TLR9 expression is required for the development of cigarette smoke-induced emphysema in mice

Robert F. Foronjy, Matthias A Salathe, Abdoulaye J. Dabo, Nathalie Baumlin, Neville Cummins, Edward Eden, Patrick Geraghty

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

The expression of Tolllike receptor (TLR)-9, a pathogen recognition receptor that recognizes unmethylated CpG sequences in microbial DNA molecules, is linked to the pathogenesis of several lung diseases. TLR9 expression and signaling was investigated in animal and cell models of chronic obstructive pulmonary disease (COPD). We observed enhanced TLR9 expression in mouse lungs following exposure to cigarette smoke. Tlr9-/- mice were resistant to cigarette smoke-induced loss of lung function as determined by mean linear intercept, total lung capacity, lung compliance, and tissue elastance analysis. Tlr9 expression also regulated smoke-mediated immune cell recruitment to the lung; apoptosis; expression of granulocyte-colony stimulating factor (G-CSF), the CXCL5 protein, and matrix metalloproteinase-2 (MMP-2); and protein tyrosine phosphatase 1B (PTP1B) activity in the lung. PTP1B, a phosphatase with anti-inflammatory abilities, was identified as binding to TLR9. In vivo delivery of a TLR9 agonist enhanced TLR9 binding to PTP1B, which inactivated PTP1B. Ptp1b-/- mice had elevated lung concentrations of G-CSF, CXCL5, and MMP-2, and tissue expression of type-1 interferon following TLR9 agonist administration, compared with wild-type mice. TLR9 responses were further determined in fully differentiated normal human bronchial epithelial (NHBE) cells isolated from nonsmoker, smoker, and COPD donors, and then cultured at air liquid interface. NHBE cells from smokers and patients with COPD expressed more TLR9 and secreted greater levels of G-CSF, IL-6, CXCL5, IL-1β, and MMP-2 upon TLR9 ligand stimulation compared with cells from nonsmoker donors. Although TLR9 combats infection, our results indicate that TLR9 induction can affect lung function by inactivating PTP1B and upregulating expression of proinflammatory cytokines.

Original languageEnglish (US)
Pages (from-to)L154-L166
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume311
Issue number1
DOIs
StatePublished - Jul 1 2016

Fingerprint

Non-Receptor Type 1 Protein Tyrosine Phosphatase
Emphysema
Smoke
Tobacco Products
Lung
Matrix Metalloproteinase 2
Granulocyte Colony-Stimulating Factor
Chronic Obstructive Pulmonary Disease
Epithelial Cells
Tissue Donors
Toll-Like Receptor 9
Total Lung Capacity
Lung Compliance
Interferon Type I
Interleukin-1
Phosphoric Monoester Hydrolases
Lung Diseases
Interleukin-6
Carrier Proteins
Anti-Inflammatory Agents

Keywords

  • Chronic obstructive pulmonary disease
  • Cigarette smoke
  • Phosphatase
  • Toll-like receptors

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology (medical)

Cite this

TLR9 expression is required for the development of cigarette smoke-induced emphysema in mice. / Foronjy, Robert F.; Salathe, Matthias A; Dabo, Abdoulaye J.; Baumlin, Nathalie; Cummins, Neville; Eden, Edward; Geraghty, Patrick.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 311, No. 1, 01.07.2016, p. L154-L166.

Research output: Contribution to journalArticle

Foronjy, Robert F. ; Salathe, Matthias A ; Dabo, Abdoulaye J. ; Baumlin, Nathalie ; Cummins, Neville ; Eden, Edward ; Geraghty, Patrick. / TLR9 expression is required for the development of cigarette smoke-induced emphysema in mice. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2016 ; Vol. 311, No. 1. pp. L154-L166.
@article{cf5dd8cdc0b249f4a6f1f554888a74bd,
title = "TLR9 expression is required for the development of cigarette smoke-induced emphysema in mice",
abstract = "The expression of Tolllike receptor (TLR)-9, a pathogen recognition receptor that recognizes unmethylated CpG sequences in microbial DNA molecules, is linked to the pathogenesis of several lung diseases. TLR9 expression and signaling was investigated in animal and cell models of chronic obstructive pulmonary disease (COPD). We observed enhanced TLR9 expression in mouse lungs following exposure to cigarette smoke. Tlr9-/- mice were resistant to cigarette smoke-induced loss of lung function as determined by mean linear intercept, total lung capacity, lung compliance, and tissue elastance analysis. Tlr9 expression also regulated smoke-mediated immune cell recruitment to the lung; apoptosis; expression of granulocyte-colony stimulating factor (G-CSF), the CXCL5 protein, and matrix metalloproteinase-2 (MMP-2); and protein tyrosine phosphatase 1B (PTP1B) activity in the lung. PTP1B, a phosphatase with anti-inflammatory abilities, was identified as binding to TLR9. In vivo delivery of a TLR9 agonist enhanced TLR9 binding to PTP1B, which inactivated PTP1B. Ptp1b-/- mice had elevated lung concentrations of G-CSF, CXCL5, and MMP-2, and tissue expression of type-1 interferon following TLR9 agonist administration, compared with wild-type mice. TLR9 responses were further determined in fully differentiated normal human bronchial epithelial (NHBE) cells isolated from nonsmoker, smoker, and COPD donors, and then cultured at air liquid interface. NHBE cells from smokers and patients with COPD expressed more TLR9 and secreted greater levels of G-CSF, IL-6, CXCL5, IL-1β, and MMP-2 upon TLR9 ligand stimulation compared with cells from nonsmoker donors. Although TLR9 combats infection, our results indicate that TLR9 induction can affect lung function by inactivating PTP1B and upregulating expression of proinflammatory cytokines.",
keywords = "Chronic obstructive pulmonary disease, Cigarette smoke, Phosphatase, Toll-like receptors",
author = "Foronjy, {Robert F.} and Salathe, {Matthias A} and Dabo, {Abdoulaye J.} and Nathalie Baumlin and Neville Cummins and Edward Eden and Patrick Geraghty",
year = "2016",
month = "7",
day = "1",
doi = "10.1152/ajplung.00073.2016",
language = "English (US)",
volume = "311",
pages = "L154--L166",
journal = "American Journal of Physiology - Cell Physiology",
issn = "0363-6143",
publisher = "American Physiological Society",
number = "1",

}

TY - JOUR

T1 - TLR9 expression is required for the development of cigarette smoke-induced emphysema in mice

AU - Foronjy, Robert F.

AU - Salathe, Matthias A

AU - Dabo, Abdoulaye J.

AU - Baumlin, Nathalie

AU - Cummins, Neville

AU - Eden, Edward

AU - Geraghty, Patrick

PY - 2016/7/1

Y1 - 2016/7/1

N2 - The expression of Tolllike receptor (TLR)-9, a pathogen recognition receptor that recognizes unmethylated CpG sequences in microbial DNA molecules, is linked to the pathogenesis of several lung diseases. TLR9 expression and signaling was investigated in animal and cell models of chronic obstructive pulmonary disease (COPD). We observed enhanced TLR9 expression in mouse lungs following exposure to cigarette smoke. Tlr9-/- mice were resistant to cigarette smoke-induced loss of lung function as determined by mean linear intercept, total lung capacity, lung compliance, and tissue elastance analysis. Tlr9 expression also regulated smoke-mediated immune cell recruitment to the lung; apoptosis; expression of granulocyte-colony stimulating factor (G-CSF), the CXCL5 protein, and matrix metalloproteinase-2 (MMP-2); and protein tyrosine phosphatase 1B (PTP1B) activity in the lung. PTP1B, a phosphatase with anti-inflammatory abilities, was identified as binding to TLR9. In vivo delivery of a TLR9 agonist enhanced TLR9 binding to PTP1B, which inactivated PTP1B. Ptp1b-/- mice had elevated lung concentrations of G-CSF, CXCL5, and MMP-2, and tissue expression of type-1 interferon following TLR9 agonist administration, compared with wild-type mice. TLR9 responses were further determined in fully differentiated normal human bronchial epithelial (NHBE) cells isolated from nonsmoker, smoker, and COPD donors, and then cultured at air liquid interface. NHBE cells from smokers and patients with COPD expressed more TLR9 and secreted greater levels of G-CSF, IL-6, CXCL5, IL-1β, and MMP-2 upon TLR9 ligand stimulation compared with cells from nonsmoker donors. Although TLR9 combats infection, our results indicate that TLR9 induction can affect lung function by inactivating PTP1B and upregulating expression of proinflammatory cytokines.

AB - The expression of Tolllike receptor (TLR)-9, a pathogen recognition receptor that recognizes unmethylated CpG sequences in microbial DNA molecules, is linked to the pathogenesis of several lung diseases. TLR9 expression and signaling was investigated in animal and cell models of chronic obstructive pulmonary disease (COPD). We observed enhanced TLR9 expression in mouse lungs following exposure to cigarette smoke. Tlr9-/- mice were resistant to cigarette smoke-induced loss of lung function as determined by mean linear intercept, total lung capacity, lung compliance, and tissue elastance analysis. Tlr9 expression also regulated smoke-mediated immune cell recruitment to the lung; apoptosis; expression of granulocyte-colony stimulating factor (G-CSF), the CXCL5 protein, and matrix metalloproteinase-2 (MMP-2); and protein tyrosine phosphatase 1B (PTP1B) activity in the lung. PTP1B, a phosphatase with anti-inflammatory abilities, was identified as binding to TLR9. In vivo delivery of a TLR9 agonist enhanced TLR9 binding to PTP1B, which inactivated PTP1B. Ptp1b-/- mice had elevated lung concentrations of G-CSF, CXCL5, and MMP-2, and tissue expression of type-1 interferon following TLR9 agonist administration, compared with wild-type mice. TLR9 responses were further determined in fully differentiated normal human bronchial epithelial (NHBE) cells isolated from nonsmoker, smoker, and COPD donors, and then cultured at air liquid interface. NHBE cells from smokers and patients with COPD expressed more TLR9 and secreted greater levels of G-CSF, IL-6, CXCL5, IL-1β, and MMP-2 upon TLR9 ligand stimulation compared with cells from nonsmoker donors. Although TLR9 combats infection, our results indicate that TLR9 induction can affect lung function by inactivating PTP1B and upregulating expression of proinflammatory cytokines.

KW - Chronic obstructive pulmonary disease

KW - Cigarette smoke

KW - Phosphatase

KW - Toll-like receptors

UR - http://www.scopus.com/inward/record.url?scp=84984653764&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84984653764&partnerID=8YFLogxK

U2 - 10.1152/ajplung.00073.2016

DO - 10.1152/ajplung.00073.2016

M3 - Article

VL - 311

SP - L154-L166

JO - American Journal of Physiology - Cell Physiology

JF - American Journal of Physiology - Cell Physiology

SN - 0363-6143

IS - 1

ER -