The LIM-Only Protein FHL2 Attenuates Lung Inflammation during Bleomycin-Induced Fibrosis

Abdulaleem Alnajar,Stephan Ludwig,Viktor Wixler,Ruth Chiquet-Ehrismann,Tanja Schied,Carolin Nordhoff,Thomas Vogl,Karin Loser,Oliver Eickelberg

doi:10.1371/journal.pone.0081356

Abstract

Fibrogenesis is usually initiated when regenerative processes have failed and/or chronic inflammation occurs. It is characterised by the activation of tissue fibroblasts and dysregulated synthesis of extracellular matrix proteins. FHL2 (four-and-a-half LIM domain protein 2) is a scaffolding protein that interacts with numerous cellular proteins, regulating signalling cascades and gene transcription. It is involved in tissue remodelling and tumour progression. Recent data suggest that FHL2 might support fibrogenesis by maintaining the transcriptional expression of alpha smooth muscle actin and the excessive synthesis and assembly of matrix proteins in activated fibroblasts. Here, we present evidence that FHL2 does not promote bleomycin-induced lung fibrosis, but rather suppresses this process by attenuating lung inflammation. Loss of FHL2 results in increased expression of the pro-inflammatory matrix protein tenascin C and downregulation of the macrophage activating C-type lectin receptor DC-SIGN. Consequently, FHL2 knockout mice developed a severe and long-lasting lung pathology following bleomycin administration due to enhanced expression of tenascin C and impaired activation of inflammation-resolving macrophages.

Highlights

Fibrosis is a consequence of the excessive expression and deposition of extracellular matrix (ECM) components, which can result in sclerosis and scarring of tissues
To analyse the potential role of FHL2 in the development of lung fibrosis, wild type (WT) and FHL2-deficient mice were first treated with different doses of BLM to compare their sensitivity to the drug
As an adaptor protein FHL2 is involved in regulation of numerous cellular functions [15] and it appears to be dispensable for normal development [26,44], deficiency in FHL2 is associated with delayed mesenchymal regeneration

Summary

Introduction

Fibrosis is a consequence of the excessive expression and deposition of extracellular matrix (ECM) components, which can result in sclerosis and scarring of tissues. Idiopathic pulmonary fibrosis is a progressive and fatal fibrosing disease of the lung with unknown aetiology, but several environmental factors such as smoking, chronic microaspiration or viral infection are known to promote its development [7,8]. The disease is characterized by damage of interstitial tissue and myofibroblast transdifferentiation with exaggerated accumulation of ECM proteins leading to scarring of alveolar compartments of the lung where gas exchange occurs [4,8,9]. Available data increasingly indicate that chronic inflammation and aberrant wound healing play an important role in the development of the disease [8,9,10,11]

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