Up-regulation of HSP90α in HDM-induced asthma causes pyroptosis of airway epithelial cells by activating the cGAS-STING-ER stress pathway.

Heat Shock protein 90 α (HSP90α), an main subtype of chaperone protein HSP90, involves important biological functions such as DNA damage repair, protein modification, innate immunity. However, the potential role of HSP90α in asthma occurrence and development is still unclear. This study aimed to elucidate the underlying mechanism of HSP90α in asthma by focusing on the cGAS-STING-Endoplasmic Reticulum stress pathway in inflammatory airway epithelial cell death (i.e., pyroptosis; inflammatory cell death). To accomplish that, we modeled allergen exposure in C57/6BL mice and bronchial epithelial cells with house dust mite. Protein technologies and immunofluorescence utilized to study the expression of HSP90α, activation of cGAS-STING pathway and pyroptosis. The effect of inhibitors on HDM-exposed mice detected by histological techniques and examination of bronchoalveolar lavage fluid. Results showed that HSP90α promotes asthma inflammation via pyroptosis and activation of the cGAS-STING-ER stress pathway. Treatment with the HSP90 inhibitor tanespimycin (17-AAG) significantly relieved airway inflammation and abrogated the effect of HSP90α on pyroptosis and cGAS-STING-ER stress in vitro and in vivo models of HDM. Further data indicated that up-regulation of HSP90α stabilized STING through interaction, which increased localization of STING on the ER. Activation of STING triggered ER stress and leaded to pyroptosis-related airway inflammation. The finding showed the potential role of pyroptosis caused by dysregulation of HSP90α on airway epithelial cells in allergic inflammation, suggested that targeting HSP90α in airway epithelial cells might prove to be a potential additional treatment strategy for asthma.

Tetrandrine alleviates pulmonary fibrosis by inhibiting alveolar epithelial cell senescence through PINK1/Parkin-mediated mitophagy.

Idiopathic pulmonary fibrosis (IPF) is a fatal and insidious interstitial lung disease. So far, there are no effective drugs for preventing the disease process. Cellular senescence plays a critical role in the development of IPF, with the senescence and insufficient mitophagy of alveolar epithelial cells being implicated in its pathogenesis. Tetrandrine is a natural alkaloid which is now produced synthetically. It was known that the tetrandrine has anti-fibrotic effects, but the efficacy and mechanisms are still not well evaluated. Here, we reveal the roles of tetrandrine on AECs senescence and the antifibrotic effects by using a bleomycin challenged mouse model of pulmonary fibrosis and a bleomycin-stimulated mouse alveolar epithelial cell line (MLE-12). We performed the ß-galactosidase staining, immunohistochemistry and fluorescence to assess senescence in MLE-12 cells. The mitophagy levels were detected by co-localization of LC3 and COVIX. Our findings indicate that tetrandrine suppressed bleomycin-induced fibroblast activation and ultimately blocked the increase of collagen deposition in mouse model lung tissue. It has significantly inhibited the bleomycin-induced senescence and senescence-associated secretory phenotype (SASP) in alveolar epithelial cells (AECs). Mechanistically, tetrandrine suppressed the decrease of mitochondrial autophagy-related protein expression to rescue the bleomycin-stimulated impaired mitophagy in MLE-12 cells. We revealed that knockdown the putative kinase 1 (PINK1) gene by a short interfering RNA (siRNA) could abolish the ability of tetrandrine and reverse the MLE-12 cells senescence, which indicated the mitophagy of MLE-12 cells is PINK1 dependent. Our data suggest the tetrandrine could be a novel and effective drug candidate for lung fibrosis and senescence-related fibrotic diseases.

RNF130 protects against pulmonary fibrosis through suppressing aerobic glycolysis by mediating c-myc ubiquitination.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease,characterized by an excessive accumulation of extracellular matrix (ECM) proteins in response to chronic lung injury. Current evidence suggests that metabolic reprogramming is always accompanied by myofibroblast activation in IPFof whichthe underlying mechanisms remain unclear. Ring finger protein 130 (RNF130), was demonstrated involved in multiple diseases. However, whether RNF130 plays a critical role in the pathogenesis of IPF needs to be clarified. METHODS: We first investigated the expression of RNF130 in pulmonary fibrosis in vivo and in vitro. We then observed the effect and explored the molecular mechanism of RNF130 on the transition of fibroblast to myofibroblast and aerobic glycolysis. Further, we assessed the effects of adeno-associated virus (AAV)-induced RNF130 overexpression in the pulmonary fibrosis model, conducting pulmonary function, assessment of collagen depositionusing the hydroxyproline assay, and biochemical and histopathological analyses. RESULTS: We found that RNF130 was down-regulated in lung tissues of mice with bleomycin-induced pulmonary fibrosis and lung fibroblasts treated with transforming growth factor-ß1 (TGF-ß1). Then we demonstrated that RNF130 inhibitedthe transition of fibroblast to myofibroblast by suppressing aerobic glycolysis. Mechanistically, we revealed that RNF130 promotedc-myc ubiquitination and degradation, while c-myc overexpression reverses the inhibitory effects of RNF130. Importantly, pulmonary function, collagen deposition and fibroblast differentiation were significantly alleviated in adeno-associated virus serotype (AAV)6-RNF130 treated mice, which further validated the contribution of RNF130/c-myc signaling axis in pulmonary fibrosis pathological process. CONCLUSIONS: In summary, RNF130 participates in the pathogenesis of pulmonary fibrosis by inhibiting the transition of fibroblast to myofibroblast and aerobic glycolysis through promoting c-myc ubiquitination and degradation. Targeting RNF130-c-myc axismightrepresent a promising strategy to alleviate the progression of IPF.