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Abstract: SA-PO080

Kidney Macrophage IL-1 Receptor Limits Endoplasmic Reticulum Stress and Nephrotoxic Serum Nephritis

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Chen, Yanting, Duke University, Durham, North Carolina, United States
  • Li, Yu, Duke University, Durham, North Carolina, United States
  • Ren, Jiafa, Nanjing First Hospital, Nanjing, Jiangsu, China
  • Wu, Chia-Chun, Chi Mei Medical Center, Tainan, Taiwan
  • Lu, Xiaohan, Duke University, Durham, North Carolina, United States
  • Crowley, Steven D., Duke University, Durham, North Carolina, United States
  • Privratsky, Jamie R., Duke University, Durham, North Carolina, United States
Background

Acute kidney injury (AKI) often leads to chronic kidney disease. Macrophages play divergent roles in kidney injury and repair. Previously, we demonstrated a protective role of IL-1R1 in CD11c-expressing kidney myeloid cells in early AKI. This study aims to determine the role of IL-1R1 in myeloid cells in chronic kidney injury. We hypothesized that myeloid cell IL-1R1 signaling would limit chronic inflammation after AKI.

Methods

Mice with CD11b-expressing myeloid cells-specific deletion of IL-1R1 (LysMCre(+) / Il1r1fl/fl - MKO) and littermate wildtype controls (LysMCre(-) / Il1r1fl/fl - MWT) were subjected to nephrotoxic serum nephritis (NTS) and chronic ischemia/reperfusion (I/R) models. Kidney and glomerular injury were assessed by albuminuria, histologic injury scoring, and kidney injury biomarkers kidney injury molecular (KIM)-1 and neutrophil gelatinase-associated lipocalin (NGAL). Fluorescent cell-sorting and single cell RNA sequencing were used to profile gene expression and identify cell-specific ligand-receptor interactions. Renal HK-2 cells were co-cultured with bone marrow-derived macrophages (BMDM) from MKO and MWT mice.

Results

Compared to MWT mice, MKO mice demonstrated worsened nephritis as indicated by increased albuminuria (mean ± SD: MWT 24,638 ± 4,262 vs MKO 30,826 ± 3,237 μg/mg urinary creatinine, p=0.02), elevated KIM-1 mRNA and exacerbated histologic injury scoring. MKO mice also displayed evidence of increased tubular injury following chronic I/R. We found increased endoplasmic reticulum stress (ER stress)-mediated apoptosis and pro-inflammatory polarization in macrophages from NTS injured MKO kidneys, which was associated with elevated renal expression of type I interferons (IFNs). Nichenet analysis revealed that high mobility group protein B1 (HMGB1) is a prioritized ligand from macrophages that could induce type I IFNs in damaged tubular cells. In co-culture studies, we confirmed the increased ER stress and pro-inflammatory cytokines in MKO macrophages, which led to heightened cellular injury and elevated type I IFNs in HK-2 tubular cells. In turn, anti-IFNR1 therapy ameliorated these detrimental effects in vivo.

Conclusion

IL-1R1 signaling on macrophages constrains ER stress-mediated pro-inflammatory polarization and ameliorates type I IFNs-induced tubular injury and NTS injury.

Funding

  • NIDDK Support