Abstract
Growing evidences indicate that Ly-GDI, an inhibitory protein of Rho GTPases, plays an essential role in regulating actin cytoskeletal alteration which is indispensible for the process such as phagocytosis. However, the role of Ly-GDI in inflammation remains largely unknown. In the current study, we found that Ly-GDI expression was significantly decreased in the IgG immune complex-injured lungs. To determine if Ly-GDI might regulate the lung inflammatory response, we constructed adenovirus vectors that could mediate ectopic expression of Ly-GDI (Adeno-Ly-GDI). In vivo mouse lung expression of Ly-GDI resulted in a significant attenuation of IgG immune complex-induced lung injury, which was due to the decreased pulmonary permeability and lung inflammatory cells, especially neutrophil accumulation. Upon IgG immune complex deposition, mice with Ly-GDI over-expression in the lungs produced significant less inflammatory mediators (TNF-α, IL-6, MCP-1, and MIP-1α) in bronchoalveolar lavage fluid when compared control mice receiving airway injection of Adeno-GFP. Mechanically, IgG immune complex-induced NF-κB activity was markedly suppressed by Ly-GDI in both alveolar macrophages and lungs as measured by luciferase assay and electrophoretic mobility shift assay. These findings suggest that Ly-GDI is a critical regulator of inflammatory injury after deposition of IgG immune complexes and that it negatively regulates the lung NF-κB activity.
Highlights
Ly-GDI, known as D4-GDI, RhoGDI2, GDID4 or RhoGDIB, is a member of Rho guanidine dissociation inhibitor (RhoGDI) family that is composed of three members-RhoGDIα, RhoGDI2, and RhoGDI3 [1, 2]
A recent report shows that Ly-GDI expression significantly inhibits Fcγ receptor (FcγR)-mediated phagocytosis [1], its role in inflammation mediated by FcγR activation is unknown
In vitro experiment demonstrated that Ly-GDI expression was dramatically elevated in HEK293 cells infected by Adeno-Ly-GDI when compared with cells incubated with control virus (Adeno-GFP, Fig 2A)
Summary
Ly-GDI, known as D4-GDI, RhoGDI2, GDID4 or RhoGDIB, is a member of Rho guanidine dissociation inhibitor (RhoGDI) family that is composed of three members-RhoGDIα, RhoGDI2, and RhoGDI3 [1, 2]. When dissociated from RhoGDI and GDP, RhoGTPases become active form by binding to GTP and relocate to plasma membrane through the C-terminal isoprenyl motif [1, 4]. In T cells, Ly-GDI functions cooperatively with the GDP/GTP exchange factors (GEF), Vav, as signal transducers in the T cell receptor (TCR) pathway, which lead to the cytoskeletal reorganization required for the immunological synapse formation [7]. Consistent with these results, a recent study finds that Ly-GDI inhibits Fcγ receptor (FcγR)-mediated phagocytosis by suppressing association of Rac with plasma membrane in human monocytes [1]. The impact of Ly-GDI on inflammation including the FcγR activation-induced inflammatory responses remains unknown
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