Abstract: SA-PO736
IL34-Induced M2-Like Macrophage Polarization Promotes Renal Interstitial Fibrosis via Macrophage-to-Myofibroblast Transition
Session Information
- CKD: Mechanisms - III
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Yang, Qian, Tongji Hospital, Huazhong Univ of Science and Technology, Wuhan, HUBEI, China
- Xu, Gang, Tongji Hospital, Huazhong Univ of Science and Technology, Wuhan, HUBEI, China
- Zeng, Rui, Tongji Hospital, Huazhong Univ of Science and Technology, Wuhan, HUBEI, China
Background
M2-like macrophages play important roles during the injury and repair phases in kidney diseases. However, the relationship between M2-like macrophages and fibrosis is still controversial, with some studies showing pro-fibrotic effects while others showing anti-fibrotic effects.
Methods
Here, we used the Cre/LoxP system to generate renal tubular epithelial cells-specific IL34-overexpression mice (Cdh16-Cre; LSL-IL34 mice and Tamoxifen-induced Cdh16-iCreERT2; LSL-IL34 mice).
Results
We found that Cdh16-Cre; LSL-IL34 mice spontaneously experienced weight loss, renal injury, decreased survival rates and declined renal function after birth. Furthermore, they automatically developed into renal fibrosis, which was marked by notable intrarenal infiltration of M2-like macrophages. The similar results were also found in the Tamoxifen-induced Cdh16-iCreERT2; LSL-IL34 kidneys. The proteome and transcriptome analysis of Cdh16-Cre; LSL-IL34 kidneys showed a high degree of relationship between the extracellular matrix deposition and the infiltrated macrophages. Meanwhile, transcriptome sequencing of isolated macrophages from Cdh16-Cre; LSL-IL34 kidneys revealed the infiltrated macrophages in Cdh16-Cre; LSL-IL34 kidneys were predominantly M2-like (CD204+CD206+CD163+) and characteristically exhibited a myofibroblast phenotype (Fibronectin+Acta2+Collagens+). The M2-like macrophage polarization and macrophage-to-myofibroblast transition were further supported by flow cytometry, immunofluorescence and confocal fluorescence microscopy. On the contrary, Clodronate Liposomes (CLs)-mediated depletion of renal M2-like macrophages in Cdh16-Cre; LSL-IL34 mice alleviated the renal injury and fibrosis.
Conclusion
Tubular IL34 specifically activates M2-like macrophages, which can directly transdifferentiate into myofibroblasts (MMT) and in turn promote renal interstitial fibrosis.
Funding
- Government Support - Non-U.S.