Physiological effect of cytokines on adult neurogenesis: a focus on in vivo knock-out studies

Cytokines, central mediators of immune signaling, have emerged as pivotal regulators of neural stem cell (NSC) biology. Once regarded as immune-privileged, the central nervous system is now recognized as a dynamic site of immune-neural interaction, where meningeal and parenchymal immune cells modulate neurogenesis and brain plasticity through cytokine release. This review synthesizes current quantitative evidence on the effects of key cytokines including IL-6, FGF2, IL-15, IL-22, IL-10, and TNF-α on mouse NSCs studied exclusively in knockout models in vivo. This approach allows for a clearer understanding of their physiological roles, minimizing artefacts associated with in vitro systems, overexpression models, or inflammatory contexts, and focusing instead on their homeostatic functions. Collectively, these studies demonstrate that cytokine signaling profoundly influences NSC fate, proliferation, and differentiation. Importantly, by mapping cytokine expression within the dentate gyrus, the subventricular zone neurogenic niches, and the meninges, we put forward the provocative idea that brain borders are major sources of these factors, rather than the dentate gyrus itself. Understanding how immune-derived cues shape the NSC niche is critical for uncovering mechanisms underlying brain function, plasticity, and repair, with potential implications for neurodevelopmental, neuropsychiatric, and neurodegenerative disorders.