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.
This work was supported by a grant from the National Research Foundation of Korea (NRF), the Ministry of Science and ICT (MSIT), Republic of Korea (No. NRF-2016R1A3B1908631 ). Icons in schematic diagrams were retrieved from https://app.biorender.com/biorender-templates, and the illustration in Fig. 8 was created via BioRender.com.This work was supported by a grant from the National Research Foundation of Korea (NRF), the Ministry of Science and ICT (MSIT), Republic of Korea (No. NRF-2016R1A3B1908631). Icons in schematic diagrams were retrieved from https://app.biorender.com/biorender-templates, and the illustration in Fig. 8 was created via BioRender.com. RNA-seq data underlying Fig. 2, A-C, Fig. 3 A, and Fig. S2 A have been submitted to Gene Expression Omnibus (GEO) at The National Center for Biotechnology Information (NCBI), and are publicly available under accession number GSE235860. scRNA-seq data underlying Fig. 7, C and D are openly available in GEO at NCBI, and are publicly available under accession number GSE136831. Accession numbers and references are provided in the article for all publicly available datasets analyzed.
