Dendritic cells tolerized with adenosine A2AR agonist attenuate acute kidney injury
Li Li, Liping Huang, Hong Ye, Steven P. Song, Amandeep Bajwa, Sang Ju Lee, Emily K. Moser, Katarzyna Jaworska, Gilbert R. Kinsey, Yuan J. Day, Joel Linden, Peter I. Lobo, Diane L. Rosin, Mark D. Okusa
Li Li, Liping Huang, Hong Ye, Steven P. Song, Amandeep Bajwa, Sang Ju Lee, Emily K. Moser, Katarzyna Jaworska, Gilbert R. Kinsey, Yuan J. Day, Joel Linden, Peter I. Lobo, Diane L. Rosin, Mark D. Okusa
View: Text | PDF
Research Article

Dendritic cells tolerized with adenosine A2AR agonist attenuate acute kidney injury

Abstract

DC-mediated NKT cell activation is critical in initiating the immune response following kidney ischemia/reperfusion injury (IRI), which mimics human acute kidney injury (AKI). Adenosine is an important antiinflammatory molecule in tissue inflammation, and adenosine 2A receptor (A2AR) agonists protect kidneys from IRI through their actions on leukocytes. In this study, we showed that mice with A2AR-deficient DCs are more susceptible to kidney IRI and are not protected from injury by A2AR agonists. In addition, administration of DCs treated ex vivo with an A2AR agonist protected the kidneys of WT mice from IRI by suppressing NKT production of IFN-γ and by regulating DC costimulatory molecules that are important for NKT cell activation. A2AR agonists had no effect on DC antigen presentation or on Tregs. We conclude that ex vivo A2AR–induced tolerized DCs suppress NKT cell activation in vivo and provide a unique and potent cell-based strategy to attenuate organ IRI.

Authors

Li Li, Liping Huang, Hong Ye, Steven P. Song, Amandeep Bajwa, Sang Ju Lee, Emily K. Moser, Katarzyna Jaworska, Gilbert R. Kinsey, Yuan J. Day, Joel Linden, Peter I. Lobo, Diane L. Rosin, Mark D. Okusa

×

Figure 2

Suppression of DC-NKT interaction in vivo by A2AR activation or by treatment of mice with A2AR-activated αGC-loaded BMDCs protects kidneys from IRI.

Options: View larger image (or click on image) Download as PowerPoint
Suppression of DC-NKT interaction in vivo by A2AR activation or by treat...
(A) WT mice were pretreated with A2AR agonist ATL146e (10 ng/kg/min, osmotic mini-pump, s.c.) 24 hours prior to kidney IRI surgery. IFN-γ–producing live CD45+7-AAD–CD1d-tetramer+TCRβ+ NKT cell number was measured by FACS 24 hours after sham surgery or after 28 minutes of kidney ischemia. Values are mean ± SEM. n = 3–5. (B) Pretreatment of WT mice with vehicle (saline) or the A2AR agonist ATL313 (1 ng/kg/min, osmotic mini-pump, s.c.) was initiated at the onset of adoptive transfer of BMDCs loaded with αGC (DC-αGC) or vehicle (DC); mini-pumps were removed 2 days later, and then mice were subjected to sham surgery or subthreshold (26 minutes ischemia) mild IRI. Plasma creatinine was measured 24 hours after sham or IRI surgery. Values are mean ± SEM. n = 2–4. (C and D) WT or Adora2a–/– DCs were primed ex vivo with vehicle (DC) or αGC in the presence (DC-αGC-ATL313) or absence (DC-αGC) of ATL313 (1 nM), incubated for 2.5 days, washed, and adoptively transferred to WT mice 2 days prior to kidney surgery. WT mouse kidneys were subjected to 26 minutes of subthreshold ischemia followed by 24 hours of reperfusion. (C) Plasma creatinine was measured 24 hours after sham operation or IRI. Values are mean ± SEM. n = 5–15. **P < 0.001. (D) Representative morphology (by H&E staining) of kidney outer medulla 24 hours after sham operation or IRI. Scale bar: 100 μm. Original magnification, ×2 (insets).