Mice with double knockout of Egr-1 and RCAN1 exhibit reduced inflammation during Pseudomonas aeruginosa lung infection

Pseudomonas aeruginosa represents one of the major opportunistic pathogens, which causes nosocomial infections in immunocompromised individuals. The molecular mechanisms controlling the host immune response to P. aeruginosa infections are not completely understood. In our previous study, early growth response 1 (Egr-1) and regulator of calcineurin 1 (RCAN1) were found to positively and negatively regulate the inflammatory responses, respectively, during P. aeruginosa pulmonary infection, and both of them had an impact on activating NF-κB pathway. Herein, we examined the inflammatory responses of Egr-1/RCAN1 double knockout mice using a mouse model of P. aeruginosa acute pneumonia. As a result, the Egr-1/RCAN1 double knockout mice showed reduced production of proinflammatory cytokines (IL-1β, IL-6, TNF and MIP-2), diminished inflammatory cell infiltration and decreased mortality, which were similar to those of Egr-1-deficienct mice but different from those of RCAN1-deficient mice. In vitro studies demonstrated that Egr-1 mRNA transcription preceded RCAN1 isoform 4 (RCAN1.4) mRNA transcription in macrophages, and the macrophages with Egr-1 deficiency exhibited decreased RCAN1.4 mRNA levels upon P. aeruginosa LPS stimulation. Moreover, Egr-1/RCAN1 double-deficient macrophages had reduced NF-κB activation compared to RCAN1-deficient macrophages. Taken together, Egr-1 predominates over RCAN1 in regulating inflammation during P. aeruginosa acute lung infection, which influences RCAN1.4 gene expression.