RGS4 promotes allergen- and aspirin-associated airway hyperresponsiveness by inhibiting PGE2 biosynthesis

Wong, Gordon S.; Redes, Jamie; Balenga, Nariman; McCullough, Morgan; Fuentes, Nathalie; Gokhale, Ameya; Koziol‐White, Cynthia; Jude, Joseph; Madigan, Laura A.; Chan, Eunice C.; Jester, William F.; Biardel, Sabrina; Flamand, Nicolas; Panettieri, Reynold A.; Druey, Kirk M.

doi:10.1016/j.jaci.2020.03.004

Cited by 14 publications

(5 citation statements)

References 56 publications

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“…Expression of genes associated with the ECM formation was significantly downregulated in IL-31RA −/− mice treated with bleomycin when compared to wildtype mice. Notably, genes associated with epithelial tissue integrity ( Krt5 and Krt14 ), protein Gα signaling, as well as previously reported genes associated with lung function and remodeling ( Arg1, Ccl28 and Rgs4 ) were down regulated in IL-31RA −/− fibrotic mice ( 50 – 52 ). Weathington et al ( 53 ) have recently reported an association between increased expression of the genes KCNJ2 and Krt18 in the setting of asthma, suggesting a strong relationship between lung function and tissue remodeling.…”

Section: Discussionsupporting

confidence: 75%

The Protective Effects of IL-31RA Deficiency During Bleomycin-Induced Pulmonary Fibrosis

et al. 2021

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Idiopathic Pulmonary Fibrosis (IPF) is a severe fibrotic lung disease characterized by excessive collagen deposition and progressive decline in lung function. Th2 T cell-derived cytokines including IL-4 and IL-13 have been shown to contribute to inflammation and fibrotic remodeling in multiple tissues. Interleukin-31 (IL-31) is a newly identified cytokine that is predominantly produced by CD4 Th2 T cells, but its signaling receptor IL-31RA is primarily expressed by non-hematopoietic cells. However, the potential role of the IL-31-IL31RA axis in pulmonary inflammation and fibrosis has remained largely unknown. To determine the role of IL-31RA deficiency in pulmonary fibrosis, wildtype, and IL-31RA knockout mice were treated with bleomycin and measured changes in collagen deposition and lung function. Notably, the loss of IL-31 signaling attenuated collagen deposition and lung function decline during bleomycin-induced pulmonary fibrosis. The total lung transcriptome analysis showed a significant reduction in fibrosis-associated gene transcripts including extracellular matrix and epithelial cell-associated gene networks. Furthermore, the lungs of human IPF showed an elevated expression of IL-31 when compared to healthy subjects. In support, the percentage of IL-31 producing CD4+ T cells was greater in the lungs and PBMCs from IPF patients compared to healthy controls. Our findings suggest a pathogenic role for IL-31/IL-31RA signaling during bleomycin-induced pulmonary fibrosis. Thus, therapeutic targeting the IL-31-IL-31RA axis may prevent collagen deposition, improve lung function, and have therapeutic potential in pulmonary fibrosis.

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Section: Discussionsupporting

confidence: 75%

The Protective Effects of IL-31RA Deficiency During Bleomycin-Induced Pulmonary Fibrosis

et al. 2021

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“…RGS4 was found to be upregulated too. However, previous studies have shown that RGS4 promotes allergen- and aspirin-induced airway hyperresponsiveness [ 25 ]. Using Gene Ontology (GO) enrichment analysis, we determined that the differentially expressed mRNAs were associated with processes commonly associated with inflammation, such as immune responses, cytokines and their receptor signalling pathways, and receptor–ligand activity.…”

Section: Resultsmentioning

confidence: 99%

Mesenchymal stem cells overexpressing interleukin-10 prevent allergic airway inflammation

Kuang,

Liu,

et al. 2023

Stem Cell Res Ther

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Backgrounds Allergic airway inflammation is prevalent worldwide and imposes a considerable burden on both society and affected individuals. This study aimed to investigate the therapeutic advantages of mesenchymal stem cells (MSCs) overexpressed interleukin-10 (IL-10) for the treatment of allergic airway inflammation, as both IL-10 and MSCs possess immunosuppressive properties. Methods Induced pluripotent stem cell (iPSC)-derived MSCs were engineered to overexpress IL-10 via lentiviral transfection (designated as IL-10-MSCs). MSCs and IL-10-MSCs were administered intravenously to mice with allergic inflammation induced by ovalbumin (OVA), and the features of allergic inflammation including inflammatory cell infiltration, Th cells in the lungs, and T helper 2 cell (Th2) cytokine levels in bronchoalveolar lavage fluid (BALF) were examined. MSCs and IL-10-MSCs were co-cultured with CD4+ T cells from patients with allergic rhinitis (AR), and the levels of Th2 cells and corresponding type 2 cytokines were studied. RNA-sequence was performed to further investigate the potential effects of MSCs and IL-10-MSCs on CD4+ T cells. Results Stable IL-10-MSCs were established and characterised by high IL-10 expression. IL-10-MSCs significantly reduced inflammatory cell infiltration and epithelial goblet cell numbers in the lung tissues of mice with allergic airway inflammation. Inflammatory cell and cytokine levels in BALF also decreased after the administration of IL-10-MSCs. Moreover, IL-10-MSCs showed a stronger capacity to inhibit the levels of Th2 after co-cultured with CD4+ T cells from patients with AR. Furthermore, we elucidated lower levels of IL-5 and IL-13 in IL-10-MSCs treated CD4+ T cells, and blockade of IL-10 significantly reversed the inhibitory effects of IL-10-MSCs. We also reported the mRNA profiles of CD4+ T cells treated with IL-10-MSCs and MSCs, in which IL-10 played an important role. Conclusion IL-10-MSCs showed positive effects in the treatment of allergic airway inflammation, providing solid support for the use of genetically engineered MSCs as a potential novel therapy for allergic airway inflammation.

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“…In contrast to RGS5 knockout, RGS2-/-mice displayed increased acute inflammation upon house dust mite and LPS inoculation and an augmented development of pulmonary fibrosis [4,7,24]. Increase of RGS4 in human bronchial smooth muscle cells caused severe airway obstruction and RGS4-/-mice exhibited diminished allergen-induced AHR through the increased secretion of the bronchodilator PGE2 [25,26]. This suggests that the signaling pathways and biological roles of the different RGS proteins may be quite specific.…”

Section: Discussionmentioning

confidence: 99%

RGS5 Determines Neutrophil Migration in the Acute Inflammatory Phase of Bleomycin-Induced Lung Injury

Sharma

Nagaraj

Nagy

et al. 2021

IJMS

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The regulator of G protein signaling (RGS) represents a widespread system of controllers of cellular responses. The activities of the R4 subfamily of RGSs have been elucidated in allergic pulmonary diseases. However, the R4 signaling in other inflammatory lung diseases, with a strong cellular immune response, remained unexplored. Thus, our study aimed to discern the functional relevance of the R4 family member, RGS5, as a potential modulating element in this context. Gene profiling of the R4 subfamily showed increased RGS5 expression in human fibrosing lung disease samples. In line with this, RGS5 was markedly increased in murine lungs following bleomycin injury. RGS knock-out mice (RGS-/-) had preserved lung function while control mice showed significant combined ventilatory disorders three days after bleomycin application as compared to untreated control mice. Loss of RGS5 was associated with a significantly reduced neutrophil influx and tissue myeloperoxidase expression. In the LPS lung injury model, RGS5-/- mice also failed to recruit neutrophils into the lung, which was accompanied by reduced tissue myeloperoxidase levels after 24 h. Our in-vitro assays showed impaired migration of RGS5-/- neutrophils towards chemokines despite preserved Ca2+ signaling. ERK dephosphorylation might play a role in reduced neutrophil migration in our model. As a conclusion, loss of RGS5 preserves lung function and attenuates hyperinflammation in the acute phase of bleomycin-induced pulmonary fibrosis and LPS-induced lung injury. Targeting RGS5 might alleviate the severity of exacerbations in interstitial lung diseases.

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RGS4 promotes allergen- and aspirin-associated airway hyperresponsiveness by inhibiting PGE2 biosynthesis

Cited by 14 publications

References 56 publications

The Protective Effects of IL-31RA Deficiency During Bleomycin-Induced Pulmonary Fibrosis

The Protective Effects of IL-31RA Deficiency During Bleomycin-Induced Pulmonary Fibrosis

Mesenchymal stem cells overexpressing interleukin-10 prevent allergic airway inflammation

RGS5 Determines Neutrophil Migration in the Acute Inflammatory Phase of Bleomycin-Induced Lung Injury

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