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Abstract: FR-PO099

Multifaceted Role of ST2/IL-33 Axis During Kidney Injury

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Sabapathy, Vikram, Division of Nephrology and CIIR, Charlottesville, Virginia, United States
  • Venkatadri, Rajkumar, Division of Nephrology and CIIR, Charlottesville, Virginia, United States
  • Dogan, Murat, Division of Nephrology and CIIR, Charlottesville, Virginia, United States
  • Mohammad, Saleh, Division of Nephrology and CIIR, Charlottesville, Virginia, United States
  • Cheru, Nardos Tesfaye, National Institutes of Health, Bethesda, Maryland, United States
  • Price, Airi, Division of Nephrology and CIIR, Charlottesville, Virginia, United States
  • Stevens, Brian K., Division of Nephrology and CIIR, Charlottesville, Virginia, United States
  • Sharma, Rahul, Division of Nephrology and CIIR, Charlottesville, Virginia, United States
Background

Renal diseases are a major cause of morbidity and mortality. Inflammation elicited by variety of cytokines and chemokines are a major player in initiation and progression of the disease. Interleukin 33 (IL-33) belongs to IL-1 family of cytokines, which was identified for eliciting T helper-2 (Th2) cytokines. IL-33 acts as an ‘alarmin’ that regulates the immune response during injury. IL-33 acts in an autocrine/paracrine manner on the ST2 membrane receptor IL33R or Il1rl1, triggering innate and adaptive immune response. ST2 is widely expressed in immune cells including regulatory T cells (Tregs). Importance of ST2/IL-33 signaling in Tregs has been demonstrated in multiple inflammatory conditions. However, cell specific contribution of ST2/IL33 signaling is not understood. Here, we investigated the cell specific ST2/IL33 signaling activity using murine renal injury models.

Methods

Murine ischemia-reperfusion injury (IRI) model was used to investigate cell specific ST2/IL-33 signaling using IL1RL1tm1a and cell specific Pepck, Foxd1 and Foxp3 -cre mice to delete ST2 expression in proximal tubular cells (PTC), pericytes and Tregs respectively. The structure and function of the kidney were probed using flow cytometry, histology, immunohistochemistry, qRT-PCR and biochemical analysis.

Results

In vivo experimental data indicated that deletion of ST2 in PTC and pericytes attenuated renal injury suggesting that activation of ST2/IL33 signaling in these cells leads to impaired renal function following IRI, leading to fibrosis. On the contrary, elimination of ST2/IL33 signaling from Tregs resulted in greater renal injury to the indicating that activation of ST2/IL33 signaling in Tregs mediate renal protection during inflammation and injury.

Conclusion

This study addresses the cell specific role of ST2/IL33 signaling in immune-regulation, fibrosis and repair. Our findings try to delineate the multifaceted role of ST2/IL33 axis in renal injury. We conclude modulation of ST2/IL33 siganling as a promising therapeutic option.

IL33/ST2 Signaling is a Double Edge Sword

Funding

  • NIDDK Support