TLR9 expression is required for the development of cigarette smoke-induced emphysema in mice.
The expression of Toll-like 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.
Division of Pulmonary & Critical Care Medicine, Department of Medicine, State University of New York Downstate Medical Center, Brooklyn, New York; Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York;
Robert F
RF
Foronjy
Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Miami, Miami, Florida; and.
Matthias A
MA
Salathe
Division of Pulmonary & Critical Care Medicine, Department of Medicine, State University of New York Downstate Medical Center, Brooklyn, New York; Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York;
Abdoulaye J
AJ
Dabo
Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Miami, Miami, Florida; and.
Nathalie
N
Baumlin
Division of Pulmonary and Critical Care Medicine, Mount Sinai Roosevelt, Mount Sinai Health System, New York, New York.
Neville
N
Cummins
Division of Pulmonary and Critical Care Medicine, Mount Sinai Roosevelt, Mount Sinai Health System, New York, New York.
Edward
E
Eden
Division of Pulmonary & Critical Care Medicine, Department of Medicine, State University of New York Downstate Medical Center, Brooklyn, New York; Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York; Patrick.Geraghty@downstate.edu.
Patrick
P
Geraghty
D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011014:Pneumonia / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism; D011656:Pulmonary Emphysema / Q000209:etiology / Q000276:immunology / Q000378:metabolism*; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects; D051217:Toll-Like Receptor 9 / Q000096:biosynthesis / Q000235:genetics*; D015854:Up-Regulation; D055815:Young Adult
D016207:Cytokines; D012906:Smoke; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse
Toll-like receptors; chronic obstructive pulmonary disease; cigarette smoke; phosphatase