SRC-mediated and TKS5-enabled podosome formation is an inherent property of IPF fibroblasts, promoting ECM invasion and pulmonary fibrosis

Author:

Barbayianni Ilianna,Kanellopoulou Paraskevi,Fanidis Dionysios,Ntouskou Eleftheria-Dimitra,Nastos Dimitris,Galaris Apostolos,Harokopos Vaggelis,Hatzis Pantelis,Tsitoura Eliza,Homer Robert,Kaminski NaftaliORCID,Antoniou Katerina M.,Crestani Bruno,Tzouvelekis Argyrios,Aidinis VassilisORCID

Abstract

AbstractThe activation and accumulation of lung fibroblasts (LFs), resulting in aberrant deposition of collagens and other extracellular matrix (ECM) components, is a pathogenic hallmark of Idiopathic Pulmonary Fibrosis (IPF), a lethal and incurable disease. In this report, increased expression of TKS5, a scaffold protein essential for the formation of podosomes, was detected in the lung tissue of IPF patients and bleomycin (BLM)-treated mice, correlating with increased collagen type I alpha 1 chain (COL1A1) expression. The profibrotic milieu, TGFβ, as well as a stiff Col1a1-rich acellular fibrotic ECM, were found to induceTKS5expression and the formation of prominent podosome rosettes in LFs, culminating in increased ECM invasion. Podosomes were retainedex vivoin the absence of any stimulation, indicating that the formation of TKS5-enabled podosomes is an inherent property of IPF LFs. Remarkably, haploinsufficientTks5+/-mice were relatively resistant to BLM-induced pulmonary fibrosis. Disease protection was largely attributable to diminished podosome formation in LFs and decreased ECM invasion, thus indicating TKS5-enabled and podosome-mediated ECM invasion as a major pathogenic mechanism in pulmonary fibrosis. Expression profiling revealed an ECM-podosome cross talk, and pharmacologic connectivity map analysis suggested several inhibitors that could prevent podosome formation and thus pulmonary fibrosis. Among them, inhibition of src kinase was shown to potently attenuate podosome formation in LFs, ECM invasion, as well as pulmonary fibrosis in post BLM precision cut lung slices, suggesting that pharmacological targeting of TKS5-enabled podosome formation is a very promising therapeutic option in pulmonary fibrosis.

Publisher

Cold Spring Harbor Laboratory

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3