Follistatin-like 1 Promotes Neutrophil-mediated Host Defense against Klebsiella pneumoniae

Klebsiella pneumoniae is a leading cause of pneumonia and highly burdensome etiology of antibiotic-resistant infections constituting an urgent public health threat. Follistatin-like 1 (FSTL-1) is implicated in many processes including lung development and homeostasis, tissue remodeling, and inflammation though its role in antibacterial immunity remains poorly defined. We have observed that FSTL-1 is elevated in the lungs of both humans and mice during bacterial pneumonia. Using an inducible Fstl1 knockout mouse model, we demonstrate that FSTL-1 is required for pulmonary bacterial clearance and neutrophil recruitment during K. pneumoniae infection. Recombinant FSTL-1 rescues Fstl1-deficient susceptibility and enhances clearance of K. pneumoniae in wild-type mice. Mechanistically, FSTL-1-mediated protection was lost upon neutrophil depletion and in Cd14-deficient or Nr4a1 deficient mice, components of a lung-specific neutrophil transcriptional program. These findings identify FSTL-1 as a lung-derived factor that licenses neutrophil-mediated antibacterial defense via a novel FSTL-1/CD14/NR4A1-dependent signaling pathway critical for protection against bacterial pneumonia.