Targeting NAMPT restrains inflammatory macrophage metabolism and attenuates acute lung injury

Abstract

Acute lung injury is a life-threatening inflammatory syndrome characterised by disruption of the alveolar–capillary barrier, pulmonary oedema and impaired gas exchange. Effective targeted therapies remain limited, partly because the metabolic requirements that sustain pathogenic inflammation are incompletely understood. Here we identify nicotinamide phosphoribosyltransferase (NAMPT)-dependent NAD⁺ salvage as an important regulator of inflammatory macrophage function in acute lung injury. Integrated analysis of human and mouse single-cell transcriptomic datasets showed that NAMPT was enriched in recruited inflammatory macrophages. In an LPS-induced acute lung injury model, pharmacological NAMPT inhibition with FK866 and Lyz2-Cre -mediated myeloid Nampt deletion attenuated pulmonary oedema, inflammatory-cell accumulation, alveolar injury and cytokine production and prolonged survival. In primary macrophages, pharmacological or genetic disruption of NAMPT reduced intracellular NAD⁺ availability, suppressed inflammatory effector responses and impaired responsiveness to secondary inflammatory challenge; the latter effect was reversible after NAD⁺ recovery. Metabolic analyses showed coordinated impairment of glycolysis and mitochondrial respiration, together with depletion of tricarboxylic acid cycle intermediates. These changes were accompanied by reduced mTORC1 downstream signalling and diminished HIF-1α abundance, and were partially restored by nicotinamide mononucleotide supplementation. Together, these findings identify NAMPT-dependent NAD⁺ metabolism as a key requirement for inflammatory macrophage bioenergetics and support temporally restricted, cell-selective NAMPT targeting as a potential strategy for acute inflammatory lung injury.