IFNγ-Driven Th17 and Neutrophil Responses Promote Rapid Polycystic Kidney Disease Progression 2304963

Abstract Introduction Rapidly progressing polycystic kidney disease (PKD) leads to earlier loss of kidney function and an increased likelihood of kidney transplantation, however the mechanisms driving rapid disease progression are poorly understood. Single-cell RNA sequencing data from our laboratory identified interferon gamma (IFNγ) as a potential mediator of accelerated cyst growth following kidney injury. Based on these findings, we hypothesized that IFNγ promotes rapidly progressing PKD by driving a pathogenic inflammatory immune response. Methods We tested our hypothesis in two PKD mouse models. We first crossed our PKD mouse model to IFNγ-deficient mice, followed by inducing folic acid (FA) kidney injury, and disease progression assessment 56 days post-FA. The second model utilized a non-injured rapidly progressing PKD model which received anti-IFNγ antibody or isotype control 3 times weekly for 3 weeks, before kidneys were collected and disease progression assessed. Results Genetic deletion of IFNγ significantly attenuated injury-accelerated PKD severity, as demonstrated by reduced kidney weight to bodyweight ratio and cystic index. IFNγ deficiency was also associated with decreased kidney fibrosis and improved kidney function. Flow cytometric analysis revealed reduced proportions of neutrophils and Th17 cells, while qPCR demonstrated significantly lower expression of Th17- and neutrophil-associated cytokines. Consistently, antibody-mediated blockade of IFNγ in the non-injured Pkd2f/f model led to a significantly reduced cyst burden and immune cell infiltration, mirroring the genetic knockout findings Conclusion These findings suggest that IFNγ is a key mediator of rapid PKD progression. IFNγ-driven Th17 and neutrophil responses may represent a critical immunopathogenic axis underlying aggressive disease, highlighting this pathway as a potential therapeutic target for slowing disease progression, preserving kidney function, and delaying the need for kidney transplantation. Funding Source N/A Topic Categories Immune Mechanisms of Human Disease (HUM)