title: Sustained activation of toll-like receptor 9 induces an invasive phenotype in lung fibroblasts: possible implications in idiopathic pulmonary fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is characterized by excessive scarring of the lung parenchyma, resulting in a steady decline of lung function and ultimately respiratory failure. The disease course of IPF is extremely variable, with some patients exhibiting stability of symptoms for prolonged periods of time, whereas others exhibit rapid progression and loss of lung function. Viral infections have been implicated in IPF and linked to disease severity; however, whether they directly contribute to progression is unclear. We previously classified patients as rapid and slow progressors on the basis of clinical features and expression of the pathogen recognition receptor, Toll-like receptor 9 (TLR9). Activation of TLR9 in vivo exacerbated IPF in mice and induced differentiation of myofibroblasts in vitro, but the mechanism of TLR9 up-regulation and progression of fibrosis are unknown. Herein, we investigate whether transforming growth factor (TGF)-β, a pleiotropic cytokine central to IPF pathogenesis, regulates TLR9 in lung myofibroblasts. Results showed induction of TLR9 expression by TGF-β in lung myofibroblasts and a distinct profibrotic myofibroblast phenotype driven by stimulation with the TLR9 agonist, CpG-DNA. Chronic TLR9 stimulation resulted in stably differentiated α-smooth muscle actin(+)/platelet-derived growth factor receptor α(+)/CD44(+)/matrix metalloproteinase-14(+)/matrix metalloproteinase-2(+) myofibroblasts, which secrete inflammatory cytokines, invade Matrigel toward platelet-derived growth factor, and resist hypoxia-induced apoptosis. These results suggest a mechanism by which TGF-β and TLR9 responses in myofibroblasts collaborate to drive rapid progression of IPF.
authors: Department of Pathology, Stony Brook University School of Medicine, Stony Brook, New York.
authors: Varvara
authors: V
authors: Kirillov
authors: Department of Pathology, Stony Brook University School of Medicine, Stony Brook, New York.
authors: Jonathan T
authors: JT
authors: Siler
authors: Department of Pathology, Stony Brook University School of Medicine, Stony Brook, New York.
authors: Mahalakshmi
authors: M
authors: Ramadass
authors: Department of Pathology, Stony Brook University School of Medicine, Stony Brook, New York.
authors: Lingyin
authors: L
authors: Ge
authors: Department of Pathology, Stony Brook University School of Medicine, Stony Brook, New York.
authors: James
authors: J
authors: Davis
authors: Department of Molecular and Microbiology, School of Systems Biology, George Mason University, Fairfax, Virginia.
authors: Geraldine
authors: G
authors: Grant
authors: Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Falls Church, Virginia.
authors: Steven D
authors: SD
authors: Nathan
authors: Respiratory Disease Area, Novartis Institutes for Biomedical Research, Horsham, United Kingdom.
authors: Gabor
authors: G
authors: Jarai
authors: Department of Pathology, Stony Brook University School of Medicine, Stony Brook, New York. Electronic address: glenda.trujillo@bms.com.
authors: Glenda
authors: G
authors: Trujillo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016022:Case-Control Studies; D015687:Cell Hypoxia / Q000187:drug effects; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D008168:Lung / Q000473:pathology*; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D051379:Mice; D058628:Myofibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051217:Toll-Like Receptor 9 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D010982:Platelet-Derived Growth Factor; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D016212:Transforming Growth Factor beta; C095477:platelet-derived growth factor AB; D053511:Matrix Metalloproteinase 14