Interferon Regulatory Factor-5 in Resident Macrophage Promotes Polycystic Kidney Disease.

Background: Autosomal dominant polycystic kidney disease is caused by genetic mutations in or . Macrophages and their associated inflammatory cytokines promote cyst progression; however, transcription factors within macrophages that control cytokine production and cystic disease are unknown.

Methods: In these studies, we used conditional mice to test the hypothesis that macrophage-localized interferon regulatory factor-5 (IRF5), a transcription factor associated with production of cyst-promoting cytokines (TNF, IL-6), is required for accelerated cyst progression in a unilateral nephrectomy (1K) model. Analyses of quantitative real-time PCR (qRT-PCR) and flow-cytometry data 3 weeks post nephrectomy, a time point before the onset of severe cystogenesis, indicate an accumulation of inflammatory infiltrating and resident macrophages in 1K mice compared with controls. qRT-PCR data from FACS cells at this time demonstrate that macrophages from 1K mice have increased expression of compared with controls. To determine the importance of macrophage-localized in cyst progression, we injected scrambled or IRF5 antisense oligonucleotide (ASO) in 1K mice and analyzed the effect on macrophage numbers, cytokine production, and renal cystogenesis 6 weeks post nephrectomy.

Results: Analyses of qRT-PCR and IRF5 ASO treatment significantly reduced macrophage numbers, expression in resident-but not infiltrating-macrophages, and the severity of cystic disease. In addition, IRF5 ASO treatment in 1K mice reduced expression in resident macrophages, which was correlated with reduced STAT3 phosphorylation and downstream p-STAT3 target gene expression.

Conclusions: These data suggest that promotes inflammatory cytokine production in resident macrophages resulting in accelerated cystogenesis.