Kidney Week

Abstract: SA-PO074

Paradoxical Role of Myeloid Cell PD-L1 Expression in AKI

Session Information

• AKI: Inflammation and Cell Cycle
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Pelletier, Oliver B., University of Virginia School of Medicine, Charlottesville, Virginia, United States

Oliver B. Pelletier, PhD

• Herbert, Franklin Jebaraj, University of Virginia School of Medicine, Charlottesville, Virginia, United States

Franklin Jebaraj Herbert, MSc, PhD

• Sabapathy, Vikram, University of Virginia School of Medicine, Charlottesville, Virginia, United States

Vikram Sabapathy, PhD

• Mehkri, Bushra, University of Virginia School of Medicine, Charlottesville, Virginia, United States

Bushra Mehkri, MS

• Sharma, Rahul, University of Virginia School of Medicine, Charlottesville, Virginia, United States

Rahul Sharma, MS, PhD

Background

Blocking of immune checkpoint molecules Programmed Death-1 (PD-1) and its ligands PD-L1 and PD-L2 have revolutionized cancer therapy via activation of anti-tumor immunity. However, this checkpoint inhibitor therapy also led to increase in immune check-point inhibitor (ICPI)-associated inflammatory diseases including acute kidney injury (AKI) suggesting a protective role of PD-1 and its ligands in AKI. While PD-1 is mainly expressed on T-cells, PD-L1 and PD-L2 are expressed on tumor, stromal, and immune cells including myeloid cells. Treatment of mice with antibodies to PD-1, PD-L1 and PD-L2 worsens ischemia reperfusion injury (IRI). Expression of PD-1 on the T-regulatory cells (Tregs) is important for protection from IRI (ASN Kidney week 2020, PO-0152). However, the role of PD-L1 expression on myeloid cells, as related to AKI remains a knowledge gap.

Methods

To investigate the role of PD-L1 expression on myeloid cells, we generated mice with deletion of PD-L1 in myeloid cells using lysozyme-driven Cre (LysM-Cre) to generate PD-L1^fl/fl.LysM-Cre mice. Mice were subjected to unilateral IRI and euthanized on day 14 after nephrectomy of contralateral kidney on day 13 or subjected to Cisplatin-induced renal injury. Blood, spleen and kidneys were analyzed for immunophenotype, and kidneys were analyzed for inflammation and injury by flow cytometry, histopathology and quantitative PCR.

Results

Deletion of PD-L1 in myeloid cells resulted in an overall inflammatory phenotype in mice as represented by lymphadenopathy and splenomegaly with greater accumulation of activated and memory T-cells that produced more proinflammatory cytokines. However, despite the inflammatory conditions, PD-L1^fl/fl.LysM-Cre mice displayed lower levels of injury and kidney dysfunction as compared to PD-L1 sufficient mice with IRI or cisplatin. While the infiltration of neutrophils in the PD-L1 deficient mice was lower, the infiltration of monocytes was significantly higher. Interestingly, the dendritic cells in the spleen and kidneys of PD-L1 deficient mice expressed lower levels of co-stimulatory molecules suggesting of lower activation status.

Conclusion

The data reveals a paradoxical role of PD-L1 expression in myeloid cells in promoting ischemic and cisplatin AKI, such that myeloid-cell specific deletion of PD-L1 was protective in AKI via promoting a tolerogenic milieu.

Funding

• NIDDK Support