Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation.
Adult
Airway Remodeling
Asthma
/ immunology
Biomarkers
/ metabolism
Cells, Cultured
Cohort Studies
Cross-Sectional Studies
Epithelial Cells
/ physiology
Gene Expression Regulation
Humans
Inflammation
/ immunology
Interleukin-6
/ metabolism
Lung
/ physiology
Male
Phenotype
Receptors, Interleukin-6
/ metabolism
Respiratory Hypersensitivity
Signal Transduction
Sputum
/ metabolism
Transcriptome
Asthma
IL-6 signaling
airway inflammation
eosinophils
epithelial integrity
exacerbation frequency
hierarchical clustering
lung epithelium
remodeling
transcriptomics
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
11
10
2017
revised:
15
04
2018
accepted:
04
05
2018
pubmed:
15
6
2018
medline:
18
2
2020
entrez:
15
6
2018
Statut:
ppublish
Résumé
Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear. We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients. An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens. Activation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS-high asthma with increased epithelial expression of IL-6TS-inducible genes in the absence of systemic inflammation. The IL-6TS-high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1β, IL-8, and IL-1β. Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.
Sections du résumé
BACKGROUND
Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear.
OBJECTIVE
We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients.
METHODS
An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens.
RESULTS
Activation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS-high asthma with increased epithelial expression of IL-6TS-inducible genes in the absence of systemic inflammation. The IL-6TS-high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1β, IL-8, and IL-1β.
CONCLUSIONS
Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.
Identifiants
pubmed: 29902480
pii: S0091-6749(18)30847-9
doi: 10.1016/j.jaci.2018.05.026
pii:
doi:
Substances chimiques
Biomarkers
0
Interleukin-6
0
Receptors, Interleukin-6
0
Types de publication
Journal Article
Observational Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
577-590Subventions
Organisme : Medical Research Council
ID : G0800649
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 088365/Z/09/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 104553/Z/14/Z
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 076472/2/05/Z
Pays : United Kingdom
Investigateurs
I M Adcock
(IM)
H Ahmed
(H)
C Auffray
(C)
P Bakke
(P)
A T Bansal
(AT)
F Baribaud
(F)
S Bates
(S)
E H Bel
(EH)
J Bigler
(J)
H Bisgaard
(H)
M J Boedigheimer
(MJ)
K Bønnelykke
(K)
J Brandsma
(J)
P Brinkman
(P)
E Bucchioni
(E)
D Burg
(D)
A Bush
(A)
M Caruso
(M)
A Chaiboonchoe
(A)
P Chanez
(P)
F K Chung
(FK)
C H Compton
(CH)
J Corfield
(J)
A D'Amico
(A)
S E Dahlen
(SE)
B De Meulder
(B)
R Djukanovic
(R)
V J Erpenbeck
(VJ)
D Erzen
(D)
K Fichtner
(K)
N Fitch
(N)
L J Fleming
(LJ)
E Formaggio
(E)
S J Fowler
(SJ)
U Frey
(U)
M Gahlemann
(M)
T Geiser
(T)
V Goss
(V)
Y Guo
(Y)
S Hashimoto
(S)
J Haughney
(J)
G Hedlin
(G)
P W Hekking
(PW)
T Higenbottam
(T)
J M Hohlfeld
(JM)
C Holweg
(C)
I Horváth
(I)
A J James
(AJ)
R Knowles
(R)
A J Knox
(AJ)
N Krug
(N)
D Lefaudeux
(D)
M J Loza
(MJ)
A Manta
(A)
J G Matthews
(JG)
A Mazein
(A)
A Meiser
(A)
R J M Middelveld
(RJM)
M Miralpeix
(M)
P Montuschi
(P)
N Mores
(N)
C S Murray
(CS)
J Musial
(J)
D Myles
(D)
L Pahus
(L)
I Pandis
(I)
S Pavlidis
(S)
A Postle
(A)
P Powel
(P)
G Praticò
(G)
N Rao
(N)
J Riley
(J)
A Roberts
(A)
G Roberts
(G)
A Rowe
(A)
T Sandström
(T)
J P R Schofield
(JPR)
W Seibold
(W)
A Selby
(A)
D E Shaw
(DE)
R Sigmund
(R)
F Singer
(F)
P J Skipp
(PJ)
A R Sousa
(AR)
P J Sterk
(PJ)
K Sun
(K)
B Thornton
(B)
W M van Aalderen
(WM)
M van Geest
(M)
J Vestbo
(J)
N H Vissing
(NH)
A H Wagener
(AH)
S S Wagers
(SS)
Z Weiszhart
(Z)
C E Wheelock
(CE)
S J Wilson
(SJ)
Informations de copyright
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.