Innate Cytokine Induced Early Release of IFNγ and CC Chemokines from Hypoxic Human NK Cells Is Independent of Glucose

Abstract

Natural killer (NK) cells are among the first innate immune cells to arrive at sites of tissue inflammation and regulate the immune response to infection and tumors by the release of cytokines including interferon (IFN)γ. In vitro exposure to the innate cytokines interleukin 15 (IL-15) and IL-12/IL-18 enhances NK cell IFNγ production which, beyond 16 h of culture, was shown to depend on metabolic switching to glycolysis. NK effector responses are, however, rapid by comparison. Therefore, we sought to evaluate the importance of glycolysis for shorter-term IFNγ production, considering glucose deprivation and hypoxia as adverse tissue inflammation associated conditions. Treatments with IL-15 for 6 and 16 h were equally effective in priming early IFNγ production in human NK cells in response to secondary IL-12/IL-18 stimulation. Short-term priming was not associated with glycolytic switching but induced the release of IFNγ and, additionally, CCL3, CCL4 and CCL5 from both normoxic and hypoxic NK cells in an equally efficient and, unexpectedly, glucose independent manner. We conclude that release of IFNγ and CC chemokines in the early innate immune response is a metabolically autonomous NK effector program.

Human cytokine-induced memory-like NK cells preserve increased glycolysis but the glycolytic-dependence of their effector functions differ between stimuli

“…One We first decided to analyze the expression of nutrient transporters. Our data is in accordance with results published by others, confirming that the expression of nutrient transporters in NK cells can be upregulated in response to different stimuli 30,33,[37][38][39][40][41][42][43]46 .…”

“…Considering that metabolism supports cellular functions, we hypothesized that CIML NK cells may also differ in their metabolic profile. Others have previously reported that NK cell stimulation induced an increase in the glycolytic activity 30,32,33,37,39,43,46,50 Our experiments were performed in a system with optimal conditions for NK cells.…”

“…Previous studies have shown that NK cells can modify the expression of nutrient transporters following cytokine-stimulation 30,[37][38][39][40][41][42][43] . 13,20,22,25,26 .…”

Activated Natural Killer Cells Withstand the Relatively Low Glucose Concentrations Found in the Bone Marrow of Multiple Myeloma Patients

“…A previous study using murine NK cells showed that inhibition of glycolysis reduced IFN-γ production by NK cells when triggered by engagement of activating receptors while cytokine (IL-12/IL-18)-induced IFN-γ production remained unaffected by inhibition of glycolysis ( 23 ). Similar to murine NK cells, human cytokine-activated NK cells continued to produce IFN-γ when exposed to short-term glucose deprivation of 4 hours ( 35 ) or long-term low glucose levels (as low as 0.01 mM) for two days ( 36 ). However, CD56bright NK cells showed a defective IFN-γ production when the glycolysis rate was limited for a period of 18 hours ( 25 ) underlining the difference between CD56dim and CD56bright NK cells.…”

A role for metabolism in determining neonatal immune function

“…54 In human NK cells, early cytokine responses can occur independent of glucose. 55 Long-term activation of NK cells upregulates both OXPHOS and glycolysis to meet the metabolic demands of effector function 56 supported by increased expression of nutrient transporters such as GLUT1, CD98 and CD71 following stimulation. 56,57 Inhibition of OXPHOS limits NK cell IFNγ production and degranulation, whereas glycolytic inhibition impairs cytotoxic functions such as target cell killing and degranulation.…”