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Updated: Jul 10, 2025
Measuring Carbon Content in Airway Macrophages Exposed to Carbon-Containing Particulate Matters
Published on: July 12, 2024
Particulate matter-induced metabolic recoding of epigenetics in macrophages drives pathogenesis of chronic
Myungkyung Noh1, Jeong Yeon Sim1, Jisung Kim1
1Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul 08826, South Korea.
Abstract:
Chronic obstructive pulmonary disease (COPD) is a group of illnesses associated with unresolved inflammation in response to toxic environmental stimuli. Persistent exposure to PM is a major risk factor for COPD, but the underlying mechanism remains unclear. Using our established mouse model of PM-induced COPD, we find that repeated PM exposure provokes macrophage-centered chronic inflammation and COPD development. Mechanistically, chronic PM exposure induces transcriptional downregulation of HAAO, KMO, KYNU, and QPRT in macrophages, which are the enzymes of de novo NAD+ synthesis pathway (kynurenine pathway; KP), via elevated chromatin binding of the CCCTC-binding factor (CTCF) near the transcriptional regulatory regions of the enzymes. Subsequent reduction of NAD+ and SIRT1 function increases histone acetylation, resulting in elevated expression of pro-inflammatory genes in PM-exposed macrophages. Activation of SIRT1 by nutraceutical resveratrol mitigated PM-induced chronic inflammation and COPD development. In agreement, increased levels of histone acetylation and decreased expression of KP enzymes were observed in pulmonary macrophages of COPD patients. We newly provide an evidence that dysregulated NAD+ metabolism and consecutive SIRT1 deficiency significantly contribute to the pathological activation of macrophages during PM-mediated COPD pathogenesis. Additionally, targeting PM-induced intertwined metabolic and epigenetic reprogramming in macrophages is an effective strategy for COPD treatment.
Insights
Particulate matter exposure triggers chronic inflammation and COPD by disrupting NAD+ synthesis in macrophages. Resveratrol, a SIRT1 activator, reversed these effects, offering a potential therapeutic strategy for COPD.
Area of Science:
- Environmental Health
- Immunology
- Metabolic Disease
Background:
- Chronic obstructive pulmonary disease (COPD) is linked to unresolved inflammation from environmental toxins.
- Persistent exposure to particulate matter (PM) is a significant COPD risk factor, but mechanisms are unclear.
- Macrophage-centered inflammation is implicated in PM-induced COPD development.
Purpose of the Study:
- To elucidate the mechanism of PM-induced COPD pathogenesis.
- To investigate the role of NAD+ metabolism and SIRT1 in PM-mediated inflammation.
- To evaluate resveratrol as a potential therapeutic agent for COPD.
Main Methods:
- Utilized a mouse model of PM-induced COPD.
- Analyzed transcriptional changes in macrophage enzymes of the kynurenine pathway (KP).
- Assessed chromatin binding of CTCF and histone acetylation.
- Investigated the effect of resveratrol on inflammation and COPD development.
- Examined pulmonary macrophages from COPD patients.
Main Results:
- PM exposure downregulated de novo NAD+ synthesis enzymes (HAAO, KMO, KYNU, QPRT) in macrophages via CTCF binding.
- Reduced NAD+ and SIRT1 function led to increased histone acetylation and pro-inflammatory gene expression.
- Resveratrol mitigated PM-induced inflammation and COPD.
- COPD patients showed increased histone acetylation and decreased KP enzyme expression in macrophages.
Conclusions:
- Dysregulated NAD+ metabolism and SIRT1 deficiency contribute to macrophage activation in PM-mediated COPD.
- Targeting metabolic and epigenetic reprogramming in macrophages is a promising COPD treatment strategy.
- Resveratrol shows therapeutic potential for COPD by modulating NAD+ metabolism and inflammation.
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