TITLE:
Constitutive AKT Activity Predisposes Lung Fibrosis by Regulating Macrophage, Myofibroblast and Fibrocyte Recruitment and Changes in Autophagy
AUTHORS:
Duaa Dakhlallah, Yijie Wang, Tierra A. Bobo, Emily Ellis, Xiaokui Mo, Melissa G. Piper, Timothy D. Eubank, Clay B. Marsh
KEYWORDS:
Pulmonary Fibrosis, AKT, CSF1, M-CSF Receptor, Macrophage, Myofibroblast, Fibrocytes, Autophagy
JOURNAL NAME:
Advances in Bioscience and Biotechnology,
Vol.10 No.10,
October
30,
2019
ABSTRACT: The etiology and pathogenesis of pulmonary fibrosis
is poorly understood. We and others reported that M-CSF/CSF-1, M-CSF-R and
downstream AKT activation plays an important role in lung fibrosis in mice models and in
IPF patients. To understand potential molecular pathways used by M-CSF-R
activation to direct lung fibrosis, we used a novel transgenic mouse model that
expresses a constitutively-active form of AKT, myristoylated AKT (Myr-Akt), driven by the c-fms (M-CSF-R) promoter. We were
particularly interested in the basal immune state of the lungs of these Myr-Akt mice to assess M-CSF-R-related
priming for lung fibrosis. In support of a priming effect, macrophages isolated
from the lungs of unchallenged Myr-Akt mice displayed an M2-tropism, enhanced co-expression of M-CSF-R and α-SMA, reduced autophagy reflected by reduced expression of the key autophagy
genes Beclin-1, MAP1-Lc3a(Lc3a), and MAP1-Lc3b(Lc3b), and
increased p62/STSQM1 expression compared with littermate WT mice.
Furthermore, Myr-Akt mice had
more basal circulating fibrocytes than WT mice. Lastly, upon bleomycin
challenge, Myr-Akt mice showed
enhanced collagen deposition, increased F4/80+ and CD45+ cells, reduced
autophagy genes Beclin-1, Lc3a,
and Lc3b expression, and a shorter life-span than WT littermates. These
data provide support that M-CSF-R/AKT activation may have a priming effect which can predispose lung tissue to pulmonary
fibrosis.