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Kidney Week

Abstract: TH-PO101

Kidney-Protective Vagus Nerve Stimulation Modulates Splenic Immune Populations and Reduces IFNγ Production in Response to Toll-like Receptor Agonists

Session Information

  • AKI: Mechanisms - I
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Nash, William, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Tanaka, Shinji, University of Tokyo Graduate School of Medicine, Bunkyo City, Tokyo, Japan
  • Okusa, Mark D., University of Virginia School of Medicine, Charlottesville, Virginia, United States
Background

Vagus nerve stimulation (VNS) prior to injury is able to reduce inflammation and protect mice from acute kidney injury (AKI). This protection requires an intact spleen since splenectomy prior to VNS and AKI removes the protection. Since the immune system and spleen are closely intertwined, we sought to identify alterations in splenic immune cells post-VNS to gain insight into the potential anti-inflammatory and kidney-protective effects of VNS.

Methods

Mice underwent VNS or sham surgery. The vagus nerve was exposed at the neck and electrodes placed on it. Electrical pulses were delivered for 10 minutes, sham mice did not receive pulses. After 48 hours, spleens were processed into single cell suspensions. An aliquot was assessed via flow cytometry to quantify immune cell populations. The rest was used to seed 96-well plates for ex vivo stimulation. 7.5x105 cells were plated per well and incubated with agonists for toll-like receptors (TLR). Each well received either vehicle control or an agonist to TLR3, 4, or 9. After 20-24 hours, media from each well was collected for cytokine concentration analysis via 32-plex Luminex assay.

Results

Spleens from VNS-treated mice weighed less (sham avg=0.064±0.01 g; VNS avg=0.046±0.01 g) and exhibited reduced abundance of most splenic immune cell populations. The most significantly impacte were T cells (p=0.007), B cells (p=0.01), NK cells (p=0.01), dendritic cells (p=0.01), and basophils (p=0.02). Monocytes and eosinophils also showed trends toward lower numbers, but NKT cells, macrophages, and neutrophils exhibited no reduction. Ex vivo cytokine production was also depressed. The profile of cytokines affected varied depending on TLR agonist, but a subset exhibited common regulation across multiple TLR-stimulation conditions (IFNγ, CCL2, CXCL9, VEGF, CCL3, CXCL10, GM-CSF, CCL4, IL-10, and IL-9). In particular, IFNγ production was decreased in all conditions tested.

Conclusion

VNS modulates immune cell abundance and suppresses cytokine production profiles in response to TLR agonists, which may contribute to establishing an anti-inflammatory state. Our results indicate VNS can dynamically control the inflammatory capacity of immune cells and the apparent ubiquitous impact on IFNγ provides a good candidate for further mechanistic investigation into the kidney-protective effects of VNS.

Funding

  • NIDDK Support