TNF-α-induces type I IFN signalling to suppress neurogenesis and recruit T cells

Abstract

Adult hippocampal neurogenesis (AHN) is essential for learning, memory, and mood regulation, and its disruption is implicated in ageing, neurodegeneration, and mood disorders. However, the mechanisms linking inflammation to AHN impairment remain unclear. Here, we identify chronic tumour necrosis factor-alpha (TNF-) signalling as a key driver of neurogenic dysregulation via a previously unrecognised type I interferon (IFN) autocrine/paracrine loop in human hippocampal progenitor cells (HPCs). Using a human in vitro neurogenesis model, single-cell RNA sequencing, and functional T cell migration assays, we show that TNF- induces a robust type I IFN response in HPCs, promoting chemokine-mediated, and CXCR3-dependent T cell recruitment and suppressing neurogenesis. This inflammatory signalling cascade drives a fate switch in HPCs from a neurogenic trajectory towards an immune-defensive phenotype, with critical implications for infectious and inflammatory disease pathogenesis. These findings uncover a key inflammatory checkpoint regulating human AHN and highlight potential therapeutic targets to restore neurogenesis in chronic inflammatory states.