Mechanisms of NK cell-mediated injury in ischemia reperfusion injury in the kidney

Abstract

Acute Kidney Injury (AKI) is a major concern in today’s healthcare system and is caused by various conditions such as trauma, major surgery, and sepsis. Regardless of causation, fifty percent of AKI cases are induced by ischemia, resulting in necrosis and apoptosis of nephrons, the functional units of the kidney. I employ a novel hanging weight model of AKI that, recapitulates the pathogenesis and clinical manifestations of ischemia reperfusion injury (IRI). Through these studies, we highlight NK cell activity and their direct contributions to damage in IRI of the kidney. NK cells are innate lymphoid cells that are important for immune surveillance, detecting cells that have been altered by stress, infection, and/or transformation. A direct outcome of IRI is hypoxia, which induces the expression of stress markers that can be recognized by NK cells. To assess the role of NK cells in AKI, we depleted NK cells using anti-NK1.1 depleting antibody and showed kidney dysfunction was ameliorated after 1 day of reperfusion. Protective effects of anti-NK1.1 were due to ablation of NK cells and not NKT cells. We further interrogated recently described NK cell subsets, conventional (cNK) and tissue-resident (trNK) cells, and show robust depletion of both NK cell subsets using anti-NK1.1 antibody. Further analysis of NK cell subsets show trNK cells express higher levels of activation markers and reduced inhibitory markers, making them primed to induce injury. Through phenotypic analysis, I show that cNK cells highly express asialo-GM1 (AsGM1) with differential expression on trNK cells. Further investigation of AsGM1 expression shows that this occurs across multiple organs and genetic backgrounds in the mouse. Indeed, anti-AsGM1 antibody treatment resulted in a robust depletion of cNK cells, leaving trNK cells largely intact. This method of NK cell depletion demonstrates that trNK are sufficient to mediate kidney dysfunction after IRI. These data demonstrate that despite being numerically small, trNK cells are potent inducers of injury, and may play a role in other models where αAsGM1 depleting regimens were used to deplete NK cells.