Therapeutic Blocking of IL-17A Binding to IL-17RA Diminishes PD-L1 Expression Is a Novel Therapeutic Approach for ADPKD
- Genetic Diseases: Cystic - Therapeutic Investigations and Prognosis
November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic
- Samarpita, Snigdha, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
- Li, Xiaoyan, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
- Agborbesong, Ewud, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
- Zhou, Xia, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
- Torres, Vicente E., Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
- Li, Xiaogang, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
Interleukin (IL) - 17A is a critical pro-inflammatory determinant that has been demonstrated to expedite cell proliferation and inflammatory responses in the disease microenvironment. Howbeit, its role in ADPKD has not yet been reported.
To verify the role of IL-17A in ADPKD, we administered cyanidin, a small molecule flavonoid that disrupts IL-17A/IL-17RA interaction, to Pkd1 mutant mouse models. To determine the molecular basis of IL-17A/IL-17RA signaling inhibition, we performed western blotting, qRT-PCR and knockdown studies in Pkd1 mutant renal epithelial cells and tissues. We also determined the relationship of IL-17A/IL-17RA signaling with PD-L1 immune-checkpoint molecule via co-IP and siRNA knockdown studies. Flow cytometry analysis was carried out to determine CD8 and CD4 Th17 cell population.
We found that disruption of IL-17A/IL-17RA interaction by cyanidin significantly impeded cyst growth as well as the recruitment of macrophages via decreased levels of MCP-1 secretion into the cystic microenvironment in Pkd1 mutant mouse kidneys. Mechanistically, ablation of IL-17A/IL-17RA signaling blunted the activation of PKD associated signaling pathways (AKT, MAPK, NF-κB) to reduce cyst growth and inflammatory responses in Pkd1 mutant cells and kidneys. In essence, the therapeutic utility of IL-17A signaling blockade in inhibiting cyst proliferation was mediated via decrease in mitochondrial fragmentation in Pkd1 mutant cells. Interruption of IL-17A binding to IL-17RA also reduced the expression of TGF-β and then abrogated renal fibrosis and collagen deposition in Pkd1 mutant kidneys. We further found that - 1) disruption the interaction of IL-17A/IL-17RA with cyanidin and knockdown of IL-17RA decreased the expression of PD-L1 immune checkpoint molecule, and 2) IL-17RA interacted with PD-L1 to alter its activity. As a result, the adaptive immune response was tempered via dramatic rise in CD8+ T cells infiltration and reduction in the CD4+ Th17 population due to lowering of the levels of CCL-20.
This study elucidates the roles of IL-17A/IL-17RA signaling and its novel relationship with PD-L1 in ADPKD, suggesting that disruption of IL-17 signaling either alone or in combination with anti-PD-L1 immunotherapy can be a viable powerful strategy in ADPKD treatment.
- NIDDK Support