Depletion of NK cells attenuates paraquat-induced acute lung injury by manipulating macrophage polarization

Acute lung injury is the main causative factor in paraquat dichloride (PQ)-induced mortality. The innate immune system-triggered detrimental inflammatory cascade plays a vital role in PQ-induced acute lung injury. However, the role of natural killer (NK) cells, which are essential for innate response, in PQ-induced acute lung injury remains largely unknown. Here, we found that in an acute PQ poisoning model, depletion of NK cells attenuated PQ-induced lung injury by inhibiting macrophage polarization towards the M1 type. Specifically, the percentages of NK cells were reduced in the lung, spleen, and peripheral blood in a murine model of acute PQ poisoning. NK cells were aberrantly activated, evidenced by upregulation of the activating markers CD69, CD107a, and NKG2D and downregulation of the inhibitive marker KLRG1. Further, NK-specific depletion in mice greatly prolonged the survival time and ameliorated reactive oxygen species-induced damage following PQ treatment compared with the control group. Importantly, NK cell depletion alleviated macrophage and neutrophil infiltration in the lung and reversed PQ induced-macrophage polarization towards the pro-inflammatory M1 type. Our study demonstrates a crucial role of NK cells and NK cell-to-macrophage interaction in PQ-induced acute lung injury.