A Novel Role for the Nuclear Receptor, NR4A1, in Klebsiella pneumoniae Lung Infection

Abstract

Klebsiella pneumoniae is a Gram-negative bacterial pathogen and common cause of pneumonia and bacteremia. Increasingly, K. pneumoniae has become a public health concern due to its rate of nosocomial infection and emerging, broad-spectrum antibiotic resistance. The nuclear receptor NR4A1 exhibits functionality in a multitude of organ systems and is implicated as having a role in the immune response to bacterial infection, though its role in K. pneumoniae infection is unknown. To determine if Nr4a1 functions in response to K. pneumoniae pulmonary disease, we infected wild-type and Nr4a1-/- mice with K. pneumoniae and assessed bacterial growth, immune cell recruitment and function, and cytokine production. We found that Nr4a1-/- mice had increased bacterial burden in the lungs and spleen, though no differences in cell recruitment. Pro-inflammatory cytokines, Il1{beta} and Il6, as well as chemokine, Cxcl2, were significantly decreased in the BAL fluid cells of Nr4a1-/- mice 5 hours post-infection. Additionally, Nr4a1-/- mice had reduced IL-1{beta} and myeloperoxidase protein production. We then examined the bactericidal function of macrophages and neutrophils from WT and Nr4a1-/- mice. We identified that Nr4a1-/- neutrophils had decreased bactericidal function compared to wild-type neutrophils, which was associated with reduced expression of Il1{beta}, Lcn2, Mpo, and Lyz2. These data suggest Nr4a1 plays a novel and essential role in neutrophil function during the host immune response to K. pneumoniae pulmonary infection.