Attenuation of renal injury by depleting cDC1 and by repurposing Flt3 inhibitor in anti-GBM disease.

Abstract

Previous studies found cDC1s to be protective in early stage anti-GBM disease through Tregs, but pathogenic in late stage Adriamycin nephropathy through CD8+ T cells. Flt3 ligand is a growth factor essential for cDC1 development and Flt3 inhibitors are currently used for cancer treatment. We conducted this study to clarify the role and mechanisms of effects of cDC1s at different time points in anti-GBM disease. In addition, we aimed to utilize drug repurposing of Flt3 inhibitors to target cDC1s as a treatment of anti-GBM disease. We found that in human anti-GBM disease, the number of cDC1s increased significantly, proportionally more than cDC2s. The number of CD8+ T cells also increased significantly and their number correlated with cDC1 number. In XCR1-DTR mice, late (day 12-21) but not early (day 3-12) depletion of cDC1s attenuated kidney injury in mice with anti-GBM disease. cDC1s separated from kidneys of anti-GBM disease mice were found to have a pro-inflammatory phenotype (i.e. express high level of IL-6, IL-12 and IL-23) in late but not early stage. In the late depletion model, the number of CD8+ T cells was also reduced, but not Tregs. CD8+ T cells separated from kidneys of anti-GBM disease mice expressed high levels of cytotoxic molecules (granzyme B and perforin) and inflammatory cytokines (TNF-α and IFN-γ), and their expression reduced significantly after cDC1 depletion with diphtheria toxin. These findings were reproduced using a Flt3 inhibitor in wild type mice. Therefore, cDC1s are pathogenic in anti-GBM disease through activation of CD8+ T cells. Flt3 inhibition successfully attenuated kidney injury through depletion of cDC1s. Repurposing Flt3 inhibitors has potential as a novel therapeutic strategy for anti-GBM disease.

• Authors: Titi Chen, Qi Cao, Ruifeng Wang, Guoping Zheng, Farhana Azmi, Vincent W Lee, Yuan Ming Wang, Hongqi Li, Di Yu, Natasha M Rogers, Stephen I Alexander, David C H Harris, Yiping Wang
• Journal: Clinical immunology (Orlando, Fla.) (Clin Immunol) Vol. 250 Pg. 109295 (05 2023) ISSN: 1521-7035 [Electronic] United States
• PMID: 36933629 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier Inc. All rights reserved.

Chemical References

• FLT3 protein, human
• fms-Like Tyrosine Kinase 3

Topics

• Animals
• Humans
• Mice
• Anti-Glomerular Basement Membrane Disease (drug therapy)
• CD8-Positive T-Lymphocytes (metabolism)
• Dendritic Cells (metabolism)
• Drug Repositioning
• fms-Like Tyrosine Kinase 3 (antagonists & inhibitors)
• Kidney (metabolism)
• Signal Transduction