TLR9 is expressed in idiopathic interstitial pneumonia and its activation promotes in vitro myofibroblast differentiation.
Infectious diseases can be cofactors in idiopathic interstitial pneumonias (IIP) pathogenesis; recent data suggests that toll-like receptors 9 (TLR9) ligands contribute to experimental chronic tissue remodeling. Real-time TAQMAN and immunohistochemical analysis of IIP normal surgical lung biopsies (SLBs), primary fibroblast lines grown from both IIP and normal SLBs indicate that TLR9 is prominently and differentially expressed in a disease-specific manner. TLR9 expression was increased in biopsies from patients with IIP compared with normal lung biopsies and its expression is localized to areas of marked interstitial fibrosis. TLR9 in fibroblasts appeared to be increased by profibrotic Th2 cytokines (IL-4 and IL-13) and this was true in fibroblasts cultured from the most severe form of IIP, idiopathic pulmonary fibrosis (IPF) SLBs, in non-specific interstitial pneumonia fibroblast lines, and in normal fibroblasts. Finally, confocal microscopy studies have shown that TLR9 activation by its synthetic agonist CpG-ODN significantly increased the expression of alpha smooth muscle actin, the main marker of myofibroblast differentiation. These data indicate that TLR9 expression may drive the abnormal tissue healing response in severe forms of IIP and its activation can have a key role in myofibroblast differentiation promoting the progression of disease during the terminal phase of IPF.
Meneghin
A
A
Department of Pathology, University of Michigan Medical School, Room 4710, BSRB, 109 Zina Pitcher Pl, Ann Arbor, MI 48109-2200, USA. alessiam@med.umich.edu
Choi
E S
ES
Evanoff
H L
HL
Kunkel
S L
SL
Martinez
F J
FJ
Flaherty
K R
KR
Toews
G B
GB
Hogaboam
C M
CM
D000199:Actins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D006801:Humans; D054988:Idiopathic Interstitial Pneumonias / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007150:Immunohistochemistry; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D018613:Microscopy, Confocal; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
D000199:Actins; C408982:CPG-oligonucleotide; D018793:Interleukin-13; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D011994:Recombinant Proteins; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D015847:Interleukin-4