Author(s)

Duaa Dakhlallah^1,2*, Yijie Wang¹, Tierra A. Bobo^1,2, Emily Ellis², Xiaokui Mo³, Melissa G. Piper¹, Timothy D. Eubank^1,2,4, Clay B. Marsh^1,2*

¹Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
²Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV, USA.
³The Center for Biostatistics, The Ohio State University, Columbus, OH, USA.
⁴Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV, USA.

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.

Pulmonary Fibrosis, AKT, CSF1, M-CSF Receptor, Macrophage, Myofibroblast, Fibrocytes, Autophagy

Dakhlallah, D. , Wang, Y. , Bobo, T. , Ellis, E. , Mo, X. , Piper, M. , Eubank, T. and Marsh, C. (2019) Constitutive AKT Activity Predisposes Lung Fibrosis by Regulating Macrophage, Myofibroblast and Fibrocyte Recruitment and Changes in Autophagy. Advances in Bioscience and Biotechnology, 10, 346-373. doi: 10.4236/abb.2019.1010027.