Lymphotoxin beta receptor signaling directly controls airway smooth muscle deregulation and asthmatic lung dysfunction.
AHR
LIGHT
LTβR
TNF superfamily
TNFSF14
airway smooth muscle
asthma
contractility
noncanonical NF-κB
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:
04 2023
04 2023
Historique:
received:
23
05
2022
revised:
25
10
2022
accepted:
18
11
2022
pmc-release:
01
04
2024
medline:
11
4
2023
pubmed:
7
12
2022
entrez:
6
12
2022
Statut:
ppublish
Résumé
Dysregulation of airway smooth muscle cells (ASM) is central to the severity of asthma. Which molecules dominantly control ASM in asthma is unclear. High levels of the cytokine LIGHT (aka TNFSF14) have been linked to asthma severity and lower baseline predicted FEV Our study sought to determine whether signaling via lymphotoxin beta receptor (LTβR) or herpesvirus entry mediator from LIGHT dominantly drives ASM hyperreactivity induced by allergen. Conditional knockout mice deficient for LTβR or herpesvirus entry mediator in smooth muscle cells were used to determine their role in ASM deregulation and airway hyperresponsiveness (AHR) in vivo. Human ASM were used to study signals induced by LTβR. LTβR was strongly expressed in ASM from normal and asthmatic subjects compared to several other receptors implicated in smooth muscle deregulation. Correspondingly, conditional deletion of LTβR only in smooth muscle cells in smMHC LTβR signals directly and dominantly drive airway smooth muscle hyperresponsiveness relevant for pathogenesis of airway remodeling in severe asthma.
Sections du résumé
BACKGROUND
Dysregulation of airway smooth muscle cells (ASM) is central to the severity of asthma. Which molecules dominantly control ASM in asthma is unclear. High levels of the cytokine LIGHT (aka TNFSF14) have been linked to asthma severity and lower baseline predicted FEV
OBJECTIVE
Our study sought to determine whether signaling via lymphotoxin beta receptor (LTβR) or herpesvirus entry mediator from LIGHT dominantly drives ASM hyperreactivity induced by allergen.
METHODS
Conditional knockout mice deficient for LTβR or herpesvirus entry mediator in smooth muscle cells were used to determine their role in ASM deregulation and airway hyperresponsiveness (AHR) in vivo. Human ASM were used to study signals induced by LTβR.
RESULTS
LTβR was strongly expressed in ASM from normal and asthmatic subjects compared to several other receptors implicated in smooth muscle deregulation. Correspondingly, conditional deletion of LTβR only in smooth muscle cells in smMHC
CONCLUSIONS
LTβR signals directly and dominantly drive airway smooth muscle hyperresponsiveness relevant for pathogenesis of airway remodeling in severe asthma.
Identifiants
pubmed: 36473503
pii: S0091-6749(22)01622-0
doi: 10.1016/j.jaci.2022.11.016
pmc: PMC10081945
mid: NIHMS1855188
pii:
doi:
Substances chimiques
Receptors, Tumor Necrosis Factor, Member 14
0
Lymphotoxin beta Receptor
0
Allergens
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
976-990.e5Subventions
Organisme : NIAID NIH HHS
ID : R21 AI111000
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI070535
Pays : United States
Informations de copyright
Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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