NK Cells Induce Apoptosis in Tubular Epithelial Cells and Contribute to Renal Ischemia-Reperfusion Injury

Abstract

Renal ischemia-reperfusion injury (IRI) can result in acute renal failure with mortality rates of 50% in severe cases. NK cells are important participants in early-stage innate immune responses. However, their role in renal tubular epithelial cell (TEC) injury in IRI is currently unknown. Our data indicate that NK cells can kill syngeneic TEC in vitro. Apoptotic death of TEC in vitro is associated with TEC expression of the NK cell ligand Rae-1, as well as NKG2D on NK cells. In vivo following IRI, there was increased expression of Rae-1 on TEC. FACS analyses of kidney cell preparations indicated a quantitative increase in NKG2D-bearing NK cells within the kidney following IRI. NK cell depletion in wild-type C57BL/6 mice was protective, while adoptive transfer of NK cells worsened injury in NK, T, and B cell-null Rag2−/−γc−/− mice with IRI. NK cell-mediated kidney injury was perforin (PFN)-dependent as PFN−/− NK cells had minimal capacity to kill TEC in vitro compared with NK cells from wild-type, FasL-deficient (gld), or IFN-γ−/− mice. Taken together, these results demonstrate for the first time that NK cells can directly kill TEC and that NK cells contribute substantially to kidney IRI. NK cell killing may represent an important underrecognized mechanism of kidney injury in diverse forms of inflammation, including transplantation.

Inflammation in AKI

“…Blockade of TLR2, however, has recently been tested in humans and is in phase 2 trials in the United States and Europe (OPN-305; Opsona Therapeutics). 31 Virtually all immune cells have been implicated in AKI, and some are thought to be deleterious (e.g., neutrophils, 10,16 monocytes/macrophages, 25,32 DCs, 33,34 NKT cells, 17,35 NK cells, 19 and B cells 18,36 ), whereas others are likely protective (e.g., Tregs 20,21 ). Others, such as macrophages, play different roles depending on the type and time at which they arrive in the injured tissue.…”

“…6,11 However, responses of almost equal rapidity occur from the bloodstream involving endothelial adherence and activation of neutrophils and monocytes as well as intraparenchymal infiltration by neutrophils, monocytes, effector memory T cells, and other less frequent myeloid and lymphoid effectors. 6,[15][16][17][18][19] The initial activation-induced responses of these resident and recruited immune cells are typically dominated by the production of archetypal proinflammatory mediators (cytokines, chemokines, enzymes, free radical species, and lipid mediators) with high cytotoxic potential, which tend to amplify and extend cell damage and cell death. 4,6 In this manner, the phase of acute inflammatory response may be seen as consolidating and worsening organ dysfunction after injury.…”

RIPK3-Mediated Necroptosis Regulates Cardiac Allograft Rejection

“…Slides were scored by a pathologist in a blinded fashion (0: no change, 1þ: <25% area change, 2þ: 25-50% area change, 3þ: 50-75% area change, 4þ: 75% area change) (34,36). Criteria for allograft injury included endothelial cell damage, infarction, lymphocyte infiltrate, fibrosis, thrombosis, hemorrhage and myocyte damage.…”

The Impact of Ischemia and Reperfusion Injury in Kidney Allograft Outcome

“…IRI induced the expression of an NK cell-activating ligand (Rae-1) on tubule epithelial cells (TECs) and in vitro studies demonstrated that the interaction of the NKG2D receptor on NK cells with Rae-1 on TECs causes perforin-dependent lysis of cultured kidney cells. Antibody-mediated depletion of NK cells inhibited IRI in wild-type (WT) mice and adoptive transfer of WT, but not perforin KO, NK cells into a T, B and NK cell-deficient mouse enhanced IRI (Zhang et al, 2008).…”