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IFN Regulatory Factor 3 Potentiates Emphysematous Aggravation by Lipopolysaccharide

Takashi Ishii, Keisuke Hosoki, Yuichi Nikura, Naohide Yamashita, Takahide Nagase and Naomi Yamashita
J Immunol May 1, 2017, 198 (9) 3637-3649; DOI: https://doi.org/10.4049/jimmunol.1601069
Takashi Ishii
*Department of Pharmacotherapy, Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo 202-8585, Japan;
†Department of Respiratory Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan; and
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Keisuke Hosoki
*Department of Pharmacotherapy, Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo 202-8585, Japan;
†Department of Respiratory Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan; and
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Yuichi Nikura
*Department of Pharmacotherapy, Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo 202-8585, Japan;
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Naohide Yamashita
‡Department of Advanced Medical Science, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
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Takahide Nagase
†Department of Respiratory Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan; and
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Naomi Yamashita
*Department of Pharmacotherapy, Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo 202-8585, Japan;
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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.

Footnotes

  • This study was supported in part by Ministry of Education, Culture, Sports, Science and Technology, Japan Grant-in-Aid for Scientific Research 25460660 (to Naomi Yamashita).

  • Abbreviations used in this article:

    BALF
    bronchoalveolar lavage fluid
    COPD
    chronic obstructive pulmonary disease
    CSE
    cigarette smoke extract
    CT
    computed tomography
    HU
    Hounsfield unit
    IP-10
    IFN-γ–inducible protein-10
    IRF3
    IFN regulatory factor-3
    MFI
    mean fluorescence intensity
    micro-CT
    microcomputed tomography
    PI
    propidium iodide
    PPE
    porcine pancreatic elastase
    TRIF
    Toll/IL-1R domain–containing adaptor inducing IFN-β
    WT
    wild-type.

  • Received June 22, 2016.
  • Accepted February 23, 2017.
  • Copyright © 2017 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 198 (9)
The Journal of Immunology
Vol. 198, Issue 9
1 May 2017
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IFN Regulatory Factor 3 Potentiates Emphysematous Aggravation by Lipopolysaccharide
Takashi Ishii, Keisuke Hosoki, Yuichi Nikura, Naohide Yamashita, Takahide Nagase, Naomi Yamashita
The Journal of Immunology May 1, 2017, 198 (9) 3637-3649; DOI: 10.4049/jimmunol.1601069

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IFN Regulatory Factor 3 Potentiates Emphysematous Aggravation by Lipopolysaccharide
Takashi Ishii, Keisuke Hosoki, Yuichi Nikura, Naohide Yamashita, Takahide Nagase, Naomi Yamashita
The Journal of Immunology May 1, 2017, 198 (9) 3637-3649; DOI: 10.4049/jimmunol.1601069
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