John, S. S. | Search bioRxiv

bioRxiv2025

TNF-α-induced type I IFN signalling decreases neurogenesis and drives T cell chemotaxis

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.

neuroscience↗

bioRxiv2019

Galanin inhibits visceral afferent responses to noxious mechanical and inflammatory stimuli

Galanin is a neuropeptide expressed by sensory neurones innervating the gastrointestinal (GI) tract. Galanin displays inhibitory effects on vagal afferent signalling within the upper GI tract, and the goal of this study was to determine the actions of galanin on colonic spinal afferent function. Specifically, we sought to evaluate the effect of galanin on lumbar splanchnic nerve (LSN) mechanosensitivity to noxious distending pressures and the development of hypersensitivity in the presence of inflammatory stimuli and colitis. Using ex vivo electrophysiological recordings we show that galanin produces a dose-dependent inhibition of colonic LSN responses to mechanical stimuli and prevents the development of hypersensitivity to acutely administered inflammatory mediators. Using galanin receptor (GalR) agonists, we show that GalR1 activation, but not GalR2/3 activation, inhibits mechanosensitivity. The inhibitory effect of galanin on colonic afferent activity was not observed in tissue from mice with dextran sodium sulphate-induced colitis. We conclude that galanin has a marked inhibitory effect on colonic mechanosensitivity at noxious distending pressures and prevents the acute development of mechanical hypersensitivity to inflammatory mediator, an effect not seen in the inflamed colon. These actions highlight a potential role for galanin in the regulation of mechanical nociception from the bowel and the therapeutic potential of targeting galaninergic signalling to treat visceral hypersensitivity.\n\nKey point summaryO_LIGalanin inhibits visceral afferent mechanosensitivity to noxious phasic distension of the colon via GalR1.\nC_LIO_LIGalanin attenuates afferent mechanical hypersensitivity induced by the application of inflammatory mediators.\nC_LIO_LIInhibition of afferent mechanosensitivity by galanin is not observed in tissues isolated from mice undergoing DSS-induced colitis\nC_LIO_LIGalanin inhibits the transmission of noxious mechanical stimuli by colonic afferents and its sensitisation by inflammatory mediators highlighting an antinociceptive role for galanin in the colon.\nC_LI

neuroscience↗