA

Histone deacetylase 3 controls lung alveolar macrophage development and homeostasis.

Project description:Alveolar macrophages (AMs) derived from embryonic precursors seed the lung before birth and self-maintain locally throughout adulthood, but are regenerated by bone marrow (BM) under stress conditions. However, the regulation of AM development and maintenance remains poorly understood. Here, we show that histone deacetylase 3 (HDAC3) is a key epigenetic factor required for AM embryonic development, postnatal homeostasis, maturation, and regeneration from BM. Loss of HDAC3 in early embryonic development affects AM development starting at E14.5, while loss of HDAC3 after birth affects AM homeostasis and maturation. Single-cell RNA sequencing analyses reveal four distinct AM sub-clusters and a dysregulated cluster-specific pathway in the HDAC3-deficient AMs. Moreover, HDAC3-deficient AMs exhibit severe mitochondrial oxidative dysfunction and deteriorative cell death. Mechanistically, HDAC3 directly binds to Pparg enhancers, and HDAC3 deficiency impairs Pparg expression and its signaling pathway. Our findings identify HDAC3 as a key epigenetic regulator of lung AM development and homeostasis.

| S-EPMC7393351 | biostudies-literature

Lung Secretoglobin Scgb1a1 Influences Alveolar Macrophage-Mediated Inflammation and Immunity.

Project description:Alveolar macrophage (AM) is a mononuclear phagocyte key to the defense against respiratory infections. To understand AM's role in airway disease development, we examined the influence of Secretoglobin family 1a member 1 (SCGB1A1), a pulmonary surfactant protein, on AM development and function. In a murine model, high-throughput RNA-sequencing and gene expression analyses were performed on purified AMs isolated from mice lacking in Scgb1a1 gene and were compared with that from mice expressing the wild type Scgb1a1 at weaning (4 week), puberty (8 week), early adult (12 week), and middle age (40 week). AMs from early adult mice under Scgb1a1 sufficiency demonstrated a total of 37 up-regulated biological pathways compared to that at weaning, from which 30 were directly involved with antigen presentation, anti-viral immunity and inflammation. Importantly, these pathways under Scgb1a1 deficiency were significantly down-regulated compared to that in the age-matched Scgb1a1-sufficient counterparts. Furthermore, AMs from Scgb1a1-deficient mice showed an early activation of inflammatory pathways compared with that from Scgb1a1-sufficient mice. Our in vitro experiments with AM culture established that exogenous supplementation of SCGB1a1 protein significantly reduced AM responses to microbial stimuli where SCGB1a1 was effective in blunting the release of cytokines and chemokines (including IL-1b, IL-6, IL-8, MIP-1a, TNF-a, and MCP-1). Taken together, these findings suggest an important role for Scgb1a1 in shaping the AM-mediated inflammation and immune responses, and in mitigating cytokine surges in the lungs.

| S-EPMC7558713 | biostudies-literature

Effects of Multiday Ethanol Intoxication on Postburn Inflammation, Lung Function, and Alveolar Macrophage Phenotype.

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| S-EPMC6252170 | biostudies-literature

Alveolar Macrophage ABCG1 Deficiency Promotes Pulmonary Granulomatous Inflammation.

Project description:Pulmonary granuloma formation is a complex and poorly understood response to inhaled pathogens and particulate matter. To explore the mechanisms of pulmonary granuloma formation and maintenance, our laboratory has developed a multiwall carbon nanotube (MWCNT)-induced murine model of chronic granulomatous inflammation. We have demonstrated that the MWCNT model closely mimics pulmonary sarcoidosis pathophysiology, including the deficiency of alveolar macrophage ATP-binding cassette (ABC) lipid transporters ABCA1 and ABCG1. We hypothesized that deficiency of alveolar macrophage ABCA1 and ABCG1 would promote pulmonary granuloma formation and inflammation. To test this hypothesis, the effects of MWCNT instillation were evaluated in ABCA1, ABCG1, and ABCA1/ABCG1 myeloid-specific knockout (KO) mice. Histological examination revealed significantly larger pulmonary granulomas in ABCG1-KO and ABCA1/ABCG1 double-KO animals when compared with wild-type animals. Evaluation of BAL cells indicated increased expression of CCL2 and osteopontin, genes shown to be involved in the formation and maintenance of pulmonary granulomas. Single deficiency of alveolar macrophage ABCA1 did not affect MWCNT-induced granuloma formation or proinflammatory gene expression. These observations indicate that the deficiency of alveolar macrophage ABCG1 promotes pulmonary granulomatous inflammation and that this is augmented by additional deletion of ABCA1.

| S-EPMC6839925 | biostudies-literature

Alveolar macrophage depletion increases the severity of acute inflammation following nonlethal unilateral lung contusion in mice.

Project description:BackgroundLung contusion (LC) is a common injury resulting from blunt thoracic trauma. LC is an important risk factor for the development acute lung injury, adult respiratory distress syndrome, and ventilator-associated pneumonia, all of which increase mortality from trauma. LC produces a nonspecific immune cellular response. Neutrophil recruitment is known to increase the severity of inflammation during LC. However, the exact role of macrophages in modulating the response to LC has not been well described.MethodsWe used a cortical contusion impactor to induce unilateral LC in mice. Thoracic micro computed tomographic scans of these animals were obtained to document radiologic changes over time following LC. To understand the role of macrophages during LC, liposomal clodronate was used to deplete macrophage levels before traumatic insult. Acute inflammatory attributes after LC were assessed, by measuring pressure-volume mechanics; quantifying bronchial alveolar lavage levels of leukocytes, albumin, and cytokines; and finally examining lung specimen histopathology at 5, 24, 48, and 72 hours after injury.ResultsAfter LC, alveolar macrophage numbers were significantly reduced and exhibited slowed recovery. Simultaneously, there was a significant increase in bronchial alveolar lavage neutrophil counts. The loss of macrophages could be attributed to both cellular apoptosis and necrosis. Pretreatment with clodronate increased the severity of lung inflammation as measured by worsened pulmonary compliance, increased lung permeability, amplification of neutrophil recruitment, and increases in early proinflammatory cytokine levels.ConclusionThe presence of regulatory alveolar macrophages plays an important role in the pathogenesis of acute inflammation following LC.

| S-EPMC4543300 | biostudies-literature

NADPH Oxidase 4-mediated Alveolar Macrophage Recruitment to Lung Attenuates Neutrophilic Inflammation in Staphylococcus aureus Infection.

Project description:When the lungs are infected with bacteria, alveolar macrophages (AMs) are recruited to the site and play a crucial role in protecting the host by reducing excessive lung inflammation. However, the regulatory mechanisms that trigger the recruitment of AMs to lung alveoli during an infection are still not fully understood. In this study, we identified a critical role for NADPH oxidase 4 (NOX4) in the recruitment of AMs during Staphylococcus aureus lung infection. We found that NOX4 knockout (KO) mice showed decreased recruitment of AMs and increased lung neutrophils and injury in response to S. aureus infection compared to wild-type (WT) mice. Interestingly, the burden of S. aureus in the lungs was not different between NOX4 KO and WT mice. Furthermore, we observed that depletion of AMs in WT mice during S. aureus infection increased the number of neutrophils and lung injury to a similar level as that observed in NOX4 KO mice. Additionally, we found that expression of intercellular adhesion molecule-1 (ICAM1) in NOX4 KO mice-derived lung endothelial cells was lower than that in WT mice-derived endothelial cells. Therefore, we conclude that NOX4 plays a crucial role in inducing the recruitment of AMs by controlling ICAM1 expression in lung endothelial cells, which is responsible for resolving lung inflammation during acute S. aureus infection.

| S-EPMC10643333 | biostudies-literature

CD11b restricts alveolar macrophage activation during pneumococcal pneumonia and prevents excessive lung inflammation

Project description:Bacterial lung infections are associated with strong infiltration of CD11b+ myeloid cells, which limit life-threatening disease, but also severely damage lung tissue. In a murine lung infection model with Streptococcus pneumoniae, we found intrinsic upregulation of CD11b on resident alveolar macrophages. Such CD11b expression was associated with transcriptomic and proteomic adaptations by alveolar macrophages, leading to the identification of specific molecules and pathways that depended on CD11b. In the absence of CD11b, the antimicrobial defense of alveolar macrophages was strongly reduced, and the production of neutrophil-recruiting chemokines was more pronounced. Moreover, CD11b expression limited the infection and prevented excessive alveolar damage. In conclusion, our study provides detailed molecular insights into the alveolar macrophage-specific immune response to Streptococcus pneumoniae lung infection and reveals profound CD11b-dependent alterations that are critical for effective antimicrobial immunity, neutrophil recruitment, and prevention of alveolar damage.

2023-10-08 | PXD035269 | Pride

Lung inflammation and interstitial fibrosis by targeted alveolar epithelial type I cell death.

Project description:IntroductionThe pathogenesis of chronic lung diseases is multifaceted with a major role of recurrent micro-injuries of the epithelium. While several reports clearly indicated a prominent role for surfactant-producing alveolar epithelial type 2 (AT2) cells, the contribution of gas exchange-permissive alveolar epithelial type 1 (AT1) cells has not been addressed yet. Here, we investigated whether repeated injury of AT1 cells leads to inflammation and interstitial fibrosis.MethodsWe chose an inducible model of AT1 cell depletion following local diphtheria toxin (DT) administration using an iDTR flox/flox (idTRfl/fl) X Aquaporin 5CRE (Aqp5CRE) transgenic mouse strain.ResultsWe investigated repeated doses and intervals of DT to induce cell death of AT1 cells causing inflammation and interstitial fibrosis. We found that repeated DT administrations at 1ng in iDTRfl/fl X Aqp5CRE mice cause AT1 cell death leading to inflammation, increased tissue repair markers and interstitial pulmonary fibrosis.DiscussionTogether, we demonstrate that depletion of AT1 cells using repeated injury represents a novel approach to investigate chronic lung inflammatory diseases and to identify new therapeutic targets.

| S-EPMC10568624 | biostudies-literature

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