RGS2 is an innate immune checkpoint for suppressing Gaq mediated IFN? generation and lung injury
Infections can trigger the release of IFN?, a type II interferon, which exacerbates tissue inflammation and may lead to severe acute lung injury (ALI). However, the regulatory mechanisms of IFN? production in the lungs are not fully understood. In this study, we identified RGS2 as a crucial regulator of IFN? levels in the lungs during infection. The absence of RGS2 led to persistently elevated IFN? production in macrophages, resulting in unresolved inflammatory lung damage. Notably, this effect was absent in RGS2-deficient chimeric mice that received wild-type bone marrow or RGS2 expression in alveolar macrophages (AMs), as well as in those treated with an IFN?-blocking antibody. RGS2 exerts its regulatory role by inhibiting Gaq-mediated IFN? production and inflammatory signaling in AMs. Consequently, the inhibition of Gaq in RGS2-deficient mice prevented IFN? production in AMs and shifted their transcriptomic profile from an inflammatory to a reparative state. These findings suggest that the RGS2-Gaq signaling pathway could be a promising therapeutic target for mitigating inflammatory lung injury. Overall design: In this experiment, RNA sequencing (RNA-seq) was performed to investigate the transcriptomic effects of lipopolysaccharide (LPS)-induced inflammation in the lungs of wild-type (WT) and Rgs2 knockout (KO) mice. Bronchoalveolar lavage (BAL) collected 64 hours after LPS administration from both WT and Rgs2 KO mice, with or without treatment with the Gaq inhibitor (BIM-46187) (three mice per group pooled together). Total RNA was extracted using the RNeasy mini kit (Qiagen USA), and ribosomal RNA was depleted using the RiboMinus™ Eukaryote kit v2 (Thermo Fisher Scientific). RNA libraries were then constructed with the TruSeq RNA library prep kit v2 (Illumina) and sequenced using the NovaSeq 6000 platform with paired-end 150 bp reads.