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

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 first-in-class 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.