Kurt A Zimmerman1, Jifeng Huang2, Lan He2, Dustin Z Revell1, Zhang Li1, Jung-Shan Hsu2, Wayne R Fitzgibbon3, E Starr Hazard4, Gary Hardiman5, Michal Mrug2,6, P Darwin Bell2, Bradley K Yoder1, Takamitsu Saigusa2. 1. Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama. 2. Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama. 3. Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina. 4. Academic Affairs Faculty and Computational Biology Resource Center, Medical University of South Carolina, Charleston, South Carolina. 5. School of Biological Sciences, Institute for Global Food Security, Queens University Belfast, Belfast, United Kingdom. 6. Birmingham Veterans Affairs Medical Center, Birmingham, Alabama.
Abstract
BACKGROUND: Autosomal dominant polycystic kidney disease is caused by genetic mutations in PKD1 or PKD2. 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 Pkd1 mice to test the hypothesis that macrophage-localized interferon regulatory factor-5 (IRF5), a transcription factor associated with production of cyst-promoting cytokines (TNFα, 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 Pkd1 mice compared with controls. qRT-PCR data from FACS cells at this time demonstrate that macrophages from 1K Pkd1 mice have increased expression of Irf5 compared with controls. To determine the importance of macrophage-localized Irf5 in cyst progression, we injected scrambled or IRF5 antisense oligonucleotide (ASO) in 1K Pkd1 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, Irf5 expression in resident-but not infiltrating-macrophages, and the severity of cystic disease. In addition, IRF5 ASO treatment in 1K Pkd1 mice reduced Il6 expression in resident macrophages, which was correlated with reduced STAT3 phosphorylation and downstream p-STAT3 target gene expression. CONCLUSIONS: These data suggest that Irf5 promotes inflammatory cytokine production in resident macrophages resulting in accelerated cystogenesis.
BACKGROUND: Autosomal dominant polycystic kidney disease is caused by genetic mutations in PKD1 or PKD2. 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 Pkd1 mice to test the hypothesis that macrophage-localized interferon regulatory factor-5 (IRF5), a transcription factor associated with production of cyst-promoting cytokines (TNFα, 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 Pkd1 mice compared with controls. qRT-PCR data from FACS cells at this time demonstrate that macrophages from 1K Pkd1 mice have increased expression of Irf5 compared with controls. To determine the importance of macrophage-localized Irf5 in cyst progression, we injected scrambled or IRF5 antisense oligonucleotide (ASO) in 1K Pkd1 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, Irf5 expression in resident-but not infiltrating-macrophages, and the severity of cystic disease. In addition, IRF5 ASO treatment in 1K Pkd1 mice reduced Il6 expression in resident macrophages, which was correlated with reduced STAT3 phosphorylation and downstream p-STAT3 target gene expression. CONCLUSIONS: These data suggest that Irf5 promotes inflammatory cytokine production in resident macrophages resulting in accelerated cystogenesis.
Authors: Ayumi Takakura; Erik A Nelson; Nadeem Haque; Benjamin D Humphreys; Kambiz Zandi-Nejad; David A Frank; Jing Zhou Journal: Hum Mol Genet Date: 2011-08-05 Impact factor: 6.150
Authors: Jian-Kang Chen; Kojiro Nagai; Jianchun Chen; David Plieth; Masayo Hino; Jinxian Xu; Feng Sha; T Alp Ikizler; C Chad Quarles; David W Threadgill; Eric G Neilson; Raymond C Harris Journal: J Clin Invest Date: 2015-05-18 Impact factor: 14.808
Authors: Wayne R Fitzgibbon; Yujing Dang; Marlene A Bunni; Catalin F Baicu; Michael R Zile; Adam E Mullick; Takamitsu Saigusa Journal: Am J Physiol Renal Physiol Date: 2017-10-11
Authors: Ernald Jules G Aloria; Cheng J Song; Zhang Li; Mandy J Croyle; Michal Mrug; Kurt A Zimmerman; Bradley K Yoder Journal: Kidney360 Date: 2021-06-24
Authors: Cheng J Song; Zhang Li; Ummey Khalecha Bintha Ahmed; Sarah J Bland; Alex Yashchenko; Shanrun Liu; Ernald J Aloria; Jeremie M Lever; Nancy M Gonzalez; Marisa A Bickel; Cory B Giles; Constantin Georgescu; Jonathan D Wren; Mark L Lang; Etty N Benveniste; Laurie E Harrington; Leo Tsiokas; James F George; Kenneth L Jones; David K Crossman; Anupam Agarwal; Michal Mrug; Bradley K Yoder; Katharina Hopp; Kurt A Zimmerman Journal: J Am Soc Nephrol Date: 2022-02-02 Impact factor: 14.978
Authors: Ryousuke Satou; Martha Franco; Courtney M Dugas; Akemi Katsurada; L Gabriel Navar Journal: Int J Mol Sci Date: 2022-07-12 Impact factor: 6.208