Regulator of G-protein signaling 2 repression exacerbates airway hyper-responsiveness and remodeling in asthma

Haihong Jiang, Yan Xie, Peter W. Abel, Dennis W. Wolff, Myron L. Toews, Reynold A. Panettieri, Thomas B. Casale, Yaping Tu

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

G protein-coupled receptors (GPCRs) are important regulators of cell functions in asthma. We recently reported that regulator of G-protein signaling (RGS) 2, a selective modulator of Gq-coupled GPCRs, is a key regulator of airway hyper-responsiveness (AHR), the pathophysiologic hallmark of asthma. Because RGS2 protein levels in airway cells were significantly lower in patients with asthma compared with patients without asthma, we further investigated the potential pathological importance of RGS2 repression in asthma. The human RGS2 gene maps to chromosome 1q31. We first screened patients with asthma for RGS2 gene promoter single-nucleotide polymorphisms (SNPs) and found significant differences in the distribution of two RGS2 SNPs (A638G, rs2746071 and C395G, rs2746072) between patients with asthma and nonasthmatic subjects. These two SNPs are always associated with each other and have the same higher prevalence in patients with asthma (65%) as compared with nonasthmatic subjects (35%). Point mutations corresponding to these SNPs decrease RGS2 promoter activity by 44%. The importance of RGS2 down-regulation was then determined in an acute IL-13 mouse model of asthma. Intranasal administration of IL-13 in mice also decreased RGS2 expression in lungs by ∼50% and caused AHR. Although naive RGS2 knockout (KO) mice exhibit spontaneous AHR, acute IL-13 exposure further increased AHR in RGS2 KO mice. Loss of RGS2 also significantly enhanced IL-13-induced mouse airway remodeling, including peribronchial smooth muscle thickening and fibrosis, without effects on goblet cell hyperplasia or airway inflammation in mice. Thus, genetic variations and increased inflammatory cytokines can lead to RGS2 repression, which exacerbates AHR and airway remodeling in asthma.

Original languageEnglish
Pages (from-to)42-49
Number of pages8
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume53
Issue number1
DOIs
StatePublished - Jul 1 2015

Fingerprint

Respiratory Hypersensitivity
GTP-Binding Protein Regulators
Asthma
Interleukin-13
Polymorphism
Single Nucleotide Polymorphism
Nucleotides
Airway Remodeling
G-Protein-Coupled Receptors
Knockout Mice
Genes
Gq-G11 GTP-Binding Protein alpha Subunits
Intranasal Administration
Goblet Cells
Chromosomes
Modulators
Point Mutation
Muscle
Hyperplasia
Smooth Muscle

All Science Journal Classification (ASJC) codes

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Regulator of G-protein signaling 2 repression exacerbates airway hyper-responsiveness and remodeling in asthma. / Jiang, Haihong; Xie, Yan; Abel, Peter W.; Wolff, Dennis W.; Toews, Myron L.; Panettieri, Reynold A.; Casale, Thomas B.; Tu, Yaping.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 53, No. 1, 01.07.2015, p. 42-49.

Research output: Contribution to journalArticle

Jiang, Haihong ; Xie, Yan ; Abel, Peter W. ; Wolff, Dennis W. ; Toews, Myron L. ; Panettieri, Reynold A. ; Casale, Thomas B. ; Tu, Yaping. / Regulator of G-protein signaling 2 repression exacerbates airway hyper-responsiveness and remodeling in asthma. In: American Journal of Respiratory Cell and Molecular Biology. 2015 ; Vol. 53, No. 1. pp. 42-49.
@article{385489098ad04fcd9ecc5578b8310546,
title = "Regulator of G-protein signaling 2 repression exacerbates airway hyper-responsiveness and remodeling in asthma",
abstract = "G protein-coupled receptors (GPCRs) are important regulators of cell functions in asthma. We recently reported that regulator of G-protein signaling (RGS) 2, a selective modulator of Gq-coupled GPCRs, is a key regulator of airway hyper-responsiveness (AHR), the pathophysiologic hallmark of asthma. Because RGS2 protein levels in airway cells were significantly lower in patients with asthma compared with patients without asthma, we further investigated the potential pathological importance of RGS2 repression in asthma. The human RGS2 gene maps to chromosome 1q31. We first screened patients with asthma for RGS2 gene promoter single-nucleotide polymorphisms (SNPs) and found significant differences in the distribution of two RGS2 SNPs (A638G, rs2746071 and C395G, rs2746072) between patients with asthma and nonasthmatic subjects. These two SNPs are always associated with each other and have the same higher prevalence in patients with asthma (65{\%}) as compared with nonasthmatic subjects (35{\%}). Point mutations corresponding to these SNPs decrease RGS2 promoter activity by 44{\%}. The importance of RGS2 down-regulation was then determined in an acute IL-13 mouse model of asthma. Intranasal administration of IL-13 in mice also decreased RGS2 expression in lungs by ∼50{\%} and caused AHR. Although naive RGS2 knockout (KO) mice exhibit spontaneous AHR, acute IL-13 exposure further increased AHR in RGS2 KO mice. Loss of RGS2 also significantly enhanced IL-13-induced mouse airway remodeling, including peribronchial smooth muscle thickening and fibrosis, without effects on goblet cell hyperplasia or airway inflammation in mice. Thus, genetic variations and increased inflammatory cytokines can lead to RGS2 repression, which exacerbates AHR and airway remodeling in asthma.",
author = "Haihong Jiang and Yan Xie and Abel, {Peter W.} and Wolff, {Dennis W.} and Toews, {Myron L.} and Panettieri, {Reynold A.} and Casale, {Thomas B.} and Yaping Tu",
year = "2015",
month = "7",
day = "1",
doi = "10.1165/rcmb.2014-0319OC",
language = "English",
volume = "53",
pages = "42--49",
journal = "American Journal of Respiratory Cell and Molecular Biology",
issn = "1044-1549",
publisher = "American Thoracic Society",
number = "1",

}

TY - JOUR

T1 - Regulator of G-protein signaling 2 repression exacerbates airway hyper-responsiveness and remodeling in asthma

AU - Jiang, Haihong

AU - Xie, Yan

AU - Abel, Peter W.

AU - Wolff, Dennis W.

AU - Toews, Myron L.

AU - Panettieri, Reynold A.

AU - Casale, Thomas B.

AU - Tu, Yaping

PY - 2015/7/1

Y1 - 2015/7/1

N2 - G protein-coupled receptors (GPCRs) are important regulators of cell functions in asthma. We recently reported that regulator of G-protein signaling (RGS) 2, a selective modulator of Gq-coupled GPCRs, is a key regulator of airway hyper-responsiveness (AHR), the pathophysiologic hallmark of asthma. Because RGS2 protein levels in airway cells were significantly lower in patients with asthma compared with patients without asthma, we further investigated the potential pathological importance of RGS2 repression in asthma. The human RGS2 gene maps to chromosome 1q31. We first screened patients with asthma for RGS2 gene promoter single-nucleotide polymorphisms (SNPs) and found significant differences in the distribution of two RGS2 SNPs (A638G, rs2746071 and C395G, rs2746072) between patients with asthma and nonasthmatic subjects. These two SNPs are always associated with each other and have the same higher prevalence in patients with asthma (65%) as compared with nonasthmatic subjects (35%). Point mutations corresponding to these SNPs decrease RGS2 promoter activity by 44%. The importance of RGS2 down-regulation was then determined in an acute IL-13 mouse model of asthma. Intranasal administration of IL-13 in mice also decreased RGS2 expression in lungs by ∼50% and caused AHR. Although naive RGS2 knockout (KO) mice exhibit spontaneous AHR, acute IL-13 exposure further increased AHR in RGS2 KO mice. Loss of RGS2 also significantly enhanced IL-13-induced mouse airway remodeling, including peribronchial smooth muscle thickening and fibrosis, without effects on goblet cell hyperplasia or airway inflammation in mice. Thus, genetic variations and increased inflammatory cytokines can lead to RGS2 repression, which exacerbates AHR and airway remodeling in asthma.

AB - G protein-coupled receptors (GPCRs) are important regulators of cell functions in asthma. We recently reported that regulator of G-protein signaling (RGS) 2, a selective modulator of Gq-coupled GPCRs, is a key regulator of airway hyper-responsiveness (AHR), the pathophysiologic hallmark of asthma. Because RGS2 protein levels in airway cells were significantly lower in patients with asthma compared with patients without asthma, we further investigated the potential pathological importance of RGS2 repression in asthma. The human RGS2 gene maps to chromosome 1q31. We first screened patients with asthma for RGS2 gene promoter single-nucleotide polymorphisms (SNPs) and found significant differences in the distribution of two RGS2 SNPs (A638G, rs2746071 and C395G, rs2746072) between patients with asthma and nonasthmatic subjects. These two SNPs are always associated with each other and have the same higher prevalence in patients with asthma (65%) as compared with nonasthmatic subjects (35%). Point mutations corresponding to these SNPs decrease RGS2 promoter activity by 44%. The importance of RGS2 down-regulation was then determined in an acute IL-13 mouse model of asthma. Intranasal administration of IL-13 in mice also decreased RGS2 expression in lungs by ∼50% and caused AHR. Although naive RGS2 knockout (KO) mice exhibit spontaneous AHR, acute IL-13 exposure further increased AHR in RGS2 KO mice. Loss of RGS2 also significantly enhanced IL-13-induced mouse airway remodeling, including peribronchial smooth muscle thickening and fibrosis, without effects on goblet cell hyperplasia or airway inflammation in mice. Thus, genetic variations and increased inflammatory cytokines can lead to RGS2 repression, which exacerbates AHR and airway remodeling in asthma.

UR - http://www.scopus.com/inward/record.url?scp=84936990929&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84936990929&partnerID=8YFLogxK

U2 - 10.1165/rcmb.2014-0319OC

DO - 10.1165/rcmb.2014-0319OC

M3 - Article

C2 - 25368964

AN - SCOPUS:84936990929

VL - 53

SP - 42

EP - 49

JO - American Journal of Respiratory Cell and Molecular Biology

JF - American Journal of Respiratory Cell and Molecular Biology

SN - 1044-1549

IS - 1

ER -