DEFICIENCY OF THE TRANSCRIPTION FACTOR NR4A1 ENHANCES BACTERIAL CLEARANCE AND PREVENTS LUNG INJURY DURING ESCHERICHIA COLI PNEUMONIA

摘要

Background: Bacterial pneumonia is one of the most common diagnoses and a leading cause of death in the intensive care unit. NR4A1 is an early response gene that has been identified as a vital regulator of immune and inflammatory responses. This study aims to explore the role of NR4A1 in Escherichia coli (E. coli) pneumonia. Methods: Alveolar macrophages (AMs) were isolated from wild-type (WT) and NR4A1 knock out (Nr4a1(-/-)) mice, and the NR4A1 expression and phagocytic capacity against E. coli were measured in vitro. WT and Nr4a1(-/-) mice were subjected to E. coli or sham pneumonia. Bacterial load, lung injury severity, inflammatory cell infiltration, and cytokines were assessed at 0, 4, and 18h after surgery. Survival rates within 48 h were evaluated in WT and Nr4a1(-/-) mice. In addition, NR4A1 antagonist (DIM-C-pPhCO2Me) was also used to confirm the role of NR4A1 in vivo and ex vivo. Results: NR4A1 was rapidly induced in AMs at 15 min after E. coli stimulation. Compared with untreated WT AMs, NR4A1 deficiency and DIM-C-pPhCO2Me treatment showed an enhanced phagocytic function (47.72 +/- 0.74% vs. 62.3 +/- 0.9%, P < 0.001; 11.79 +/- 1.21% vs. 30.08 +/- 0.79%, P < 0.001, respectively) at 30 min after the E. coli challenge in vitro. NR4A1 deficiency significantly improved the survival rate (33.3% in WT vs. 82.4% in Nr4a1(-/-), P < 0.01), which is comparable with DIM-C-pPhCO2Me pretreatment. The survival advantage of Nr4a1(-/-) mice was associated with decreased bacterial burden and inflammation and alleviated lung damage. Conclusions: These data demonstrate that NR4A1 impairs the phagocytic capacity of AMs and disrupts the host defense against invading bacteria, worsening the outcome of E. coli pneumonia in mice.