Nuclear receptor 4A1 is Critical for Neutrophil-Dependent Pulmonary Immunity to Klebsiella pneumoniae Infection

Norie Sugitani ¹ Matthew Henkel ¹ Jessica Partyka ¹ Alexander Applegate ¹ Felicia Kemp ¹ Craig Alan Byersdorfer ^1,2 Taylor Eddens ¹ Brian Thomas Campfield ^1*

• ¹ School of Medicine, University of Pittsburgh, Pittsburgh, United States
• ² University of Minnesota Health Sciences, University of Minnesota Medical Center, Minneapolis, Minnesota, United States

Bacterial pneumonia is a burdensome, costly disease and increasingly challenging to treat due to antibiotic resistance. Complex host-pathogen interactions regulate protective immunity, and immune-directed therapies could yield novel treatments. Neutrophils play a central role in pulmonary bacterial immunity, and mechanistic understanding of neutrophil antibacterial functions in pneumonia has potential clinical and fundamental application. Nuclear receptor 4a1 (Nr4a1), a member of the nuclear orphan receptor family, has been described to regulate inflammation and immune development in a cell type-specific manner, but its role in pulmonary host defense is not well understood. This study demonstrates that Nr4a1 is essential for protection against K. pneumoniae as Nr4a1 -/-mice showed increased lung bacterial burden, dissemination, and reduced survival. Notably, neutrophil-specific Nr4a1 expression was critical for defense against K. pneumoniae infection by regulating the neutrophil transcriptome. These findings suggest targeting neutrophil-specific Nr4a1 may be beneficial for bacterial pneumonia treatment.