Interferon regulatory factor 5 in myeloid cells promotes obstructive nephropathy-induced renal fibrosis in vivo
Jia Wei, Gengyu Du, Zixia Li, Min Yang, Ting Chen, Zihao Xu, Zhen Yuan, Yidan Zheng, Xiang Yan
Jia Wei, Gengyu Du, Zixia Li, Min Yang, Ting Chen, Zihao Xu, Zhen Yuan, Yidan Zheng, Xiang Yan
View: Text | PDF
Research Article Immunology Nephrology

Interferon regulatory factor 5 in myeloid cells promotes obstructive nephropathy-induced renal fibrosis in vivo

Abstract

Obstructive nephropathy is a significant and preventable contributor to chronic kidney disease, yet no disease-modifying antifibrotic agents are currently available. We hypothesized that interferon regulatory factor 5 (IRF5) functions as a macrophage transcriptional regulator that directly transactivates matrix metalloproteinase 9 (MMP9) to initiate early extracellular matrix (ECM) remodeling. Analysis of 30 human obstructive nephropathy biopsy specimens demonstrated that IRF5+CD68+ macrophage density increased progressively with fibrosis severity and correlated significantly with α-smooth muscle actin–positive (α-SMA+) areas. In the murine unilateral ureteral obstruction (UUO) model, both global and myeloid-specific Irf5 deletion significantly attenuated collagen deposition, immune cell infiltration, and fibrotic gene expression compared with WT controls. Cleavage under targets and tagmentation (CUT&Tag) analysis demonstrated that IRF5 directly binds the Mmp9 enhancer region and increases chromatin accessibility. Consequently, myeloid-specific Irf5 KO significantly reduced Mmp9 mRNA and MMP9 protein levels. Pharmacological inhibition using the IRF5 inhibitor N5-1 mitigated established fibrosis, downregulated α-SMA and MMP9 expression, and reduced CD68+ macrophage infiltration. These findings identify the IRF5/MMP9 axis as a therapeutically targetable pathway driving macrophage-mediated ECM expansion and provide preclinical evidence supporting IRF5 inhibition as a potential treatment strategy for patients with obstructive nephropathy.

Authors

Jia Wei, Gengyu Du, Zixia Li, Min Yang, Ting Chen, Zihao Xu, Zhen Yuan, Yidan Zheng, Xiang Yan

×

Figure 5

IRF5 KO mitigates inflammation and fibrosis in the UUO mouse model.

Options: View larger image (or click on image) Download as PowerPoint
IRF5 KO mitigates inflammation and fibrosis in the UUO mouse model. (A) ...
(A) Representative H&E, masson staining, and IHC images of α-SMA, VIM, and CD68 of WT mice and Irf5–/– mice in sham group and UUO group. Scale bars: 50 μm. (B) Collagen deposition is increased in UUO-induced WT renal tissues yet decreased in Irf5–/– mice. VIM+α-SMA+ area was significantly upregulated in the UUO-induced WT renal tissues and downregulated in the Irf5–/– renal tissues. The number of CD68+ cells is markedly reduced in UUO-induced Irf5–/– renal tissues compared with WT renal tissues. (C) Renal mRNA expression of Acta2 and Vim in the indicated mouse groups were measured by qPCR. (D and F) Renal protein expression of α-SMA and VIM in the indicated mouse groups were measured by Western blot, the results were subjected to quantitative analysis. (E) Renal mRNA expression of Il-1β, Il-6, and Tnf-α in the indicated mouse groups were measured by qPCR. The mRNA expression level was reduced in the UUO-induced Irf5–/– renal tissues. Data are expressed as the mean ± SD. Statistical comparisons among multiple groups were performed using 1-way ANOVA followed by Tukey’s post hoc test. n = 3–9. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.