RRC ID 47772
Author Ishii T, Hosoki K, Nikura Y, Yamashita N, Nagase T, Yamashita N.
Title IFN Regulatory Factor 3 Potentiates Emphysematous Aggravation by Lipopolysaccharide.
Journal J Immunol
Abstract Acute exacerbation of chronic obstructive pulmonary disease (COPD) is often induced by infection and often has a poor prognosis. Bacterial LPS activates innate immune receptor TLR4 followed by activation of a transcriptional factor IFN regulatory factor-3 (IRF3) as well as NF-κB, resulting in upregulation of various inflammatory mediators. To clarify the role of IRF3 in the pathogenesis of LPS-triggered COPD exacerbation, porcine pancreatic elastase (PPE) followed by LPS was administered intranasally to wild-type (WT) or IRF3-/- male mice. Sequential quantitative changes in emphysema were evaluated by microcomputed tomography, and lung histology was evaluated at the sixth week. WT mice treated with PPE and LPS exhibited enlarged alveolar spaces, whereas this feature was attenuated in similarly treated IRF3-/- mice. Moreover, LPS-induced emphysema aggravation was detected only in WT mice. Analysis of acute inflammation induced by PPE plus LPS revealed that the lungs of treated IRF3-/- mice had decreased mRNA transcripts for MCP-1, MIP-1α, TNF-α, and IFN-γ-inducible protein-10 but had increased neutrophils. IRF3 was involved in the production of mediators from macrophages, alveolar epithelial cells, and neutrophils. Furthermore, compared with isolated WT neutrophils from inflamed lung, those of IRF3-/- neutrophils exhibited impaired autophagic activation, phagocytosis, and apoptosis. These results suggest that IRF3 accelerated emphysema formation based on distinct profiles of mediators involved in LPS-induced COPD exacerbation. Regulation of the IRF3 pathway can affect multiple cell types and contribute to ameliorate pathogenesis of infection-triggered exacerbation of COPD.
Volume 198(9)
Pages 3637-3649
Published 2017-5-1
DOI 10.4049/jimmunol.1601069
PII jimmunol.1601069
PMID 28363903
MeSH Animals Apoptosis / genetics Autophagy / genetics Cells, Cultured Chemokine CCL2 / genetics Chemokine CCL2 / metabolism Emphysema / immunology* Humans Interferon Regulatory Factor-3 / genetics Interferon Regulatory Factor-3 / metabolism* Interferon-gamma / metabolism Lipopolysaccharides / immunology Lung / immunology* Male Mice Mice, Inbred C57BL Mice, Knockout Neutrophils / immunology* Pulmonary Disease, Chronic Obstructive / immunology* Tumor Necrosis Factor-alpha / genetics Tumor Necrosis Factor-alpha / metabolism
IF 4.886
Times Cited 8
Mice RBRC00858