Human Milk Proresolving Mediators Stimulate Resolution of Acute Inflammation

Abstract

Human milk contains nutrients and bioactive products relevant to infant development and immunological protection. Here, we investigated the pro-resolving properties of milk using human milk lipid mediator isolates (HLMI) and determined their impact on resolution programs in vivo and with human macrophages. HLMI reduced maximum neutrophil numbers (14.6±1.2×106 to 11.0±1.0×106 cells/exudate) and shortened the resolution interval (Ri; 50% neutrophil reduction) 54% compared to peritonitis. Using rigorous liquid-chromatography tandem-mass spectrometry (LC-MS-MS)-based lipid mediator (LM) metabololipidomics, we demonstrated that human milk possesses a proresolving LM-SPM signature profile, containing specialized proresolving mediators (SPM; e.g. resolvins, protectins, maresins and lipoxins) at bioactive levels (pico-nanomolar concentrations) that enhanced human macrophage efferocytosis and bacterial containment. SPM identified in human milk included D-series resolvins, (e.g. Resolvin (Rv) D1, RvD2, RvD3, AT-RvD3 and RvD4), Protectin (PD)1, Maresin (MaR)1, E-series resolvins (e.g. RvE1, RvE2 and RvE3) and lipoxins (LXA4 and LXB4). Of the SPM identified in human milk, RvD2 and MaR1 (50 ng/mouse) individually shortened Ri ~75%. Milk from mastitis gave higher LTB4 and prostanoids and lower SPM levels. Taken together, these findings provide evidence that human milk has pro-resolving actions via comprehensive LM-SPM profiling, describing a potentially novel mechanism in maternal-infant biochemical imprinting.