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

Abstract Adult hippocampal neurogenesis 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 adult hippocampal neurogenesis impairment remain unclear. Here, we identify chronic tumour necrosis factor-alpha signalling as a key driver of neurogenic dysregulation via a previously unrecognised type I interferon autocrine/paracrine loop in human hippocampal progenitor cells. Using a female-derived human in vitro neurogenesis model, single-cell RNA sequencing, and functional T cell migration assays, we show that tumour necrosis factor-alpha induces a robust type I interferon response in hippocampal progenitor cells, promoting chemokine-mediated and CXC motif chemokine receptor 3-dependent T cell recruitment and suppressing neurogenesis. This inflammatory signalling cascade drives a fate switch in hippocampal progenitor cells 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 adult hippocampal neurogenesis and highlight potential therapeutic targets to restore neurogenesis in chronic inflammatory states.