Molecular Signature of Neuroinflammation Induced in Cytokine-Stimulated Human Cortical Spheroids

Crucial in the pathogenesis of neurodegenerative diseases is the process of neuroinflammation that is often linked to the pro-inflammatory cytokines Tumor necrosis factor alpha (TNF alpha) and Interleukin-1beta (IL-1 beta). Human cortical spheroids (hCSs) constitute a valuable tool to study the molecular mechanisms underlying neurological diseases in a complex three-dimensional context. We recently designed a protocol to generate hCSs comprising all major brain cell types. Here we stimulate these hCSs for three time periods with TNF alpha and with IL-1 beta. Transcriptomic analysis reveals that the main process induced in the TNF alpha- as well as in the IL-1 beta-stimulated hCSs is neuroinflammation. Central in the neuroinflammatory response are endothelial cells, microglia and astrocytes, and dysregulated genes encoding cytokines, chemokines and their receptors, and downstream NF kappa B- and STAT-pathway components. Furthermore, we observe sets of neuroinflammation-related genes that are specifically modulated in the TNF alpha-stimulated and in the IL-1 beta-stimulated hCSs. Together, our results help to molecularly understand human neuroinflammation and thus a key mechanism of neurodegeneration.

Automated summary

Neuroinflammation is crucial in the pathogenesis of neurodegenerative diseases. Through stimulation experiments on human cortical spheroids, transcriptomic analysis reveals that the main response induced by the pro-inflammatory cytokines TNF alpha and IL-1 beta is neuroinflammation. Endothelial cells, microglia, astrocytes, and dysregulated genes encoding cytokines, chemokines, and pathway components are central in the neuroinflammatory response.