STSLP Reduces lTSLP-Induced Inflammatory Cytokine Production of Airway Epithelial by Suppressing Aerobic Glycolysis

Abstract

Background: Up-regulation of aerobic glycolysis has been reported as a characterization of asthma and facilitates airway inflammation. Thymic stromal lymphopoietin (TSLP) has been previously reported to have dual immunoregulatory roles due to long and short isoform (lTSLP and sTSLP) in asthma. However, their role in aerobic glycolysis in asthma airway epithelial was poorly defined. Methods: Asthmatic model was established in challenging Male BALB/c mice and 16-HBE (human bronchial epithelial) cell line with house dust mite (HDM). Indicators of glycolysis were assessed to measure whether involve in lTSLP and sTSLP regulating airway epithelial inflammation in asthmatic model in vivo and in vitro. Results: lTSLP promoted the enhancement of aerobic glycolysis as well as HDM in 16-HBE. HIF-1α was increased significantly in 16-HBE growing with lTSLP which suppressed VHL expression by promoting miR-223 expression. Inhibition of aerobic glycolysis restrained HDM- and lTSLP-induced inflammatory cytokines production. sTSLP had almost no potential to alter aerobic glycolysis of 16-HBE alone but might have prevented effects of lTSLP in 16-HBE, decreased LDH and LD in BALF, and HIF-1α and LDHA in airway epithelial of asthma mouse model. lTSLP and sTSLP both induced formation of TSLPR and IL-7R receptor complex, and lTSLP obviously facilitated phosphorylation of JAK1, JAK2 and STAT5, while sTSLP induced a little phosphorylation of JAK1 and STAT5. Conclusion: We identified a novel mechanism that lTSLP could promote inflammatory cytokines production by miR-223/VHL/HIF-1α pathway to upregulate aerobic glycolysis in airway epithelial in asthma. This pathway is suppressed by sTSLP through occupying binding site of lTSLP in TSLPR and IL-7R receptor complex. Funding Statement: This study was supported by the National Natural Science Foundation of China (81700034， 81670026, 81470228，81770033, 81500023), Natural Science Foundation of Guangdong Province (2017A030310106, 2015A030313236, 2017A030313849), the Precision Medicine Research of The National Key Research and Development Plan of China (2016YFC0905803), and China Postdoctoral Science Foundation (2017M620377, 2018T110885). Declaration of Interests: The authors declare that they have no conflicts of interest. Ethics Approval Statement: The asthmatic models experiment were approved by the Animal Subjects Committee of South Medical University.