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

IFN{gamma}, 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 IFNg leads to uncontrolled innate response and perpetuated lung injury. LPS induced a sustained increase in IFNg 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 IFNg levels in AM and thereby lungs innate immune response. RGS2 functioned by forming a complex with TLR4 shielding Gaq from inducing IFNg generation and AM inflammatory signaling. Thus, inhibition of Gaq blocked IFNg generation and subverted AM transcriptome from being inflammatory to reparative type in RGS2 null mice, resolving lung injury. HighlightsO_LIRGS2 levels are inversely correlated with IFN{gamma} in ARDS patients AM. C_LIO_LIRGS2 in alveolar macrophages regulate the inflammatory lung injury. C_LIO_LIDuring pathogenic insult RGS2 functioned by forming a complex with TLR4 shielding Gq from inducing IFN{gamma} generation and AM inflammatory signaling. C_LI eToc BlurbAuthors demonstrate an essential role of RGS2 in macrophages in airspace to promoting anti-inflammatory function of alveolar macrophages in lung injury. The authors provided new insight into the dynamic control of innate immune response by Gq and RGS2 axis to prevent ALI.