Iguratimod Modulates M1 Macrophage Polarization Via the NOTCH4–KLF4 Axis to Alleviate Antibody-Mediated Rejection

Background: Iguratimod (IGT) is a small-molecule anti-inflammatory agent that effectively attenuates the progression of antibody-mediated rejection (ABMR). However, the underlying mechanism of action of IGT remains poorly understood. Thus, this study aimed to investigate the mechanism through which IGT regulates macrophage polarization and ABMR. Methods: A mouse model of ABMR was established by performing kidney transplantation after skin graft-induced sensitization. Experimental interventions included neurogenic locus notch homolog protein 4 (NOTCH4) knockout mice and oral administration of IGT. RNA sequencing, quantitative polymerase chain reaction, Western blotting (WB), flow cytometry, and immunofluorescence (IF) staining were performed to investigate M1 macrophage polarization and the Jagged1–NOTCH4 signaling pathway. Results: This study found that IGT significantly reduced M1 macrophage infiltration into renal allografts in a mouse model of ABMR. Transcriptomic sequencing and subsequent biological experiments indicated that IGT may regulate macrophage polarization through the Jagged1–NOTCH4 pathway. Conclusion: M1 macrophage polarization may contribute to the initiation and progression of ABMR following kidney transplantation. IGT attenuates M1 macrophage polarization by inhibiting Jagged1–NOTCH4–Krüppel-like Factor 4 (KLF4) signaling.