Extracellular HSP90α Interacts With ER Stress to Promote Fibroblasts Activation Through PI3K/AKT Pathway in Pulmonary Fibrosis

Abstract

Pulmonary fibrosis is characterized by alveolar epithelial cell injury, lung fibroblast proliferation, differentiation, and extracellular matrix (ECM) deposition. Our previous study indicated that extracellular HSP90α (eHSP90α) promotes pulmonary fibrosis by activating the MAPK signaling pathway. Thus, treatment with 1G6-D7 (a selective HSP90α monoclonal antibody) to antagonize eHSP90α could effectively ameliorate fibrosis. This study aimed to elucidate the mechanism underlying the effects of eHSP90α in pulmonary fibrosis by focusing on its link with endoplasmic reticulum (ER) stress. Our results showed that eHSP90α promoted lung fibroblast differentiation by activating ER stress. Treatment with the ER stress inhibitor tauroursodeoxycholate (TUDCA) or glucose-regulated protein 78 kDa (GRP78) depletion significantly abrogated the effect of eHSP90α on ER stress and fibroblast activation. In addition, eHSP90α induced ER stress in fibroblasts via the phosphoinositide-4,5-bisphosphate 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway, which could be blocked by the PI3K/AKT inhibitor LY294002, and blockade of eHSP90α by 1G6-D7 markedly inhibited ER stress in the model, indicating preventive and therapeutic applications. Intriguingly, we observed that TUDCA effectively reduced the secretion of eHSP90α in vitro and in vivo. In conclusion, this study shows that the interaction between eHSP90α and ER stress plays a crucial role in pulmonary fibrosis, indicating a positive feedback in lung fibroblasts. Targeting eHSP90α and alleviating fibroblast ER stress may be promising therapeutic approaches for pulmonary fibrosis.

Probiotic-Functionalized Silk Fibroin/Sodium Alginate Scaffolds with Endoplasmic Reticulum Stress-Relieving Properties for Promoted Scarless Wound Healing

“…casei CFS. Similarly, Zhang et al . showed that TGF-β1 upregulated the expression of GRP78 and α-SMA in lung fibroblasts, while the ERS inhibitor taurodeoxycholic acid (TUDCA) attenuated the expression of these markers.…”

“…Mild ERS can induce fibroblasts to transform into myofibroblasts and promote wound contraction . However, persistent ERS can lead to the formation of fibrotic diseases, such as skin contracture scar, myocardial fibrosis, and idiopathic pulmonary fibrosis (IPF) . So far, only a few studies have focused on ERS in wound healing.…”

Extracellular Heat Shock Protein-90 (eHsp90): Everything You Need to Know

“…Using BLM-induced pulmonary injury and the fibrosis mouse model, which represents failed wound healing, Dong and colleagues showed that mAb 1G6-D7, a monoclonal antibody against eHsp90α, inhibited eHsp90α function and significantly protected against BLM-induced pulmonary fibrosis by ameliorating fibroblast overactivation and ECM production [ 79 ]. The same group proposed a possible mechanism by which eHsp90α links the ER stress to the PI-3K-Akt pathway [ 80 ]. Ballaye and colleagues reported the significant increase of both eHsp90α and eHsp90β in the circulation of patients with idiopathic pulmonary fibrosis (IPF), and the higher levels correlated with disease severity.…”

Targeting extracellular Hsp90: A unique frontier against cancer

“…Plasma levels of Hsp90 have also been shown to be elevated in patients with systemic sclerosis and associated with increased inflammatory activity and worse lung function ( Storkanova et al, 2021 ). eHsp90 has also been implicated in the pathogenesis of pulmonary fibrosis through activation of ER stress in fibroblasts via PI3K/Akt signaling ( Zhang et al, 2021 ). Blockade of eHsp90 with a monoclonal antibody (mAb) was able to inhibit ER stress in both cellular and animal models of pulmonary fibrosis ( Zhang et al, 2021 ).…”

“…eHsp90 has also been implicated in the pathogenesis of pulmonary fibrosis through activation of ER stress in fibroblasts via PI3K/Akt signaling ( Zhang et al, 2021 ). Blockade of eHsp90 with a monoclonal antibody (mAb) was able to inhibit ER stress in both cellular and animal models of pulmonary fibrosis ( Zhang et al, 2021 ). In the autoimmune disorder bullous pemphigoid eHsp90 was increased at the site of inflammation and autoantibodies were found to dysregulate the extracellular and intracellular distribution of Hsp90 in patients with this disease ( Tukaj et al, 2013 ).…”