Introduction The significance of endoplasmic reticulum (ER) stress in asthma is unclear. Here, we demonstrate that ER stress and the unfolded protein response (UPR) are related to disease severity and inflammatory phenotype.
Methods Induced sputum (n=47), bronchial lavage (n=23) and endobronchial biopsies (n=40) were collected from participants with asthma with varying disease severity, inflammatory phenotypes and from healthy controls. Markers for ER stress and UPR were assessed. These markers were also assessed in established eosinophilic and neutrophilic murine models of asthma.
Results Our results demonstrate increased ER stress and UPR pathways in asthma and these are related to clinical severity and inflammatory phenotypes. Genes associated with ER protein chaperone (BiP, CANX, CALR), ER-associated protein degradation (EDEM1, DERL1) and ER stress-induced apoptosis (DDIT3, PPP1R15A) were dysregulated in participants with asthma and are associated with impaired lung function (forced expiratory volume in 1 s) and active eosinophilic and neutrophilic inflammation. ER stress genes also displayed a significant correlation with classic Th2 (interleukin-4, IL-4/13) genes, Th17 (IL-17F/CXCL1) genes, proinflammatory (IL-1b, tumour necrosis factor α, IL-8) genes and inflammasome activation (NLRP3) in sputum from asthmatic participants. Mice with allergic airway disease (AAD) and severe steroid insensitive AAD also showed increased ER stress signalling in their lungs.
Conclusion Heightened ER stress is associated with severe eosinophilic and neutrophilic inflammation in asthma and may play a crucial role in the pathogenesis of asthma.
- asthma mechanisms
- allergic lung disease
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information.
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Contributors PP, PABW, AC-YH, DWW and KB designed and wrote the manuscript. PP, ATR, KN, ACB and DWW contributed to data analysis and interpretation. PABW, PMH, PGG, LW, JCH and JLS contributed by revising the manuscript, overall editing and supervision.
Funding This research work was funded by the National Health and Medical Research Council (NHMRC) of Australia (APP2002953), and CRE for Severe asthma, The University of Newcastle, Australia. PMH is funded by Fellowship/Investigator grants from the NHMRC (1079187, 1175134).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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