Transcription factor ELF-1 drives inflammatory macrophage to exacerbate AKI by GBP4/NLRs/NF-κB axis

Abstract

Acute kidney injury (AKI) is an unavoidable complication and critical determinant of prognosis in renal transplantation. M1-polarized macrophages are known to exacerbate AKI progression. Preliminary clinical data reveals a positive correlation between elevated E74-like ETS transcription factor 1 (ELF-1) and pro-inflammatory cytokines in macrophages from post-transplant patients. However, the role of ELF-1 in M1 macrophage and AKI pathogenesis remains unexplored. We find that ELF-1 deficiency in murine macrophages significantly decreases inflammatory M1 polarization and attenuated AKI. Mechanistically, ELF-1 directly binds to GBP4 to promote its transcription, thereby promoting the GBP4-NLR-NF-κB axis and finally driving M1 polarization. Recombinant GBP4 protein restores M1 polarization impaired by Elf-1 deletion. Similarly, adoptive transfer of ELF-1-expressing bone marrow monocytes in vivo reverses the protective effects of Elf-1 deficiency on AKI. Collectively, we identify ELF-1 as a novel transcriptional regulator of M1 macrophage polarization in post-transplant acute kidney injury. The transcription factor ELF-1 directly regulates the expression of the GBP4 gene, thereby promoting GBP4-NLR-NF-κB axis and ultimately driving the M1 polarization of renal macrophages, thereby exacerbating acute kidney injury.