Nicotinamide phosphoribosyltransferase inhibitor is a novel therapeutic candidate in LPS-induced neutrophil extracellular traps

Abstract

Neutrophil extracellular traps (NETs) are beneficial antibacterial defense structures. However, excessive NETs have also been linked to tissue damage and organ dysfunction. LPS and Gram-negative bacteria induce the formation of reactive oxygen species (ROS)-dependent NETs via the JNK pathway. It was found previously that knockdown of nicotinamide phosphoribosyltransferase (NAMPT) upregulates surfactant protein B (SFTPB or SP-B) and attenuates LPS-induced acute lung injury (ALI) via inhibiting JNK activation. This study investigated the effect of FK866, an intracellular NAMPT inhibitor, on the formation of LPS-induced NETs in mouse bronchoalveolar lavage (BAL) neutrophils and in differentiated HL-60 cells. The results show that inhibition of NAMPT by FK866 suppresses NETs formation in BAL neutrophils from the mice exposed to LPS. FK866 also suppresses NETs formation in the differentiated HL-60 cells stimulated with LPS. Additional data indicate that these effects are mediated by suppressing ROS production at least partly via inhibiting JNK activation and depleting NAD(P)H. The utility of inhibition of intracellular NAMPT may be a potential therapy for LPS-induced NETs-related diseases.

Keywords: JNK pathway; acute lung injury; neutrophil extracellular traps; nicotinamide phosphoribosyltransferase inhibitor.