Cigarette smoke extract decreased basal and lipopolysaccharide-induced expression of MARCO via degradation of p300

Kyoung Hee Lee, Jisu Woo, Jiyeon Kim, Chang Hoon Lee, Chul Gyu Yoo

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background and objective: Alveolar macrophages of patients with COPD display impaired cytokine release and diminished phagocytosis. COPD exacerbations exhibit immune dysfunction towards the respiratory pathogens. CS and CSE were reported to aggravate bacterial infections in COPD patients. Methods: MARCO is highly expressed in lungs and is involved in pathogen clearance. We investigated the effect of CSE on MARCO expression and its regulatory mechanisms. After relevant siRNA transfection and treatment with CSE and/or LPS, we measured the levels of MARCO by q-RT PCR, immunoblotting and flow cytometry. Immunofluorescence staining and immunoprecipitation were used to evaluate the mechanism. Results: CSE decreased LPS-induced expression of MARCO mRNA and protein. Upregulation of MARCO by LPS was Nrf2-dependent. Nrf2 knockdown significantly suppressed LPS-induced increase in MARCO transcripts. CSE did not block nuclear translocation of Nrf2 in LPS-treated cells, but rather CSE itself strongly accumulated Nrf2 in the nucleus through the degradation of its cytoplasmic inhibitor, KEAP1. However, CSE markedly suppressed LPS-induced Nrf2 acetylation. Histone acetyltransferase p300/CBP directly acetylates Nrf2, which augments promoter-specific DNA binding of Nrf2. Our results reveal CSE-induced polyubiquitinylation and subsequent degradation of p300 via the proteasome. Pretreatment with proteasome inhibitors completely blocked CSE-induced degradation of p300 and suppression of MARCO expression. Conclusion: These findings suggest that CSE decreases MARCO expression via the proteasomal degradation of p300 in macrophages, which may be in part responsible for impaired bacterial phagocytosis.

Original languageEnglish
Pages (from-to)102-111
Number of pages10
JournalRespirology
Volume26
Issue number1
DOIs
StatePublished - Jan 2021

Keywords

  • chronic obstructive pulmonary disease
  • cigarette smoke extract
  • macrophage receptor with collagenous structure
  • nuclear factor (erythroid-derived 2)-like 2
  • p300

Fingerprint Dive into the research topics of 'Cigarette smoke extract decreased basal and lipopolysaccharide-induced expression of MARCO via degradation of p300'. Together they form a unique fingerprint.

Cite this