RGS5 Determines Neutrophil Migration in the Acute Inflammatory Phase of Bleomycin-Induced Lung Injury
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...
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MDPI AG
2021-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/17/9342 |
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| author | Neha Sharma Chandran Nagaraj Bence M. Nagy Leigh M. Marsh Natalie Bordag Diana Zabini Malgorzata Wygrecka Walter Klepetko Elisabeth Gschwandtner Guillem Genové Akos Heinemann E Kenneth Weir Grazyna Kwapiszewska Horst Olschewski Andrea Olschewski |
| author_facet | Neha Sharma Chandran Nagaraj Bence M. Nagy Leigh M. Marsh Natalie Bordag Diana Zabini Malgorzata Wygrecka Walter Klepetko Elisabeth Gschwandtner Guillem Genové Akos Heinemann E Kenneth Weir Grazyna Kwapiszewska Horst Olschewski Andrea Olschewski |
| author_sort | Neha Sharma |
| collection | DOAJ |
| description | 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 Ca<sup>2+</sup> 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. |
| first_indexed | 2024-03-10T08:10:29Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T08:10:29Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-25fcdf70d9b2402dbc4fdf8d332b6e3d2023-11-22T10:42:06ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-08-012217934210.3390/ijms22179342RGS5 Determines Neutrophil Migration in the Acute Inflammatory Phase of Bleomycin-Induced Lung InjuryNeha Sharma0Chandran Nagaraj1Bence M. Nagy2Leigh M. Marsh3Natalie Bordag4Diana Zabini5Malgorzata Wygrecka6Walter Klepetko7Elisabeth Gschwandtner8Guillem Genové9Akos Heinemann10E Kenneth Weir11Grazyna Kwapiszewska12Horst Olschewski13Andrea Olschewski14Ludwig Boltzmann Institute for Lung Vascular Research, 8010 Graz, AustriaLudwig Boltzmann Institute for Lung Vascular Research, 8010 Graz, AustriaLudwig Boltzmann Institute for Lung Vascular Research, 8010 Graz, AustriaLudwig Boltzmann Institute for Lung Vascular Research, 8010 Graz, AustriaLudwig Boltzmann Institute for Lung Vascular Research, 8010 Graz, AustriaLudwig Boltzmann Institute for Lung Vascular Research, 8010 Graz, AustriaCenter for Infection and Genomics of the Lung (Member of the German Center for Lung Research), University of Giessen, Giessen 35392, GermanyDepartment of Thoracic Surgery, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Thoracic Surgery, Medical University of Vienna, 1090 Vienna, AustriaIntegrated CardioMetabolic Centre (ICMC), Department of Medicine, Karolinska Institute, 171 77 Huddinge, SwedenOtto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, 8010 Graz, AustriaDepartment of Medicine, University of Minnesota, Minneapolis, MN 55455, USALudwig Boltzmann Institute for Lung Vascular Research, 8010 Graz, AustriaLudwig Boltzmann Institute for Lung Vascular Research, 8010 Graz, AustriaLudwig Boltzmann Institute for Lung Vascular Research, 8010 Graz, AustriaThe 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 Ca<sup>2+</sup> 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.https://www.mdpi.com/1422-0067/22/17/9342regulator of G protein signaling 5neutrophilic inflammationchemotaxisERKinterstitial lung diseases |
| spellingShingle | Neha Sharma Chandran Nagaraj Bence M. Nagy Leigh M. Marsh Natalie Bordag Diana Zabini Malgorzata Wygrecka Walter Klepetko Elisabeth Gschwandtner Guillem Genové Akos Heinemann E Kenneth Weir Grazyna Kwapiszewska Horst Olschewski Andrea Olschewski RGS5 Determines Neutrophil Migration in the Acute Inflammatory Phase of Bleomycin-Induced Lung Injury International Journal of Molecular Sciences regulator of G protein signaling 5 neutrophilic inflammation chemotaxis ERK interstitial lung diseases |
| title | RGS5 Determines Neutrophil Migration in the Acute Inflammatory Phase of Bleomycin-Induced Lung Injury |
| title_full | RGS5 Determines Neutrophil Migration in the Acute Inflammatory Phase of Bleomycin-Induced Lung Injury |
| title_fullStr | RGS5 Determines Neutrophil Migration in the Acute Inflammatory Phase of Bleomycin-Induced Lung Injury |
| title_full_unstemmed | RGS5 Determines Neutrophil Migration in the Acute Inflammatory Phase of Bleomycin-Induced Lung Injury |
| title_short | RGS5 Determines Neutrophil Migration in the Acute Inflammatory Phase of Bleomycin-Induced Lung Injury |
| title_sort | rgs5 determines neutrophil migration in the acute inflammatory phase of bleomycin induced lung injury |
| topic | regulator of G protein signaling 5 neutrophilic inflammation chemotaxis ERK interstitial lung diseases |
| url | https://www.mdpi.com/1422-0067/22/17/9342 |
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