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Peer-reviewedCC BY 4.0JCI Insight

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

  • Jia Wei1
  • Gengyu Du1
  • Zixia Li1
  • Min Yang2
  • Ting Chen1
  • Zihao Xu1
  • Zhen Yuan3
  • Yidan Zheng4
  • Xiang Yan1
4 affiliations
  1. 1Department of Urology and
  2. 2Department of Pathology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
  3. 3Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  4. 4Department of cardiovascular surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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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.

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Cite

BibTeXRIS
BibTeX
@article{wei2026interferon,
  title = {{Interferon regulatory factor 5 in myeloid cells promotes obstructive nephropathy-induced renal fibrosis in vivo}},
  author = {Jia Wei and Gengyu Du and Zixia Li and Min Yang and Ting Chen and Zihao Xu and Zhen Yuan and Yidan Zheng and Xiang Yan},
  journal = {JCI Insight},
  year = {2026},
  month = aug,
  doi = {10.1172/jci.insight.201877},
  url = {https://doi.org/10.1172/jci.insight.201877},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Interferon regulatory factor 5 in myeloid cells promotes obstructive nephropathy-induced renal fibrosis in vivo
AU  - Jia Wei
AU  - Gengyu Du
AU  - Zixia Li
AU  - Min Yang
AU  - Ting Chen
AU  - Zihao Xu
AU  - Zhen Yuan
AU  - Yidan Zheng
AU  - Xiang Yan
PY  - 2026
DA  - 2026/08/06
JO  - JCI Insight
DO  - 10.1172/jci.insight.201877
UR  - https://doi.org/10.1172/jci.insight.201877
AB  - 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.
SN  - 2379-3708
ER  -