| Autor: |
Pathinayake PS; Immune Health Program, Hunter Medical Research Institute and School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia., Hsu AC; Immune Health Program, Hunter Medical Research Institute and School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.; Signature Research Program in Emerging Infectious Diseases, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore, Singapore., Nichol KS; Immune Health Program, Hunter Medical Research Institute and School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia., Horvat JC; Immune Health Program, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia., Hansbro PM; Immune Health Program, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.; Faculty of Science, School of Life Sciences, Centre for Inflammation, Centenary Institute, University of Technology Sydney, Sydney, New South Wales, Australia., Wark PAB; Immune Health Program, Hunter Medical Research Institute and School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.; Department of Respiratory and Sleep Medicine, John Hunter Hospital, Newcastle, New South Wales, Australia.; School of Medicine, Monash University, Melbourne, Victoria, Australia.; AIRMED Alfred Health, Melbourne, Victoria, Australia. |
| Abstrakt: |
Thymic stromal lymphopoietin (TSLP) is an epithelial-derived pleiotropic cytokine that regulates T-helper 2 (Th2) immune responses in the lung and plays a major role in severe uncontrolled asthma. Emerging evidence suggests a role for endoplasmic reticulum (ER) stress in the pathogenesis of asthma. In this study, we determined if ER stress and the unfolded protein response (UPR) signaling are involved in TSLP induction in the airway epithelium. For this, we treated human bronchial epithelial basal cells and differentiated primary bronchial epithelial cells with ER stress inducers and the TSLP mRNA and protein expression was determined. A series of siRNA gene knockdown experiments were conducted to determine the ER stress-induced TSLP signaling pathways. cDNA collected from asthmatic bronchial biopsies was used to determine the gene correlation between ER stress and TSLP. Our results show that ER stress signaling induces TSLP mRNA expression via the PERK-C/EBP homologous protein (CHOP) signaling pathway. AP-1 transcription factor is important in regulating this ER stress-induced TSLP mRNA induction, though ER stress alone cannot induce TSLP protein production. However, ER stress significantly enhances TLR3-induced TSLP protein secretion in the airway epithelium. TSLP and ER stress (PERK) mRNA expression positively correlates in bronchial biopsies from participants with asthma, particularly in neutrophilic asthma. In conclusion, these results suggest that ER stress primes TSLP that is then enhanced further upon TLR3 activation, which may induce severe asthma exacerbations. Targeting ER stress using pharmacological interventions may provide novel therapeutics for severe uncontrolled asthma. NEW & NOTEWORTHY TSLP is an epithelial-derived cytokine and a key regulator in the pathogenesis of severe uncontrolled asthma. We demonstrate a novel mechanism by which endoplasmic reticulum stress signaling upregulates airway epithelial TSLP mRNA expression via the PERK-CHOP signaling pathway and enhances TLR3-mediated TSLP protein secretion. |
