Constitutive AKT Activity Predisposes Lung Fibrosis by Regulating Macrophage, Myofibroblast and Fibrocyte Recruitment and Changes in Autophagy.

Duaa Dakhlallah,Yijie Wang,Tierra A Bobo,Xiaokui Mo,Timothy D Eubank,Emily Ellis,Melissa G Piper,Clay B Marsh

doi:10.4236/abb.2019.1010027

Duaa Dakhlallah, Yijie Wang + Show 6 more

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https://doi.org/10.4236/abb.2019.1010027

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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.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a progressive respiratory disease with a 5-year mortality rate of 50% - 70% [1]
In support of a priming effect, macrophages isolated from the lungs of unchallenged myristoylated AKT (Myr-Akt) mice displayed an M2-tropism, enhanced co-expression of M-CSF receptor (M-CSF-R) and α-smooth muscle actin (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
Since bone marrow-derived macrophages (BMM) collected from mice expressing Myr-Akt driven by the M-CSF-R promoter had increased survival [40], we first checked if Myr-Akt mice produced more Bone marrow-derived macrophages (BMM) than WT mice

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a progressive respiratory disease with a 5-year mortality rate of 50% - 70% [1]. The serine/threonine protein kinase, AKT, is downstream of many receptor tyrosine kinases and plays an important role in cell survival, differentiation, and cellular activation [3]. In fibroblasts, activated AKT regulates collagen I and III production [5] and contributes to human hepatic fibrosis [6] and bleomycin-induced lung fibrosis in mice [7] [8]. PI3K/AKT activity is enhanced in IPF fibroblasts due to reduced levels of PTEN phosphatase function [9]. PI3K/AKT inhibitors such as PX-866 are potential therapeutic agents for IPF [7] [10]. Understanding the role of activated AKT is important in IPF

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