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Published on: May 21, 2018
IL-33 facilitates endoplasmic reticulum stress and pyroptosis in LPS-stimulated ARDS model in vitro
Pei-Long Li1, Hong-Min Fu2, Kai Liu2
1Children's Hospital Affiliated to Kunming Medical University & Kunming Children's Hospital, Kunming Medical University, Kunming, P.R. China; Department of Pulmonary and Critical Care Medicine, Yunnan Key Laboratory of Children's Major Disease Research, Yunnan Medical Center for Pediatric Diseases, Kunming Children's Hospital, Kunming Medical University, Kunming, P.R. China.
Background:
Inflammatory activation of pulmonary microvascular endothelial cells (PMVECs) initiated by endoplasmic reticulum stress (ERS) contributes to acute respiratory distress syndrome (ARDS). Interleukin 33 (IL-33) has pro-inflammatory and transcriptional regulatory effects. Therefore, this study intends to investigate the effect of IL-33 on ERS and pyroptosis in the hPMVEC.
Methods:
The hPMVEC-associated ARDS cell model was induced with lipopolysaccharide (LPS) and treated with 4-PBA (ERS inhibitor), thapsigargin (ERS activator), or IL-33 neutralizing antibody. Western blot and IF staining were performed to analyze the expression of cell-cell junction-associated (Cx37, Cx40, Cx43, Occludin, and Zo-1), ERS-associated (ATF6, IRE1a, and p-Erk), and pyroptosis-associated (NLRP3, IL-1β, and IL-18) proteins. Bioinformatics identified differential expression of IL-33 in ARDS-related datasets and targets of thapsigargin.
Results:
IL-33 was highly expressed in serum of ARDS patients and in ARDS cohorts from multiple GEO datasets (GSE237260, GSE216635, GSE89953, GSE263867, and GSE5883), and was significantly correlated with clinical features. 4-PBA decreased permeability and IL-33 levels, and increased Cx37, Cx40 and Cx43 levels in the ARDS cell model. IL-33 neutralizing antibody effectively augmented the levels of Cx43 and Zo-1, and diminished the levels of ATF6, IRE1a, p-Erk, NLRP3, IL-1β, IL-18, ROS, and Ca2 +. The therapeutic effect of IL-33 neutralizing antibodies was reverted by thapsigargin. Moreover, the Swiss Target Prediction and Super-PRED databases obtained 140 and 122 thapsigargin targets, which had 14 intersections. These intersections were associated with immunity, inflammation, apoptosis, pyroptosis, and Ca2+ homeostasis. Notably, CASP8 and PTGS2 interacted with IL-33 in these intersections.
Conclusion:
IL-33 promotes ERS and pyroptosis, thereby contributing to barrier damage in ARDS cell models. IL-33 is a promising therapeutic target for ARDS.
