CCR5+ NK cells drive hypoxemia in endotoxin-induced acute lung injury

Acute lung injury (ALI) is a life-threatening clinical syndrome characterized by intense inflammation and pulmonary physiologic dysfunction. While innate immune cells dominate early ALI pathology, lymphocytes are increasingly recognized as important contributors. Prior work demonstrated that natural killer (NK) cells are recruited through CCR5 leading to damage following ischemic lung injury. As endotoxin-induced ALI is an important pre-clinical model for acute respiratory distress syndrome (ARDS), here we asked whether NK cells recruited through CCR5 mediated injury in this clinically relevant model. We examined CCR5 and NK cells in a C57BL/6 mouse model of endotoxin-induced ALI using spectral flow cytometry and genetic knockout animals. We found that CCR5 ligands and CCR5 NK cells were increased during ALI relative to no-injury control mice. CCR5-positive NK cells had markers of tissue residence and CCR5 inhibition reduced NK cell trafficking as measured in the bronchoalveolar lavage. Further, CCR5 inhibition ameliorated lung injury across all domains. CCR5 inhibition had less of an impact on T cell trafficking, and these cells had relatively less CCR5 expression. Adoptive transfer of Ccr5-null NK cells preceding ALI resulted in reduced trafficking and injury compared to wildtype transfers. NK cell depletion and CCR5 inhibition were effective even when administered 2 hours after LPS administration. indicating potential relevance for clinical translation. In summary, this study cements CCR5-positive NK cells as mechanistically important in a clinically relevant acute lung injury model. Inhibition of CCR5-positive NK cells may have translational application for some ARDS endotypes.