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Kidney Week

Abstract: SA-PO169

An IL10Ra-Mediated Regulation of T Regulatory Cells by Myeloid Cells in AKI

Session Information

  • AKI: Mechanisms - III
    November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Herbert, Franklin Jebaraj, University of Virginia, Charlottesville, Virginia, United States
  • Sabapathy, Vikram, University of Virginia, Charlottesville, Virginia, United States
  • Gautam, Jitendra K., University of Virginia, Charlottesville, Virginia, United States
  • Sander, Molly, 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
Background

IL-10 is a cytokine with multiple effects in immunoregulation and inflammation. IL-10 can protect the kidney from ischemia-reperfusion injury (IRI) - a condition that causes tubular injury and dysfunction due to hypoxia and inflammation. IL-10 binds to its receptor (IL-10R) on the cell surface and activates intracellular signaling pathways that suppress the production of pro-inflammatory cytokines and pro-apoptosis factors. However, the mechanistic role of IL10Ra has not been investigated in AKI, especially during the resolving phase.

Methods

We generated IL10Rafl/fl LysM-Cre mice for specific deletion of IL10Ra in myeloid cells and subjected them to bilateral or unilateral IRI (uIRI) followed by reperfusion for 13 days. The mice were analyzed for immunophenotypic, histopathological, biochemical, and molecular analysis to evaluate immune profile and pathophysiology. Bioenergetics with parameters of oxidative phosphorylation and glycolysis, along with Differentiation assays were performed to gain a mechanistic view of immunomodulation.

Results

Myeloid-cell-specific deletion of IL-10Ra led to a significant increase of CD4 effector memory cells and a marked reduction of regulatory T cells in the spleen as compared to IL-10Ra-sufficient controls. The expression of pro-inflammatory cytokines, co-stimulatory markers as well as activated CD8 T cells and CD8 effector memory T cells were also elevated in the KO mice as compared to the control. There were no differences observed in kidney function in KO mice subjected to bilateral IRI for 24 hours (Acute phase). However, when subjected to uIRI, the IL10Ra deletion led to reduced kidney function as shown by increased plasma Creatinine and BUN, increased tubular Injury score, and marked elevation of injury biomarkers KIM1 and NGAL. Interestingly, KO macrophages subjected to bioenergetics analysis revealed a reduction in mitochondrial respiration and altered potential in generating Foxp3+ T-regulatory cells (Tregs).

Conclusion

Our findings reveal a previously unrecognized link between mitochondrial dysfunction, Treg-differentiation, and IL10Ra signaling in resolving of AKI, and could also serve as a potential target for therapeutic modulation.