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

doi:10.1172/jci.insight.201877

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

Jia Wei,¹ Gengyu Du,¹ Zixia Li,¹ Min Yang,² Ting Chen,¹ Zihao Xu,¹ Zhen Yuan,³ Yidan Zheng,⁴ and Xiang Yan¹

Published August 6, 2026 - More info

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Abstract

Obstructive nephropathy is a significant and preventable contributor to chronic kidney disease, yet no disease-modifying anti-fibrotic 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 (α-SMA) positive 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 wild-type 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 knockout significantly reduced Mmp9 mRNA and MMP9 protein levels. Pharmacological inhibition using the IRF5 inhibitor N5-1 mitigated established fibrosis, down-regulated 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 pre-clinical evidence supporting IRF5 inhibition as a potential treatment strategy for patients with obstructive nephropathy.

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

Jia Wei,¹ Gengyu Du,¹ Zixia Li,¹ Min Yang,² Ting Chen,¹ Zihao Xu,¹ Zhen Yuan,³ Yidan Zheng,⁴ and Xiang Yan¹

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

Jia Wei,1 Gengyu Du,1 Zixia Li,1 Min Yang,2 Ting Chen,1 Zihao Xu,1 Zhen Yuan,3 Yidan Zheng,4 and Xiang Yan1

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Jia Wei,¹ Gengyu Du,¹ Zixia Li,¹ Min Yang,² Ting Chen,¹ Zihao Xu,¹ Zhen Yuan,³ Yidan Zheng,⁴ and Xiang Yan¹