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Abstract: FR-PO1000

Novel Role of ST2+ Tubular Cells in Shaping Immune Microenvironment

Session Information

Category: CKD (Non-Dialysis)

  • 2303 CKD (Non-Dialysis): Mechanisms


  • Sabapathy, Vikram, University of Virginia, Charlottesville, Virginia, United States
  • Costlow, Gabrielle, University of Virginia, Charlottesville, Virginia, United States
  • Herbert, Franklin Jebaraj, University of Virginia, Charlottesville, Virginia, United States
  • Mehkri, Bushra, 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

IL-33 is an ‘alarmin’ cytokine that regulates the immune response during injury. After release, IL-33 acts in an autocrine/paracrine manner on its membrane receptor (ST2 aka interleukin 1 receptor-like 1, IL1RL1), triggering innate and adaptive immune responses. ST2 expression is induced in tubular cells during chronic inflammation in various kidney diseases. However, the role of ST2+ tubular cells and their implication in chronic kidney injury (CKI) is poorly understood.


ST2fl/fl mice were crossed with PEPCKCre mice for proximal tubular cell (PTC)-specific ST2 deletion. Bilateral ischemia-reperfusion (IR) induced acute injury (AKI) and mice were euthanized 24hrs later. Unilateral ischemia-reperfusion injury simulated chronic injury, with contralateral nephrectomy performed on day 13 post-IRI. Kidney structure and function were analyzed using flow cytometry, histology, immunohistochemistry, gene expression, and biochemical analysis. In vitro, ST2-deficient and ST2-sufficient primary mouse PTC were subjected to ischemic conditions and assessed for metabolic fitness using Seahorse metabolic flux analyzer and cytokine production.


ST2's potential involvement in immune cell activation and mobilization to injury sites was investigated. Selective ST2 deletion in PTC, in acute and chronic injury models, resulted in reduced renal injury. In the chronic injury model, the absence of IL33/ST2 signaling in tubular cells led to decreased immune cell infiltration, reduced inflammatory cytokine production, and lower fibrosis. Interestingly, in vitro treatment of TKPTS, PTC cell-line with recombinant IL-33 increased metabolic fitness, indicated by higher oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in a dose-dependent manner. Additionally, IL-33 treatment paradoxically enhanced the expression of autophagy and mitochondria-related genes LC3, Beclin, and Rubicon in TKPTS cells. These findings underscore the intricate role of IL-33/ST2 biology in PTC.


ST2+ tubular cells play a crucial role in leukocyte trafficking to the injured kidneys. Our data provide novel information to suggest epithelial-immune cell crosstalk mediated through the IL-33/ST2 axis and identification of novel therapeutic targets.


  • NIDDK Support