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.
Highlights
G protein-coupled receptor (GPCR) signaling is essential for the pathogenesis of inflammatory diseases and represents one of the most frequently targeted receptor pathways in modern pharmacotherapy
The gene expression of the R4 subfamily members showed up-regulated RGS1, RGS3, RGS4 and RGS5 in fibrosing ILD compared to healthy controls (Figure 1A,B)
Immunohistochemical (IHC) staining showed that RGS5 is present in airway and vascular structural cells, as well as in inflammatory cells in controls and ILD, as well as in samples obtained from patients with acute respiratory distress (ARDS) (Figure 1D and S1)
Summary
G protein-coupled receptor (GPCR) signaling is essential for the pathogenesis of inflammatory diseases and represents one of the most frequently targeted receptor pathways in modern pharmacotherapy. Previous studies suggested that RGS2, RGS4 and RGS5 were protective against airway-hyperresponsiveness with modulated airway or bronchial contractility [4,5,6], while RGS2 was protective against bleomycin-induced lung fibrosis [7]. These specific RGS proteins are members of the R4 subfamily. As human diseases directly attributable to dysfunction of a specific R4 RGS protein are not known, it is challenging to delineate the pathways regulated by each of these proteins. Using RGS5 knockout animals, we found a selective effect of RGS5 on the neutrophilic inflammatory response in the early phase of acute respiratory distress syndrome (ARDS)
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