Breathe In, Breathe Out: Metabolic Regulation of Lung Macrophages in Host Defense Against Bacterial Infection

Andrews, J. Tucker; Voth, Daniel E.; Huang, Stanley Ching-Cheng; Huang, Lu

doi:10.3389/fcimb.2022.934460

Cited by 5 publications

(4 citation statements)

References 65 publications

(91 reference statements)

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“…In some diseases, inflammation may cause more damage than the infection itself [ 31 ]. As members of the innate immune response, macrophages participate in identifying and phagocytizing foreign substances, killing pathogens, and releasing inflammatory mediators [ 32 ]. In the early stages of bacterial infection, macrophages mainly function to recognize and phagocytize pathogens to eliminate bacteria and release inflammatory mediators.…”

Section: Discussionmentioning

confidence: 99%

The beneficial effects of Rosuvastatin in inhibiting inflammation in sepsis

Tang,

Ning,

2024

Aging

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Section: Discussionmentioning

confidence: 99%

The beneficial effects of Rosuvastatin in inhibiting inflammation in sepsis

Tang,

Ning,

2024

Aging

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“…Mitochondrial respiration at the spare respiratory capacity level was slightly higher when cells were treated with KDAC inhibitor RGFP966. This deacetylase inhibitor clearly inhibited release of proinflammatory cytokines in LPS-treated macrophages and therefore the small but significant induction of mitochondrial respiration fits with this metabolic reprogramming (71,72). One limitation of our study was the use of self-propagating cells, which was necessary to obtain a sufficient protein yield for proteomics analysis and metabolite production.…”

Section: Discussionmentioning

confidence: 81%

“…Newer KDACi, such as MS-275 (entinostat), based on a benzamide group as a Zn2+ binder, offer improved specificity. Class III KDACs, which are NAD+-dependent, can be inhibited by compounds like nicotinamide and derivatives of NAD (71).…”

Section: Kdac Inhibitorsmentioning

confidence: 99%

“…Adipose tissue macrophages from obese subjects also metabolize lipids differently and a detailed description has been compiled by Dahik et al (70). A combination of studies has shown that adipose tissue macrophages from obese subjects can synthesize lipids from free fatty acids, store them in lipid droplets, catabolize them through the lysosomal pathway or produce inflammatory lipid mediators called eicosanoids (70,71). In contrast, adipose tissue macrophages from lean subjects take up free fatty acids and subject them to oxidation (72) The higher levels of free fatty acids, coupled with higher levels of other inflammatory mediators like TNFα, IL6, and IL-1β will lead to the development of insulin resistance which can develop in obesity.…”

Section: Metabolic Reprogramming Of Macrophages In Dmtii and Obesitymentioning

confidence: 99%

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Macrophage metabolic reprogramming in chronic diseases

Russo

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Chronic obstructive pulmonary disease (COPD), cardiovascular disease, and diabetes are the most common chronic diseases worldwide.COPD is a progressive and debilitating respiratory condition characterized by persistent lung airflow limitation (1). It encompasses a group of chronic lung disorders, primarily chronic bronchitis, and emphysema (2). COPD gradually worsens over time, leading to significant respiratory symptoms, reduced lung function, and impaired quality of life. It is a global health concern, affecting millions of people worldwide and imposing a substantial burden on individuals, healthcare systems, and society as a whole. Understanding the causes, symptoms, diagnosis, and management of COPD is crucial in order to improve patient outcomes and alleviate the impact of this chronic respiratory condition.Diabetes mellitus is a chronic condition characterized by high blood sugar levels resulting from insulin deficiency or resistance. It can be classified into Type 1 diabetes, caused by a lack of insulin production, and Type 2 diabetes (T2DM), caused by insulin resistance. Globally, there are approximately 415 million diagnosed cases of diabetes (of which 87-91% have T2DM in high-income countries), a number expected to rise to 642 million by 2040 (3). Diabetes is a significant cause of morbidity and mortality, with complications including diabetic nephropathy, peripheral neuropathy, and cardiovascular diseases. Despite advancements in treatment and decreasing complication rates (4), the prevalence of newly diagnosed cases continues to rise (5). INFLAMMATIONCOPD is characterized by chronic inflammation that affects various tissues involved in respiratory function, including the lungs and airways. This persistent inflammation is marked by increased levels of pro-inflammatory cytokines and other immune mediators. In COPD, chronic inflammation is primarily triggered by long-term exposure to irritants, such as cigarette smoke or environmental pollutants. The inflammatory response in the lungs leads to structural changes, airway remodeling, and narrowing of the air passages, resulting in airflow limitation and respiratory symptoms. Pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and others, contribute to the perpetuation of the inflammatory process and tissue damage in COPD. This chronic inflammation not only worsens respiratory symptoms but also contributes to the development of comorbidities, such as cardiovascular disease. Understanding the role of chronic inflammation in COPD is crucial for the development of targeted therapies aimed 9 11 13

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Effects of lysine deacetylase inhibitor treatment on LPS responses of alveolar-like macrophages

Russo,

Kwiatkowski,

Wolters

et al. 2023

Journal of Leukocyte Biology

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Macrophages are key immune cells that can adapt their metabolic phenotype in response to different stimuli. Lysine deacetylases (KDAC) are important enzymes regulating inflammatory gene expression and KDAC inhibitors have been shown to exert anti-inflammatory effects in models of chronic obstructive pulmonary disease (COPD). We hypothesized that these anti-inflammatory effects may be associated with metabolic changes in macrophages. To validate this hypothesis, we used an unbiased and a targeted proteomic approach to investigate metabolic enzymes as well as LC- and GC-MS to quantify metabolites in combination with the measurement of functional parameters in primary murine alveolar-like macrophages after lipopolysaccharide (LPS)-induced activation in the presence or absence of KDAC inhibition. We found that KDAC inhibition resulted in reduced production of inflammatory mediators such as TNF-α and IL-1β. However, only minor changes in macrophage metabolism were observed, as only one of the KDAC inhibitors slightly increased mitochondrial respiration while no changes in metabolite levels were seen. However, KDAC inhibition specifically enhanced expression of proteins involved in ubiquitination, which may be a driver of the anti-inflammatory effects of KDAC inhibitors. Our data illustrate that a multi-omics approach provides novel insights into how macrophages interact with cues from their environment. More detailed studies investigating ubiquitination as a potential driver of KDAC inhibition will help developing novel anti-inflammatory drugs for difficult to treat diseases such as COPD.

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Breathe In, Breathe Out: Metabolic Regulation of Lung Macrophages in Host Defense Against Bacterial Infection

Cited by 5 publications

References 65 publications

The beneficial effects of Rosuvastatin in inhibiting inflammation in sepsis

The beneficial effects of Rosuvastatin in inhibiting inflammation in sepsis

Macrophage metabolic reprogramming in chronic diseases

Effects of lysine deacetylase inhibitor treatment on LPS responses of alveolar-like macrophages

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