Synergistic role of HSP90α and HSP90β to promote myofibroblast persistence in lung fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of the lung parenchyma, causing significant morbidity through worsening dyspnoea and overall functional decline. IPF is characterised by apoptosis-resistant myofibroblasts, which are a major source for the excessive production of extracellular matrix (ECM) overtaking normal lung tissue. We sought to study the role of heat shock protein (HSP) isoforms HSP90α and HSP90β, whose distinct roles in lung fibrogenesis remain elusive.We determined the level of circulating HSP90α in IPF patients (n=31) and age-matched healthy controls (n=9) by ELISA. The release of HSP90α and HSP90β was evaluated in primary IPF and control lung fibroblasts and after mechanical stretch on fibrotic lung slices from rats receiving adenovector-mediated transforming growth factor-β1.We demonstrate that circulating HSP90α is upregulated in IPF patients in correlation with disease severity. The release of HSP90α is enhanced by the increase in mechanical stress of the fibrotic ECM. This increase in extracellular HSP90α signals through low-density lipoprotein receptor-related protein 1 (LRP1) to promote myofibroblast differentiation and persistence. In parallel, we demonstrate that the intracellular form of HSP90β stabilises LRP1, thus amplifying HSP90α extracellular action.We believe that the specific inhibition of extracellular HSP90α is a promising therapeutic strategy to reduce pro-fibrotic signalling in IPF.

HSP90 Interacts with the Fibronectin N-terminal Domains and Increases Matrix Formation

“…N-terminal HSP90 inhibition was associated with reduction in FN secretion in prostate cancer [37] and levels of HSP90 in the circulation were correlated with disease severity in patients with idiopathic pulmonary fibrosis (IPF) [38]. We previously described a link between FN and HSP90, demonstrating that the two proteins interacted directly in vitro and could be isolated as a complex from cells [30].…”

“…N-terminal inhibition of HSP90 with either geldanamycin or AUY922 increased FN expression, while AUY922 reduced FN secretion in prostate cancer which was linked to a reduction in invasion and migration [37]. Beyond cancer, increased expression of FN and extracellular matrix (ECM) are associated with idiopathic pulmonary fibrosis (IPF) [38]. Elevated extracellular HSP90α levels were associated with increased severity of IPF, where HSP90α secretion increased with increased matrix stiffness [38].…”

“…Beyond cancer, increased expression of FN and extracellular matrix (ECM) are associated with idiopathic pulmonary fibrosis (IPF) [38]. Elevated extracellular HSP90α levels were associated with increased severity of IPF, where HSP90α secretion increased with increased matrix stiffness [38]. Therefore, HSP90 modulation may provide a mechanism by which to treat disorders associated with dysregulated FN and ECM.…”

Single-Cell Transcriptomics Identifies Dysregulated Metabolic Programs of Aging Alveolar Progenitor Cells in Lung Fibrosis

“…Genes of heat shock protein family including HSPA8, HSP90AB1, and IER5 were up regulated in IPF AEC2s (Figure 4g). Heat shock proteins have been suggested having a role in pulmonary fibrosis (Bellaye et al, 2018), and they may also contribute to aging by mediating protein quality control (Calderwood et al, 2009). Annexin family genes were upregulated in IPF AEC2 (Figure 4g).…”

Thrombospondin 1 and Its Diverse Roles as a Regulator of Extracellular Matrix in Fibrotic Disease

“…Cellular responses appear to be cell type specific and possibly vary depending on which ligand engages LRP1: For example, tissue plasminogen activator binding to LRP1 engages signaling through integrins that has profibrotic effects on kidney interstitial fibroblasts. [119][120][121][122][123] Ultimately, direct examination of TSP1 N-terminal domain binding to calreticulin-LRP1 on collagen organization in fibrotic remodeling remains to be addressed using TSP-binding calreticulin peptides that block TSP1-calreticulin interactions in animal models. 13,99 The TSP family has been long known to play a role in the regulation of collagenous ECM fibril organization.…”