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

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

PROVIDER: PRJNA521523 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8550960_1.fastq.gz	Fastqsanger.gz
	SRR8550960_2.fastq.gz	Fastqsanger.gz
	SRR8550970_1.fastq.gz	Fastqsanger.gz
	SRR8550970_2.fastq.gz	Fastqsanger.gz
	SRR8550961_1.fastq.gz	Fastqsanger.gz

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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 in type 2 inflammation.

Project description: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.

| S-EPMC8381729 | biostudies-literature

Extracellular acidity reprograms macrophage metabolism and innate responsiveness

Project description:Extracellular acidity reprograms macrophage metabolism and innate responsiveness

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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

IFN-gamma is essential for alveolar macrophage driven pulmonary inflammation in macrophage activation syndrome

Project description:Macrophage activation syndrome (MAS) is a life-threatening cytokine storm syndrome complicating systemic juvenile idiopathic arthritis (SJIA) and driven by IFN-gamma. SJIA and MAS are also associated with an unexplained emerging inflammatory lung disease (SJIA-LD), with our recent work supporting pulmonary activation of IFN-gamma pathways as a pathologic link between SJIA-LD and MAS. Our objective was to mechanistically define the novel observation of pulmonary inflammation in the TLR9 mouse model of MAS. In acute MAS, lungs exhibit mild but diffuse CD4-predominant, perivascular interstitial inflammation with elevated IFN-gamma, IFN-induced chemokines, and alveolar macrophage expression of IFN-gamma-induced genes. Single-cell RNA-sequencing confirmed IFN-driven transcriptional changes across immune and parenchymal lung cell types. Resolution of MAS was associated with increased alveolar macrophage and interstitial lymphocytic infiltration. alveolar macrophage microarrays confirmed IFN-gamma-induced proinflammatory polarization during acute MAS, which switches towards an anti-inflammatory phenotype during MAS resolution. Interestingly, recurrent MAS led to increased alveolar inflammation and lung injury, and reset alveolar macrophagepolarization towards a proinflammatory state. Furthermore, in mice bearing macrophages insensitive to IFN-gamma, both systemic feature of MAS and pulmonary inflammation were attenuated. These findings demonstrate that experimental MAS induces IFN-gamma-driven pulmonary inflammation replicating key features of SJIA-LD, and provides a model system for testing novel treatments directed towards SJIA-LD.

2021-09-12 | GSE169325 | GEO

Berry e-cigarette vapour impairs alveolar macrophage mobility and infection clearance

Project description:In our lower respiratory tract, the alveolar spaces are divided from the bloodstream and the external environment by only a few microns of interstitial tissue. Alveolar macrophages (AMs) defend this delicate mucosal surface from invading infections by regularly patrolling the site. AMs have three behaviour modalities to achieve this goal: extending cell protrusions to sample surrounding areas, squeezing the whole cell body between alveoli, and patrolling by moving the cell body around each alveolus. In this study we found Rho GTPase, cell division control protein 42 (CDC42) expression significantly decreased after berry-flavoured e-cigarette (e-cig) exposure. This resulted in a shift in AM behaviour from squeezing to probing. Changes in AM behaviour led to a reduction in the clearance of inhaled bacteria, Pseudomonas aeruginosa. These findings shed light on pathways involved in AM migration and highlight the harmful impact of e-cigarette vaping on alveolar macrophage function.

2024-09-04 | PXD050380 | Pride

Extracellular acidity reprograms macrophage metabolism and innate responsiveness

Project description:Although organ hypofunction and immunosuppression are life-threatening features of severe sepsis, the hypofunctioning organs and immune cells usually regain normal functionality if patients survive. We tested the hypothesis that low extracellular pH (pHe) can induce reversible metabolic and functional changes in tissue macrophages. When compared with macrophages cultured at normal pHe, macrophages living in an acidic medium used less glucose and exogenous fatty acid to produce ATP. Lactate, glutamine, and de novo synthesized fatty acids supported ATP production by mitochondria that gained greater mass, maximal oxygen consumption rate, and spare respiratory capacity. The cells transitioned to a M2-like state, with altered immune responses to LPS and slightly decreased phagocytic ability, yet they regained basal energy production, normal mitochondrial function and pro-inflammatory responsiveness when neutral pHe was restored. Low pHe induces changes that support macrophage survival while rendering the cells less pro-inflammatory (more ‘tolerant’) and less able to phagocytose bacteria. Macrophage responses to low interstitial pH may contribute to the reversible organ hypofunction and immunoparalysis noted in many patients with sepsis.

2021-04-15 | GSE164697 | GEO

Alveolar macrophage gene expression - PIKfyve knockout

Project description:comparison of Alveolar macrophge gene expression in wild type and PIKfyve ko We identifed gene that important for alveolar macrophage development

2017-03-01 | GSE93849 | GEO

Cytomegalovirus subverts macrophage identity [Alveolar macrophages]

Project description:Cytomegalovirus subverts macrophage identity [Alveolar macrophages]

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IFN-gamma is essential for alveolar macrophage driven pulmonary inflammation in macrophage activation syndrome

Project description:IFN-gamma is essential for alveolar macrophage driven pulmonary inflammation in macrophage activation syndrome

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