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The UPR and lung disease

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Abstract

The respiratory tract has a surface area of approximately 70 m2 that is in direct contact with the external environment. Approximately 12,000 l of air are inhaled daily, exposing the airway epithelium to up to 25 million particles an hour. Several inhaled environmental triggers, like cigarette smoke, diesel exhaust, or allergens, are known inducers of endoplasmatic reticulum (ER) stress and cause a dysregulation in ER homeostasis. Furthermore, some epithelial cell types along the respiratory tract have a secretory function, producing large amounts of mucus or pulmonary surfactant, as well as innate host defense molecules like defensins. To keep up with their secretory demands, these cells must rely on the appropriate functioning and folding capacity of the ER, and they are particularly more vulnerable to conditions of unresolved ER stress. In the lung interstitium, triggering of ER stress pathways has a major impact on the functioning of vascular smooth muscle cells and fibroblasts, causing aberrant dedifferentiation and proliferation. Given the large amounts of foreign material inhaled, the lung is densely populated by various types of immune cells specialized in engulfing and killing pathogens and in secreting cytokines/chemokines for efficient microbial clearance. Unfolded protein response signaling cascades have been shown to intersect with the functioning of immune cells at all levels. The current review aims to highlight the role of ER stress in health and disease in the lung, focusing on its impact on different structural and inflammatory cell types.

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Abbreviations

AEC:

Alveolar epithelial cell

AGR2:

Anterior gradient homolog 2

ATF6:

Activating transcription factor 6

CHOP:

CCAAT/enhancer-binding protein homologous protein

CF:

Cystic fibrosis

CFTR:

Cystic fibrosis transmembrane conductance regulator

ChIP:

Chromatin immunoprecipitation

CREB:

cAMP response element binding

COPD:

Chronic obstructive pulmonary disease

CRT:

Calreticulin

CS:

Cigarette smoke

DCs:

Dendritic cells

ECs:

Epithelial cells

eIF2a:

Elongation initiation factor 2α

ER:

Endoplasmatic reticulum

ERAD:

ER-associated degradation

Foxo2a:

Forkhead box-family transcription factor 2a

GASML:

Gasdermin B

GCM:

Goblet cell metaplasia

GCN2:

General control nonrepressed

Grp78:

Glucose regulated protein 78

HDM:

House dust mite

IPF:

Idiopathic pulmonary fibrosis

IIPs:

Idiopathic interstitial pneumonias

IRE1:

Inositol requiring enzyme 1

JNK:

c-Jun N-terminal kinase

NO:

Nitric oxide

Nrf-2:

Nuclear factor erythroid 2-related factor

ORMDL3:

Orosomucoid-like 3

PAH:

Pulmonary arterial hypertension

PDI:

Protein disulfide isomerase

PERK:

Protein kinase R-like ER kinase

PM:

Particulate matter

RIDD:

Regulated IRE1-dependent decay

ROS:

Reactive oxygen species

S1P:

Sphingosine-1 phosphate

SERCA:

Sarco-endoplasmic reticulum Ca2+ ATPase pump

SMC:

Smooth muscle cells

SPDEF:

SAM pointed domain containing Ets

SPC:

Surfactant protein C

TGF-β:

Transforming growth factor β

TLR4:

Toll-like receptor 4

UPR:

Unfolded protein response

XBP1:

X-box binding protein 1

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Authors and Affiliations

  1. GROUP-ID Consortium, Laboratory of Immunoregulation and Mucosal Immunology, Department of Respiratory Diseases, University Hospital, Ghent, Belgium

    Fabiola Osorio, Bart Lambrecht & Sophie Janssens

  2. Department of Molecular Biomedical Research, VIB, Ghent, Belgium

    Fabiola Osorio, Bart Lambrecht & Sophie Janssens

Authors
  1. Fabiola Osorio
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  2. Bart Lambrecht
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  3. Sophie Janssens
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Correspondence to Bart Lambrecht.

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This article is a contribution to the special issue on “The unfolded protein response in immune diseases”—Guest Editors: Richard Blumberg and Arthur Kaser

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Osorio, F., Lambrecht, B. & Janssens, S. The UPR and lung disease. Semin Immunopathol 35, 293–306 (2013). https://doi.org/10.1007/s00281-013-0368-6

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