Endoplasmic reticulum stress enhances the expression of TLR3-induced TSLP by airway epithelium.

Pathinayake, PS; Hsu, AC-Y; Nichol, KS; Horvat, JC; Hansbro, PM; Wark, PAB

Endoplasmic reticulum stress enhances the expression of TLR3-induced TSLP by airway epithelium.

Pathinayake, PS Hsu, AC-Y Nichol, KS Horvat, JC Hansbro, PM Wark, PAB

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Publisher:: AMER PHYSIOLOGICAL SOC
Publication Type:: Journal Article
Citation:: Am J Physiol Lung Cell Mol Physiol, 2024, 326, (5), pp. L618-L626
Issue Date:: 2024-05-01

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Field	Value	Language
dc.contributor.author	Pathinayake, PS
dc.contributor.author	Hsu, AC-Y
dc.contributor.author	Nichol, KS
dc.contributor.author	Horvat, JC
dc.contributor.author	Hansbro, PM
dc.contributor.author	Wark, PAB
dc.date.accessioned	2025-01-02T05:55:24Z
dc.date.available	2025-01-02T05:55:24Z
dc.date.issued	2024-05-01
dc.identifier.citation	Am J Physiol Lung Cell Mol Physiol, 2024, 326, (5), pp. L618-L626
dc.identifier.issn	1040-0605
dc.identifier.issn	1522-1504
dc.identifier.uri	http://hdl.handle.net/10453/182838
dc.description.abstract	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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	AMER PHYSIOLOGICAL SOC
dc.relation	http://purl.org/au-research/grants/nhmrc/1175134
dc.relation.ispartof	Am J Physiol Lung Cell Mol Physiol
dc.relation.isbasedon	10.1152/ajplung.00378.2023
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	0606 Physiology, 1116 Medical Physiology
dc.subject.classification	Respiratory System
dc.subject.classification	3201 Cardiovascular medicine and haematology
dc.subject.classification	3208 Medical physiology
dc.subject.mesh	Humans
dc.subject.mesh	Endoplasmic Reticulum Stress
dc.subject.mesh	Cytokines
dc.subject.mesh	Toll-Like Receptor 3
dc.subject.mesh	Thymic Stromal Lymphopoietin
dc.subject.mesh	Asthma
dc.subject.mesh	Unfolded Protein Response
dc.subject.mesh	Epithelial Cells
dc.subject.mesh	Transcription Factor CHOP
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Respiratory Mucosa
dc.subject.mesh	Bronchi
dc.subject.mesh	eIF-2 Kinase
dc.subject.mesh	Cells, Cultured
dc.subject.mesh	Female
dc.subject.mesh	RNA, Messenger
dc.subject.mesh	Bronchi
dc.subject.mesh	Respiratory Mucosa
dc.subject.mesh	Cells, Cultured
dc.subject.mesh	Epithelial Cells
dc.subject.mesh	Humans
dc.subject.mesh	Asthma
dc.subject.mesh	eIF-2 Kinase
dc.subject.mesh	RNA, Messenger
dc.subject.mesh	Cytokines
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Female
dc.subject.mesh	Toll-Like Receptor 3
dc.subject.mesh	Transcription Factor CHOP
dc.subject.mesh	Unfolded Protein Response
dc.subject.mesh	Endoplasmic Reticulum Stress
dc.subject.mesh	Thymic Stromal Lymphopoietin
dc.subject.mesh	Humans
dc.subject.mesh	Endoplasmic Reticulum Stress
dc.subject.mesh	Cytokines
dc.subject.mesh	Toll-Like Receptor 3
dc.subject.mesh	Thymic Stromal Lymphopoietin
dc.subject.mesh	Asthma
dc.subject.mesh	Unfolded Protein Response
dc.subject.mesh	Epithelial Cells
dc.subject.mesh	Transcription Factor CHOP
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Respiratory Mucosa
dc.subject.mesh	Bronchi
dc.subject.mesh	eIF-2 Kinase
dc.subject.mesh	Cells, Cultured
dc.subject.mesh	Female
dc.subject.mesh	RNA, Messenger
dc.title	Endoplasmic reticulum stress enhances the expression of TLR3-induced TSLP by airway epithelium.
dc.type	Journal Article
utslib.citation.volume	326
utslib.location.activity	United States
utslib.for	0606 Physiology
utslib.for	1116 Medical Physiology
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Science
pubs.organisational-group	University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	University of Technology Sydney/UTS Groups
pubs.organisational-group	University of Technology Sydney/UTS Groups/Australian Institute for Microbiology & Infection (AIMI)
pubs.organisational-group	University of Technology Sydney/UTS Groups/Centre for Inflammation (CFI)
pubs.organisational-group	University of Technology Sydney/UTS Groups/Australian Institute for Microbiology & Infection (AIMI)/Australian Institute for Microbiology & Infection (AIMI) Associate Members
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
dc.date.updated	2025-01-02T05:54:29Z
pubs.issue	5
pubs.publication-status	Published
pubs.volume	326
utslib.citation.issue	5

Abstract:

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.

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http://hdl.handle.net/10453/182838