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

Pulmonary fibrosis is characterized by alveolar epithelial cell injury, lung fibroblast proliferation, differentiation, and extracellular matrix (ECM) deposition. Our previous study indicated that extracellular HSP90 alpha (eHSP90 alpha) promotes pulmonary fibrosis by activating the MAPK signaling pathway. Thus, treatment with 1G6-D7 (a selective HSP90 alpha monoclonal antibody) to antagonize eHSP90 alpha could effectively ameliorate fibrosis. This study aimed to elucidate the mechanism underlying the effects of eHSP90 alpha in pulmonary fibrosis by focusing on its link with endoplasmic reticulum (ER) stress. Our results showed that eHSP90 alpha 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 eHSP90 alpha on ER stress and fibroblast activation. In addition, eHSP90 alpha 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 eHSP90 alpha 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 eHSP90 alpha in vitro and in vivo. In conclusion, this study shows that the interaction between eHSP90 alpha and ER stress plays a crucial role in pulmonary fibrosis, indicating a positive feedback in lung fibroblasts. Targeting eHSP90 alpha and alleviating fibroblast ER stress may be promising therapeutic approaches for pulmonary fibrosis.

Automated summary

The interaction between extracellular HSP90 alpha and endoplasmic reticulum stress plays a crucial role in pulmonary fibrosis, promoting lung fibroblast differentiation by activating ER stress. Inhibiting ER stress can effectively block the effects of eHSP90 alpha. The induction of ER stress by eHSP90 alpha in fibroblasts occurs through the PI3K/AKT signaling pathway.