Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.
Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
Kidney360. 2020 Mar;1(3):179-190. doi: 10.34067/KID.0001052019. Epub 2020 Mar 26.
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.
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.
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.
These data suggest that promotes inflammatory cytokine production in resident macrophages resulting in accelerated cystogenesis.
常染色体显性多囊肾病是由 或 基因的基因突变引起的。巨噬细胞及其相关的炎症细胞因子促进囊肿的进展；然而，控制细胞因子产生和囊性疾病的巨噬细胞内的转录因子尚不清楚。
在这些研究中，我们使用条件性 小鼠来测试以下假设：巨噬细胞中局灶性的干扰素调节因子-5（IRF5）是一种与促囊生成细胞因子（TNF、IL-6）产生相关的转录因子，对于单侧肾切除术（1K）模型中加速的囊肿进展是必需的。在肾切除后 3 周（发生严重囊肿生成之前的时间点）对定量实时 PCR（qRT-PCR）和流式细胞术数据的分析表明，与对照组相比，1K 小鼠中炎症浸润和固有巨噬细胞的积累。此时来自 FACS 细胞的 qRT-PCR 数据表明，与对照组相比，1K 小鼠的巨噬细胞中 的表达增加。为了确定巨噬细胞中局灶性 在囊肿进展中的重要性，我们在 1K 小鼠中注射了 scrambled 或 IRF5 反义寡核苷酸（ASO），并分析了其对 6 周后肾切除后巨噬细胞数量、细胞因子产生和肾脏囊肿生成的影响。
qRT-PCR 分析和 IRF5 ASO 治疗显著减少了巨噬细胞数量、固有巨噬细胞中 的表达，但不减少浸润巨噬细胞中的表达，以及囊性疾病的严重程度。此外，1K 小鼠中 IRF5 ASO 的治疗减少了固有巨噬细胞中的 表达，这与 STAT3 磷酸化和下游 p-STAT3 靶基因表达的减少相关。
这些数据表明， 在固有巨噬细胞中促进炎症细胞因子的产生，从而加速囊肿的生成。
