Ficolin B secreted by alveolar macrophage exosomes exacerbates bleomycin-induced lung injury via ferroptosis through the cGAS-STING signaling pathway

Abstract

Pathogenesis exploration and timely intervention of lung injury is quite necessary as it has harmed human health worldwide for years. Ficolin B (Fcn B) is a recognition molecule that can recognize a variety of ligands and play an important role in mediating the cell cycle, immune response, and tissue homeostasis in the lung. However, the role of Fcn B in bleomycin (BLM)-induced lung injury is obscure. This study aims to investigate the sources of Fcn B and its mechanism in BLM-induced lung injury. WT, Fcna-/-, and Fcnb-/- mice were selected to construct the BLM-induced lung injury model. Lung epithelial cells were utilized to construct the BLM-induced cell model. Exosomes that were secreted from alveolar macrophages (AMs) were applied for intervention by transporting Fcn B. Clinical data suggested M-ficolin (homologous of Fcn B) was raised in plasma of interstitial lung disease (ILD) patients. In the mouse model, macrophage-derived Fcn B aggravated BLM-induced lung injury and fibrosis. Fcn B further promoted the development of autophagy and ferroptosis. Remarkably, cell experiment results revealed that Fcn B transported by BLM-induced AMs exosomes accelerated autophagy and ferroptosis in lung epithelial cells through the activation of the cGAS-STING pathway. In contrast, the application of 3-Methyladenine (3-MA) reversed the promotion effect of Fcn B from BLM-induced AMs exosomes on lung epithelial cell damage by inhibiting autophagy-dependent ferroptosis. Meanwhile, in the BLM-induced mice model, the intervention of Fcn B secreted from BLM-induced AMs exosomes facilitated lung injury and fibrosis via ferroptosis. In summary, this study demonstrated that Fcn B transported by exosomes from AMs exacerbated BLM-induced lung injury by promoting lung epithelial cells ferroptosis through the cGAS-STING signaling pathway.

Modified Qing-Zao-Jiu-Fei decoction attenuated pulmonary fibrosis induced by bleomycin in rats via modulating Nrf2/NF-κB and MAPKs pathways

“…Activation of α-SMA has been considered to play a critical role in pulmonary fibrosis. Higher concentrations of total protein in BALF, the levels of hydroxyproline and expression of α-SMA are concurrent with more collagen deposition, inducing more severe pulmonary fibrosis [ 33 , 34 ]. It has been revealed that there is a strong relationship between the extent of the fibrosis and the MMP‐9 levels, indicating that MMP‐9 plays a crucial role in the pathogenesis of pulmonary fibrosis [ 35 ].…”

Recent progress in biomaterials-driven ferroptosis for cancer therapy

“…by selecting WT, Fcna−/− and Fcnb−/− mice to construct bleomycin (BLM)-induced lung injury model, found that Ficolin B (Fcn B), which is transported by AMs exosomes, promotes ferroptosis of lung epithelial cells through cGAS-STING signaling pathway, thus aggravating BLM-induced lung injury. 101…”

Ferroptosis in organ fibrosis: From mechanisms to therapeutic medicines

“…[ 68 ] Moreover, ferroptosis was also proved to be responsible for PM2.5-mediated pulmonary fibrosis and heavy metals-induced pulmonary fibrosis. [69,70] To our knowledge, several ferroptosis pathways associated with pulmonary fibrosis have been revealed, including NCOA4-mediated ferritinophagy, [ 71 ] miR-150–5p/ SLC38A1 signaling, [ 72 ] Keap1/Nrf2 signaling, [ 73 ] cGAS/ STING signaling, [ 74 ] Nrf2/HO-1 signaling, [ 75 ] Wnt5a/Ca 2+ signaling, [ 76 ] USP3/Sirt3/p53 signaling, [ 77 ] EMPA/Nrf2/ SLC7A11 signaling, [ 78 ] and ACSL4-dependent ferroptosis pathway ( Figure 3B ).…”