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Abstract: PO2446

Classical Dendritic Cells Mediate Nephrotoxic Serum Nephritis by Activating T Cells

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Lu, Xiaohan, Duke University Hospital, Durham, North Carolina, United States
  • Ren, Jiafa, Duke University Hospital, Durham, North Carolina, United States
  • Wen, Yi, Duke University Hospital, Durham, North Carolina, United States
  • Privratsky, Jamie, Duke University Hospital, Durham, North Carolina, United States
  • Crowley, Steven D., Duke University Hospital, Durham, North Carolina, United States
Background

Glomerulonephritis is a prominent cause of chronic kidney disease (CKD) and features robust chronic inflammation. Following an inflammatory insult, myeloid cells infiltrate the kidney and drive CKD progression. Flt3L-expressing classical dendritic cells (DCs) are the most potent antigen-presenting cells, and heterozygous deletion of the ubiquitin editor A20 spontaneously activates DCs. However, the role of Flt3L-expressing classical DCs in the regulation of inflammatory CKD requires elucidation. We hypothesized that classical dendritic cells exacerbate inflammatory kidney injury by promoting the activation of renal T cells.

Methods

We induced nephrotoxic serum nephritis (NTS) in flt3L-deficient mice lacking DCs (DC KO), mice with spontaneous DC activation (CD11c Cre+ A20flox/wt = DC ACT), and wild-type (WT) controls. After 14 days of NTS, kidney injury was assessed by pathology scoring and ACRs. In addition, mRNA levels of renal injury biomarkers were determined by RT-PCR and western blot. NTS kidneys were harvested for flow cytometric analysis to determine intra-renal immune cell lineage distributions and test their mRNA levels of inflammatory cytokines.

Results

On day 14 of NTS, DC KO mice had attenuated kidney injury scores compared to WTs (1.6±0.3 vs 3.0±0.3 au, p=0.01), while kidney injury was more severe in DC ACTs than in WTs (2.3±0.3 vs 1.4±0.2 au, p=0.02). Compared to WTs, DC KOs had lower ACRs (432±36 vs 267±11, p=0.001) and reduced renal mRNA levels for NGAL (1.0±0.1 vs 0.2±0.1 au, p=0.001), collagen-I (1.0±0.1 vs 0.4±0.1, p=0.003), and fibronectin (1.0±0.1 vs 0.5±0.1, p=0.01). In contrast, DC ACTs had higher ACRs (623±84 vs 1171±243, p=0.001) and upregulated mRNA for NGAL (29.2±7.4 vs 1.0±0.3 au, p=0.004), collagen-I (6.5±0.9 vs 1.0±0.2, p=0.001), and fibronectin (3.9±0.4 vs. 1.0±0.1, p=0.001). Renal protein levels for collagen-I and fibronectin recapitulated the mRNA patterns. In DC ACT kidneys, absolute numbers of CD8+ effector memory T cells, marked by a CD62LloCD44hi surface expression were higher (2864±648 vs 836±107 cells, p=0.006) and had higher cytokine mRNA levels for TNFα (4.2±0.5 vs 1.0±0.1, p=0.001) and IL1β (2.0±0.3 vs 1.0±0.1, p=0.02) than in WTs at day 14 of NTS.

Conclusion

The pathogenesis of CKD requires classical DC-mediated T cell activation. Inhibition of classical DCs may ameliorate autoimmune nephritis.

Funding

  • NIDDK Support