The transcription factor NF-Y promotes myeloid cell survival and protects from inflammatory vascular disease

Abstract

Abstract Background Myeloid cells orchestrate vascular inflammation through transcriptional programs that regulate their maturation, effector function, and survival. While lineage-determining transcription factors establish myeloid identity, understanding of the transcriptional regulation of myeloid behavior in chronic inflammatory contexts remains limited. Nuclear factor-Y (NF-Y) is a trimeric CCAAT-binding transcription factor that regulates cell proliferation and differentiation. Here, we investigate the role of NF-Y in myeloid function and survival during chronic vascular inflammation. Methods Integrated single-cell transcriptomics of BM, blood, and atherosclerotic lesions were combined with myeloid-specific NF-YA inactivation to define NF-Y–dependent transcriptional states. Functional consequences were assessed in mice with myeloid-specific Nfya deletion on a hypercholesterolemic Apoe –/– background using models of diet-induced advanced atherosclerosis and endoluminal femoral injury. Myeloid cell recruitment, survival, apoptosis, and proliferation were further examined in models of thioglycolate-induced peritonitis. Results NF-Y subunit transcripts were detected across myeloid compartments, with Nfya enriched in proliferative macrophages and immature neutrophils. In mouse atherosclerotic lesions, low Nfya expression was associated with lipid-handling and phagocytic macrophage signatures and a pro-inflammatory neutrophil phenotype. Myeloid Nfya deficiency was further associated with reduced circulating neutrophil counts, increased macrophage and neutrophil apoptosis during acute inflammation, expanded necrotic cores, larger unstable atherosclerotic lesions, and aggravated atherosclerosis and injury-induced neointimal thickening. Conclusion Our data identify NF-Y as a transcriptional safeguard of myeloid cell survival during inflammatory stress, thereby shaping disease progression and outcomes in vascular disease.