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Abstract: FR-PO950

IL-33 (Interleukin 33)/ST2 (Interleukin 1 Receptor-Like 1) "Alarmin" Signaling Axis Regulates Innate Immune Response in Kidney Injury

Session Information

  • CKD: Pathobiology - I
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms


  • 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
  • Arandjelovic, Sanja, University of Virginia, Charlottesville, Virginia, United States
  • Sharma, Rahul, University of Virginia, Charlottesville, Virginia, United States

Macrophages (MΦs) following kidney injury play a vital role in inflammation, repair, and fibrosis. MΦs are a highly heterogeneous class of cells that are activated upon tissue injury or inflammation. IL-33 is a nuclear-localized ‘alarmin’ cytokine that is typically released upon tissue damage. IL-33 signals through a receptor complex of IL-1 receptor-like 1 (IL1RL1), also known as ST2. ST2 is expressed in a variety of immune cells, including myeloid-derived cells such as MΦs. The MΦ regulation by IL-33 following its release with respect to kidney injury is uknown.


For myeloid cell-specific deletion of ST2, ST2fl/fl mice were crossed with LysMCre mice. To examine the physiological relevance of endogenously expressed ST2+ myeloid cells during renal injury, we performed acute and chronic ischemia perfusion injury studies. The structure and function of the kidney were probed using flow cytometry, histology, immunohistochemistry, quantitative gene expression, and biochemical analysis. The invitro efferocytosis assay, RNA Seq, and seahorse assay were carried out using peritoneal MΦs and bone-marrow-derived MΦs.


We hypothesized that the ST2 receptor could play a vital role in activating and mobilizing immune cells to the injury site. Preliminary results from metanalysis of single-cell RNA seq data analysis indicated high expression of ST2 receptor on macrophages. The in vivo data from the acute injury model indicated a loss of ST2 on myeloid cells resulted in attenuation of renal injury. On the contrary, results from the chronic injury model showed absence of IL33/ST2 signaling resulted in exacerbation of injury. Intriguingly, efferocytosis assay on both peritoneal and bone-marrow-derived MΦs demonstrated loss of ST2 on MΦs, resulting in a decrease in functional phagocytosis. Through seahorse assay, it was also observed that ST2 deficient peritoneal macrophages exhibited altered mitochondrial metabolism. RNA-seq data and gene ontology analysis showed loss of ST2 affects critical genes responsible for macrophage homeostasis.


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


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