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

Abstract

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.

• Authors: 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
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 17 (Aug 28 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34502263 (Publication Type: Journal Article)

Chemical References

• Lipopolysaccharides
• RGS Proteins
• RGS5 protein, human
• Rgs5 protein, mouse
• Bleomycin

Topics

• Animals
• Bleomycin (toxicity)
• Chemotaxis (genetics)
• Disease Models, Animal
• Fibrosis (genetics)
• Humans
• Inflammation (chemically induced, metabolism)
• Lipopolysaccharides (toxicity)
• Lung Diseases, Interstitial (genetics, metabolism, pathology)
• Lung Injury (chemically induced, metabolism, pathology)
• MAP Kinase Signaling System (genetics)
• Mice
• Mice, Knockout
• Neutrophils (cytology, metabolism)
• RGS Proteins (deficiency, genetics, metabolism)
• Respiratory Distress Syndrome (genetics, metabolism)