RGS2 is an innate immune checkpoint for TLR4 and Gαq-mediated IFNγ generation and lung injury

Abstract

IFNγ, a type II interferon secreted by immune cells augments tissue responses to injury following pathogenic infections leading to lethal acute lung injury (ALI). Alveolar macrophages (AM) abundantly express Toll-like receptor-4 and represent the primary cell type of the innate immune system in the lungs. A fundamental question remains whether AM generation of IFNγ leads to uncontrolled innate response and perpetuated lung injury. LPS induced a sustained increase in IFNγ levels and unresolvable inflammatory lung injury in the mice lacking RGS2 but not in RGS2 null chimeric mice receiving WT bone marrow or receiving the RGS2 gene in AM. Thus, indicating RGS2 serves as a gatekeeper of IFNγ levels in AM and thereby lungs innate immune response. RGS2 functioned by forming a complex with TLR4 shielding Gαq from inducing IFNγ generation and AM inflammatory signaling. Thus, inhibition of Gαq blocked IFNγ generation and subverted AM transcriptome from being inflammatory to reparative type in RGS2 null mice, resolving lung injury.

Endothelial ERG programs neutrophil transcriptome for sustained anti-inflammatory vascular niche

“…The 1 × 10 6 CFU/25mL was calculated using the following formula: CFU/ml = (no. of colonies x dilution factor)/volume of the culture plate [58,62] For lung injury, the anesthetized mice receive 1 × 10 4 CFU PA dissolved in 50 μl PBS/mouse through the endotracheal route. After a 15-minute recovery period, mice were returned to their respective cages.…”