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Kidney Week

Abstract: PO0381

IL-33/ST2 Alarmin Signaling Axis in Myeloid Cells Regulates Kidney Injury

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Sabapathy, Vikram, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Costlow, Gabrielle, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Cheru, Nardos Tesfaye, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Price, Airi, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Venkatadri, Rajkumar, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Dogan, Murat, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Mohammad, Saleh, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Sharma, Rahul, University of Virginia School of Medicine, Charlottesville, Virginia, United States
Background

Macrophages are a heterogeneous class of cells that play a vital role in inflammation, repair and fibrosis post-injury; however, their role in early and late phases of injury is not well understood. IL-33 is a nuclear-localized alarmin cytokine that is released upon tissue damage and signals through IL-1 receptor-like 1 (IL1RL1 or ST2). ST2 is expressed in a variety of cells, including myeloid cells. The role of IL-33/ST2 in regulation of macrophages in ischemia reperfusion injury (IRI) is unclear. Here, we studied the role of ST2+ macrophages using acute and chronic IRI models.

Methods

For myeloid cell-specific deletion of ST2, ST2fl/fl mice were crossed with LysM-Cre mice. Bilateral IRI (26min renal pedicle clamping and 24 hours reperfusion) was used to model acute kidney injury (AKI). Unilateral IRI (24min) was used for chronic injury studies. Contralateral nephrectomy was performed on day-13 post-IRI and the mice were euthanized 24hrs later for analyses. The structure and function of kidneys were probed using flow cytometry, histology, immunohistochemistry, quantitative gene expression, and biochemical analyses. The in vitro analyses were performed using peritoneal and bone-marrow-derived macrophages.

Results

Although global ST2 deficiency in mice showed reduced renal injury, it is challenging to ascertain the contribution of different cells involved in the inflammation and fibrosis process. Preliminary metanalysis of single cell RNA seq data indicated high expression of ST2 on renal macrophages. Therefore, we performed acute and chronic IRI studies on myeloid-cell specific deletion of ST2. Interestingly, loss of ST2 on myeloid cells also resulted in attenuation of acute renal injury. In vitro, efferocytosis assays on both peritoneal and bone-marrow derived macrophages demonstrated that loss of ST2 on macrophages resulted in a decrease in functional phagocytosis of apoptotic cells. Intriguingly, results from the chronic injury model showed that the absence of myeloid-ST2 resulted in exacerbated injury and fibrosis and a significant reduction in the immunoregulatory cells and cytokines.

Conclusion

The data suggest that ST2 signaling in macrophages is essential not only for the regulation of inflammation early on after injury but is also critical for immune-mediated resolution of injury in later stages.

Funding

  • NIDDK Support