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Abstract: FR-PO375

Modeling ST2/IL-33 "Alarmin" Signaling Through Kidney Organoid-Immune Cell Co-Culture System

Session Information

Category: Development‚ Stem Cells‚ and Regenerative Medicine

  • 500 Development‚ Stem Cells‚ and Regenerative Medicine

Authors

  • Sabapathy, Vikram, University of Virginia, Charlottesville, Virginia, United States
  • Costlow, Gabrielle, University of Virginia, Charlottesville, Virginia, United States
  • Mohammad, Saleh, University of Virginia, Charlottesville, Virginia, United States
  • Sharma, Rahul, University of Virginia, Charlottesville, Virginia, United States
Background

Renal diseases are a major cause of morbidity and mortality worldwide. Inflammation elicited by a variety of cytokines and chemokines is a major player in the initiation and progression of the disease. Interleukin 33 (IL-33) belongs to the IL-1 family of cytokines, which acts as an ‘alarmin that regulates the immune response during injury. Released during injury-response, cytokine IL-33 acts in an autocrine/paracrine manner through membrane receptor (ST2) aka IL33R or IL-1 receptor-like 1 (IL1RL1), triggering an inflammatory response. ST2 is widely expressed in many cells including regulatory T cells (Tregs), which constitute a major anti-inflammatory mechanism. Although, it's been demonstrated in various studies that Tregs play a crucial role in mitigating renal injury. There is no evidence determining the role of the ST2/IL33 axis in Tregs during kidney injury.

Methods

In this study, we attempt to delineate the role of the ST2 pathway in Tregs using murine renal injury model and kidney organoids.

Results

By RNA sequencing analysis it was observed that ST2-high Tregs had higher expression of regenerative factors such as amphiregulin (AREG) and Growth/differentiation factor (GDF15). The in vivo ischemic renal injury experimental data indicated that loss of ST2/IL33 signaling from Tregs resulted in exacerbation of renal injury leading to worsening of renal function. Co-culture of kidney organoids with ST2+ Tregs protected cellular viability under invitro ischemia-reoxygenation conditions compared to ST2- Tregs. We observed that the addition of secretome from ST2+ Tregs in kidney organoid cultures improves cellular viability during in vitro hypoxic injury. Secretome analysis indicated elevated levels of AREG in spent media of ST2+ Tregs cultures. Our data shows that AREG treatment protected kidney organoids from cisplatin-induced apoptosis in a dose-dependent manner and mediates tubular cell plasticity.

Conclusion

Activation of IL-33/ST2 signaling axis in Tregs is essential for the regulation of inflammation, apoptosis, and repair in renal tissue during inflammation and injury.

Funding

  • NIDDK Support