TY - JOUR
T1 - HIF1A up-regulates the ADORA2B receptor on alternatively activated macrophages and contributes to pulmonary fibrosis
AU - Philip, Kemly
AU - Mills, Tingting Weng
AU - Davies, Jonathan
AU - Chen, Ning Yuan
AU - Karmouty-Quintana, Harry
AU - Luo, Fayong
AU - Molina, Jose G.
AU - Amione-Guerra, Javier
AU - Sinha, Neeraj
AU - Guha, Ashrith
AU - Eltzschig, Holger K.
AU - Blackburn, Michael R.
N1 - Funding Information:
The authors thank Kelly A. Volcik (UTHealth) for assisting in manuscript revisions. This work was supported by the U.S. National Institutes of Health National Heart, Lung, and Blood Institute Program Project Grant 1P01HL114457 (to M. R. Blackburn) and the Schissler Foundation Fellowship for Translational Studies of Common Human Diseases (to K. Philip).
Publisher Copyright:
© 2018 FASEB.
PY - 2017
Y1 - 2017
N2 - Idiopathic pulmonary fibrosis (IPF) is a deadly chronic lung disease. Extracellular accumulation of adenosine and subsequent activation of the ADORA2B receptor play important roles in regulating inflammation and fibrosis in IPF. Additionally, alternatively activated macrophages (AAMs) expressing ADORA2B have been implicated in mediating adenosine's effects in IPF. Although hypoxic conditions are present in IPF, hypoxia's role as a direct modulator of macrophage phenotype and identification of factors that regulate ADORA2B expression on AAMs in IPF is not well understood. In this study, an experimental mouse model of pulmonary fibrosis and lung samples from patients with IPF were used to examine the effects and interactions of macrophage differentiation and hypoxia on fibrosis. We demonstrate that hypoxia-inducible factor 1-α (HIF1A) inhibition in late stages of bleomyc in-induced injury attenuates pulmonary fibrosis in association, with reductions in ADORA2B expression in AAMs. Additionally, ADORA2B deletion or pharmacological antagonism alongwithHIF1Ainhibition disrupts AAM differentiation and subsequent IL-6 production in cultured macrophages. These findings suggest that hypoxia, through HIF1A, contributes to the development and progression of pulmonary fibrosis through its regulation of ADORA2B expression on AAMs, cell differentiation, and production of profibrotic mediators. These studies support a potential role for HIF1A or ADORA2B antagonists in the treatment of IPF.
AB - Idiopathic pulmonary fibrosis (IPF) is a deadly chronic lung disease. Extracellular accumulation of adenosine and subsequent activation of the ADORA2B receptor play important roles in regulating inflammation and fibrosis in IPF. Additionally, alternatively activated macrophages (AAMs) expressing ADORA2B have been implicated in mediating adenosine's effects in IPF. Although hypoxic conditions are present in IPF, hypoxia's role as a direct modulator of macrophage phenotype and identification of factors that regulate ADORA2B expression on AAMs in IPF is not well understood. In this study, an experimental mouse model of pulmonary fibrosis and lung samples from patients with IPF were used to examine the effects and interactions of macrophage differentiation and hypoxia on fibrosis. We demonstrate that hypoxia-inducible factor 1-α (HIF1A) inhibition in late stages of bleomyc in-induced injury attenuates pulmonary fibrosis in association, with reductions in ADORA2B expression in AAMs. Additionally, ADORA2B deletion or pharmacological antagonism alongwithHIF1Ainhibition disrupts AAM differentiation and subsequent IL-6 production in cultured macrophages. These findings suggest that hypoxia, through HIF1A, contributes to the development and progression of pulmonary fibrosis through its regulation of ADORA2B expression on AAMs, cell differentiation, and production of profibrotic mediators. These studies support a potential role for HIF1A or ADORA2B antagonists in the treatment of IPF.
KW - Adenosine receptors
KW - Hypoxia
KW - Idiopathic pulmonary fibrosis
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U2 - 10.1096/fj.201700219R
DO - 10.1096/fj.201700219R
M3 - Article
C2 - 28701304
AN - SCOPUS:85037572319
SN - 0892-6638
VL - 31
SP - 4745
EP - 4758
JO - FASEB Journal
JF - FASEB Journal
IS - 11
ER -