Neurogenesis is the name given to the creation of new neurons in the central nervous system, arising from neural stem cell populations, maturing, and then merging with existing neural networks. Neurogenesis is essential to memory and to the maintenance of brain tissue, the only way to replace neurons lost to damage or dysfunction. The pace of neurogenesis declines with age and in neurodegenerative conditions. Here, researchers investigate the link between inflammatory signaling and lost neurogenesis. The aged brain, like the aged body, is characterized by continual unresolved inflammatory signaling, a maladaptive reaction to forms of cell and tissue damage that changes cell behavior for the worse. It is disruptive to tissue structure and function. Any comprehensive package of rejuvenation therapies will have to include some way to address unwanted chronic inflammatory signaling without sabotaging the normal function of the immune system; so far, this has proven to be a difficult challenge.
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 (TNF-α) 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 (CXCR3)-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.
Link: https://doi.org/10.1038/s41467-026-74104-x
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