Kidney Week

Abstract: TH-OR05

Novel Anti-Inflammatory Effects of IL-1 Receptor in Kidney Myeloid Cells Following AKI

Session Information

• AKI Mechanisms: Cellular and Organ Cross-Talk
  November 02, 2023 | Location: Room 118, Pennsylvania Convention Center
  Abstract Time: 05:06 PM - 05:15 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Chen, Yanting, Center for Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, United States

Yanting Chen

• Lu, Xiaohan, Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States

Xiaohan Lu,

• Su, Jiahui, Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States

Jiahui Su,

• Crowley, Steven D., Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States

Steven D. Crowley,

• Privratsky, Jamie, Center for Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, United States

Jamie Privratsky,

Background

Acute kidney injury (AKI) is a leading cause of organ failure in hospitalized and critically ill patients. Following AKI, the canonical pro-inflammatory cytokine interleukin-1β (IL1β) is released predominantly from activated myeloid cells and binds to the interleukin-1 receptor R1 (IL1R1). IL1R1 activation is known to amplify the immune response and exacerbate AKI. However, the specific role of IL-1R1 on myeloid cells during AKI is poorly understood. Our objective was to study the function of myeloid cell IL-1R1 during AKI. As IL1R1 is known to signal through the pro-inflammatory Toll-like receptor (TLR)/MyD88 pathway, we initially hypothesized that myeloid cell IL1R1 activation would exacerbate AKI.

Methods

IL1R1 was selectively depleted in CD11c+ myeloid cells with CD11cCre(+) / Il1r1^fl/fl (IL1R1^CD11cKO) mice. IL1R1^CD11cKO and littermate controls (CD11cCre(-) / Il1r1^fl/fl - IL1R1^CD11cWT) were subjected to kidney ischemia/reperfusion (I/R) injury. Kidney injury was assessed by serum creatinine and histologic injury scoring. Renal tubular cells (RTC) were co-cultured with CD11c+ bone-marrow derived dendritic cells (BMDC) from IL1R1^CD11cKO and IL1R1^CD11cWT mice.

Results

Surprisingly, compared to IL1R1^CD11cWT mice, IL1R1^CD11cKO mice displayed exaggerated I/R-induced kidney injury, as indicated by elevated levels of serum creatinine (mean ± SD: 1.24 ±0.85 vs 2.06 ± 1.17 mg/dl, p<0.05), BUN (mean ± SD: 90.91 ± 35.68 vs 134.87 ± 37.92 mg/dl, p<0.01), and histologic injury scoring. In support of these findings, in vitro co-culture studies showed that RTC co-cultured with IL1R1^CD11cKO BMDC (in the presence of IL1β or LPS) exhibited higher mRNA levels of the kidney injury marker neutrophil gelatinase-associated lipocalin (NGAL) than those co-cultured with IL1R1^CD11cWT BMDC. Furthermore, we observed that IL1R1 activation on IL1R1^CD11cWT BMDC preferentially augmented expression of anti-inflammatory mediators tumor necrosis factor alpha induced protein 3 (A20) and interleukin-1 receptor antagonist (IL1Ra/Il1rn), effects that were abrogated by IL1R1^CD11cKO BMDC.

Conclusion

Our findings suggest a novel function of IL1R1 is to serve as a critical negative feedback regulator of IL1 signaling in CD11c+ cells to dampen inflammation and limit AKI. Our results lend further support for cell-specific, as opposed to global, targeting of immunomodulatory agents.

Funding

• NIDDK Support