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 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.