IFNAR Blockade Restores DCX+ Neuroblasts in 1 ng/ml TNF-α-Treated Human Hippocampal Cells
Updated
Updated · Nature.com · Jul 7
IFNAR Blockade Restores DCX+ Neuroblasts in 1 ng/ml TNF-α-Treated Human Hippocampal Cells
3 articles · Updated · Nature.com · Jul 7
Summary
Anifrolumab fully rescued the loss of DCX+ neuroblasts in human hippocampal progenitor cells chronically exposed to 1 ng/ml TNF-α, while MAP2+ neuron levels were unchanged.
Single-cell RNA sequencing of 22,133 cells showed chronic TNF-α pushed progenitors away from neurogenic clusters and into IFN-responsive, reactive glial-like states through an autocrine/paracrine type I interferon loop.
TNF-α triggered IFNB1, STAT1/STAT2 activation and strong CXCL10/CXCL11 secretion; blocking IFNAR or JAK shut down that signaling and the downstream chemokine program.
Conditioned media from TNF-α-treated cultures drove CXCR3-dependent migration of primary human CD4+ and CD8+ T cells from 3 donors, linking impaired neurogenesis to immune-cell recruitment.
The study identifies a TNF-α-IFN-β-IFNAR axis as a potential therapeutic target in ageing, neurodegeneration and other chronic inflammatory states that disrupt adult hippocampal neurogenesis.
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Restoring Adult Neurogenesis in the Inflamed Human Brain: Breakthroughs, Mechanisms, and Therapeutic Prospects for IFN-I Blockade (2026)
Overview
This report highlights a major breakthrough in understanding how inflammation, especially through Type I interferons, disrupts the brain’s ability to generate new neurons—a process called neurogenesis. Chronic inflammation directly impedes the brain’s natural repair mechanisms by sending signals that counteract neuronal regeneration. However, new research using advanced techniques has confirmed that adult human brains can still produce new neurons, even in later life. This discovery opens the door to therapies that could restore neurogenesis by targeting harmful inflammatory signals, offering hope for treating cognitive decline and neurodegenerative diseases linked to inflammation.