Xylosyltransferase-II deficiency rewires innate immune signaling and destabilizes polarization in human macrophages

Given the central role of macrophages in inflammatory signaling and tissue homeostasis, we investigated the transcriptional consequences of XYLT2 deficiency in human primary macrophages across distinct polarization states (M0, M1, M2).

Bulk mRNA sequencing revealed that XYLT2 deficiency induces a conserved and robust transcriptional reprogramming independent of polarization state. Differential expression analysis identified a shared interferon-associated gene signature, characterized by the upregulation of interferon-stimulated genes, including STAT1, IRF7, and multiple IFIT family members. Pathway enrichment analysis demonstrated significant activation of innate immune sensing pathways, including RIG-I-like, NOD-like, and Toll-like receptor signaling, alongside strong enrichment of JAK–STAT and cytokine signaling pathways.