The effects of ferroptosis, an iron-dependent cell death, on acute respiratory distress syndrome (ARDS) remain largely elusive. Hepcidin, encoded by the HAMP gene, affects inflammation, and iron homeostasis. The present study aimed to investigate whether hepcidin protects against ferroptosis in lipopolysaccharide (LPS)-induced ARDS. Our results confirmed that ferroptosis aggravated lung inflammation and damage in LPS-induced ARDS. Hepcidin defended against ferroptosis, with results similar to those of the ferroptosis inhibitor ferrostatin-1 (Fer-1). Moreover, hepcidin decreased iron uptake, as determined by Transferrin Receptor 1 (TfR1) expression levels, and increased iron storage, based on ferritin heavy chain (FTH) expression. The effects of hepcidin on the A549 cell line were in line with the in vivo results. In addition, we used si-FTH to knock down FTH expression and found that this suppressed the ability of hepcidin to protect against ferroptosis. Collectively, our data suggest that hepcidin inhibits ferroptosis by increasing FTH expression in LPS-induced ARDS; thus, hepcidin may represent a possible treatment targeting ferroptosis.
Objectives. The characteristic pathophysiological feature of acute respiratory distress syndrome (ARDS) is a dysregulated inflammatory response. T helper 17 (Th17) cells in the lung are inflammatory cells that contribute to pulmonary inflammatory cascades. In addition, Th17/regulatory T cells (Treg cells) also play an important role in the inflammatory process. Dendritic cells (DCs) can regulate the differentiation of CD4+ T cells, including Th17 and Treg cells. Recent evidence revealed that interleukin-33 (IL-33) signaling could activate and mature DCs. Therefore, the aim of this study was to investigate the effects of IL-33 on inflammation and immunoregulation by inducing the Th17 response and influencing the Th17/Treg balance in LPS-induced ARDS. Methods. IL-33 gene knockout mice and the administration of recombinant mouse IL-33 (rmIL-33) were used to investigate the role of IL-33 and the underlying mechanisms in an LPS-induced ARDS model. Hematoxylin and eosin (H&E) staining, wet/dry (W/D) weight ratios, cell counts, and the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-17 (IL-17), and interleukin-10 (IL-10) in bronchoalveolar lavage fluid (BALF) were investigated. The levels of IL-33, orphan nuclear receptor gamma t (RORγt), and forkhead transcription factor protein 3 (FOXP3) protein in lung tissue were evaluated by Western blotting. The mRNA expression levels of IL-33 and RORγt were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Th17 and Treg cell frequencies were determined by flow cytometry. The levels of IL-6 in the supernatant in a dendritic cell culture system were examined by ELISA. Results. Increased expression of IL-33 was observed in mice with LPS-induced ARDS. IL-33 deficiency significantly inhibited inflammation and attenuated LPS-induced ARDS, whereas pretreatment with rmIL-33 aggravated pulmonary inflammatory response. Furthermore, depletion of IL-33 inhibited Th17 cells, significantly decreased RORγt mRNA and protein expression and IL-17 levels in BALF, and led to less differentiation of T cells into Th17 cells than Treg cells. Moreover, IL-33-/- DCs secreted less IL-6 and IL-23 than normal control DCs. Conclusion. IL-33 deficiency alleviated lung injury in the LPS-induced ARDS model, which was closely related to suppressing Th17 responses and regulating the Th17/Treg balance. The expansion of Th17 cells and imbalance in Th17/Treg cells may be associated with IL-6 and IL-23 secreted from IL-33-activated DCs.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.