Role of interferon gamma in injury accelerated cystic kidney disease - PROJECT SUMMARY/ABSTRACT Polycystic kidney disease (PKD) is the most commonly inherited kidney disease affecting over 12 million people throughout the world. PKD is characterized by multiple fluid-filled cysts in both kidneys which lead to reduced kidney function and end-stage kidney disease. This disease is caused by mutations in primary cilia-related genes, most commonly PKD1, PKD2, and PKHD1. Patients suffering from PKD exhibit varying rates of disease progression, which is believed to be influenced by genetic and environmental modifiers. Kidney injury is one environmental modifier thought to promote rapid PKD progression in patients. In support of this idea, several studies indicate that injury to the kidneys of mice with mutations in cilia-related genes results in accelerated PKD progression. However, the mechanism connecting injury and accelerated disease progression is poorly understood. A hallmark of kidney injury in non-cystic kidneys is immune cell accumulation. Similarly, immune cell accumulation is observed in cystic kidneys following injury. Previous data from our lab showed that loss of adaptive immune cells (T and B cells) significantly reduced injury-accelerated cystic disease in cilia mutant mice. Preliminary data from our lab suggest that the rescue observed in injured cilia mutant mice lacking adaptive immune cells is likely driven by CD4+ T cells as deletion of this cell type, but not CD8+ T cells, reduces injury accelerated cystic disease. We performed single-cell RNA sequencing on T cells from injured cilia mutant mice and controls to understand T cell behavior after injury. Ligand-receptor analyses identified the cytokine interferon- gamma (IFNγ) as a highly prioritized ligand predicted to induce a pro-inflammatory macrophage phenotype and accelerate PKD progression. Furthermore, my preliminary data show that loss of IFNγ in cilia mutant mice significantly reduced cystic disease following injury. Based on these data and published data showing that pro- inflammatory macrophages promote injury-accelerated cystic disease, I hypothesize that CD4+ T cell-derived IFNγ promotes injury-accelerated cystic kidney disease in a macrophage-dependent manner. Aim 1 will determine if IFNγ (Ifng) expression in CD4+ T cells is required and sufficient for injury-accelerated cystic kidney disease. In addition to this, aim 1 will assess if macrophages stimulated by IFNγ accelerate cystic disease. This aim will employ flow cytometry, histology, bulk RNA sequencing, cell culture, and confocal microscopy to answer these questions. Aim 2 will test the clinical relevance of targeting IFNγ in autosomal dominant polycystic kidney disease (ADPKD) patients by comparing the level of IFNγ found in serum from rapidly progressing ADPKD patients compared to slowly progressing ADPKD patients and healthy controls. Lastly, I will use an IFNγ-blocking antibody to test the therapeutic potential of targeting IFNγ in rapidly progressing mouse models of PKD. If the hypothesis that IFNγ promotes rapidly progressing cystic kidney disease is correct, there is potential to repurpose FDA-approved therapies that block IFNγ signaling (Gamifant) to slow disease progression in ADPKD patients.
