Macrophage bone morphogenic protein receptor 2 depletion in idiopathic pulmonary fibrosis and Group III pulmonary hypertension.
Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology. The development of pulmonary hypertension (PH) is considered the single most significant predictor of mortality in patients with chronic lung diseases. The processes that govern the progression and development of fibroproliferative and vascular lesions in IPF are not fully understood. Using human lung explant samples from patients with IPF with or without a diagnosis of PH as well as normal control tissue, we report reduced BMPR2 expression in patients with IPF or IPF+PH. These changes were consistent with dampened P-SMAD 1/5/8 and elevated P-SMAD 2/3, demonstrating reduced BMPR2 signaling and elevated TGF-β activity in IPF. In the bleomycin (BLM) model of lung fibrosis and PH, we also report decreased BMPR2 expression compared with control animals that correlated with vascular remodeling and PH. We show that genetic abrogation or pharmacological inhibition of interleukin-6 leads to diminished markers of fibrosis and PH consistent with elevated levels of BMPR2 and reduced levels of a collection of microRNAs (miRs) that are able to degrade BMPR2. We also demonstrate that isolated bone marrow-derived macrophages from BLM-exposed mice show reduced BMPR2 levels upon exposure with IL6 or the IL6+IL6R complex that are consistent with immunohistochemistry showing reduced BMPR2 in CD206 expressing macrophages from lung sections from IPF and IPF+PH patients. In conclusion, our data suggest that depletion of BMPR2 mediated by a collection of miRs induced by IL6 and subsequent STAT3 phosphorylation as a novel mechanism participating to fibroproliferative and vascular injuries in IPF.
Department of Biochemistry and Molecular Biology, UTHealth, Houston, Texas;
Ning-Yuan
NY
Chen
Department of Biochemistry and Molecular Biology, UTHealth, Houston, Texas;
Scott
S
D Collum
Department of Biochemistry and Molecular Biology, UTHealth, Houston, Texas;
Fayong
F
Luo
Department of Biochemistry and Molecular Biology, UTHealth, Houston, Texas;
Tingting
T
Weng
Department of Biochemistry and Molecular Biology, UTHealth, Houston, Texas;
Thuy-Trahn
TT
Le
Department of Biochemistry and Molecular Biology, UTHealth, Houston, Texas;
Adriana
A
M Hernandez
Department of Biochemistry and Molecular Biology, UTHealth, Houston, Texas;
Kemly
K
Philip
Department of Biochemistry and Molecular Biology, UTHealth, Houston, Texas;
Jose G
JG
Molina
Department of Biochemistry and Molecular Biology, UTHealth, Houston, Texas;
Luis J
LJ
Garcia-Morales
Department of Surgery, UTHealth, Houston, Texas;
Yanna
Y
Cao
Department of Surgery, UTHealth, Houston, Texas;
Tien C
TC
Ko
Debakey Heart & Vascular Center, Houston Methodist Hospital, Houston, Texas;
Javier
J
Amione-Guerra
Debakey Heart & Vascular Center, Houston Methodist Hospital, Houston, Texas;
Odeaa
O
Al-Jabbari
Debakey Heart & Vascular Center, Houston Methodist Hospital, Houston, Texas;
Raquel R
RR
Bunge
Debakey Heart & Vascular Center, Houston Methodist Hospital, Houston, Texas;
Keith
K
Youker
Debakey Heart & Vascular Center, Houston Methodist Hospital, Houston, Texas;
Brian A
BA
Bruckner
Division of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee; and.
Rizwan
R
Hamid
Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
Jonathan
J
Davies
Debakey Heart & Vascular Center, Houston Methodist Hospital, Houston, Texas;
Neeraj
N
Sinha
Department of Biochemistry and Molecular Biology, UTHealth, Houston, Texas; harry.karmouty@uth.tmc.edu.
Harry
H
Karmouty-Quintana
D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation; D015870:Gene Expression; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism*; D054990:Idiopathic Pulmonary Fibrosis / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism; D020033:Protein Isoforms; D034622:RNA Interference
D015850:Interleukin-6; D035683:MicroRNAs; D020033:Protein Isoforms; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II
STAT-3; TGF; interleukin-6; miRNA; vascular remodeling