Meteorin-like ameliorates acute bacterial lung infection by enhancing neutrophil function

RATIONALE: Bacterial pneumonia is a common acute respiratory infection. The role of Meteorin-like (METRNL) in bacterial pneumonia is unknown. OBJECTIVES: To investigate the clinical and functional role of METRNL in bacterial pneumonia. METHODS: METRNL levels were examined in the animals and patients with bacterial pneumonia. Multiple genetic and pharmacologic approaches were used to investigate METRNL-mediated host immune responses during bacterial pneumonia. MEASUREMENTS AND MAIN RESULTS: METRNL production was dramatically suppressed in response to acute bacterial lung infection. METRNL loss increased mortality and bacterial burden during Pseudomonas aeruginosa and Staphylococcus aureus pneumonia, but had no effects on Aspergillus fumigatus and influenza virus pnuemonia. Conversely, METRNL overexpression resulted in decreased mortality and bacterial burden from bacterial pneumonia. Furthermore, therapeutic administration of recombinant METRNL protein improved mortality and bacterial clearance in a neutrophil-dependent manner after bacterial pneumonia. METRNL enhanced bacterial phagocytosis and subsequent killing capacity of neutrophils, and conditional knockout of KIT receptor tyrosine kinase in neutrophils abolished METRNL-mediated protection against bacterial pneumonia. Furthermore, the increased antibacterial functions of neutrophils elicited by the METRNL-KIT axis was mediated through adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. The augmented antibacterial effects of METRNL on neutrophils were also confirmed in humans, and circulating METRNL levels were reduced in patients with bacterial pneumonia, which might serve as a new biomarker for patient stratification and therapeutic guidance. CONCLUSIONS: This study suggests that a potential theranostic approach involving METRNL-guided patient stratification and targeted therapy using METRNL rescue therapy may help improve the management of patients with bacterial pneumonia.